Culture

The ability to insert desirable genes into animal or human cells is the basis of modern life science research and of widespread biomedical applications. The methods used to date for this purpose are mostly non-specific, making it difficult for scientists to control which cell will or will not take up a gene. For this gene transfer, the target genes are often packaged into "viral vectors." These are viruses in which part of the genetic material has been replaced by the target genes. When researchers add these viral vectors to cells, the vectors introduce the genes into the cells. This is the principle behind some of the current SARS-CoV-2 vaccines such as those from AstraZeneca or Johnson&Johnson. However, it is difficult - even impossible - to control into which cells the target genes enter, since the viral vectors tend to dock non-specifically onto all cells of a certain cell type. A team of researchers from the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg, led by Dr. Maximilian Hörner, Prof. Dr. Wolfgang Schamel and Prof. Dr. Wilfried Weber, has developed a new technology that enables them to introduce target genes in a controlled manner and thereby control processes in individual selected cells. The researchers have published their work in the current issue of Science Advances.

Alteration to a viral vector

In their new method, the Freiburg researchers introduce the genetic information with an optical remote control. As a result, only cells that are illuminated with red light take up the desired genes. To do this, the scientists modified a type of viral vector known as an AAV vector, which is already in clinical use. "We took away the viral vector's ability to dock with cells," Hörner explains, "which is an essential step before the genetic material can be introduced."

To enable this control by light, the researchers have taken a red light photoreceptor system from the plant Arabidopsis thaliana (thale cress). This system consists of two proteins, PhyB and PIF, which bind to each other as soon as PhyB is illuminated with red light. The Freiburg team placed the protein PIF on the surface of the viral vector and modified the other protein PhyB so that it could bind to human cells. Once this modified vector, called OptoAAV, is in a cell culture along with the cell-binding protein, the protein binds to all cells. "If a selected cell is now illuminated with red light, the modified vector can bind to this cell and introduce the target genes into the illuminated cell," Hörner explains.

A key aspect of biological signal research

This new approach allows the researchers to introduce target genes into the desired cells within a tissue culture. The scientists also succeeded in illuminating the tissue culture successively at different locations, thus enabling the targeted introduction of different genes into different cells within a culture. With this technique, it is now possible to control desired processes in individual cells. This is essential for understanding how a single cell communicates with cells in its environment, for example, to control the development or regeneration of an organ. "As these viral vectors become more widely used in the therapeutic field," Weber says, "we think this new technology has the potential to make such biomedical applications more precise."

Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies

Researchers in the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg are investigating the fundamental communication processes that determine multicellular life in humans, animals and plants. In this way, they aim to gain a higher-level, integrative understanding of biological signaling processes in order to develop tailored molecular tools using methods from synthetic and chemical biology to precisely control signaling processes. In this way, the researchers seek to develop strategies for the treatment of cancer using immunotherapies or for resource-conserving crops production, among other things. Maximilian Hörner and Wolfgang Schamel are group leader in the Cluster of Excellence, Wilfried Weber is a member of the speaker team.

Tsukuba, Japan - Sometimes a dead log isn't just a dead log. This one in Japan turned out to be the habitat of a species previously unknown to science.

In a new study published in the journal Nematology, a University of Tsukuba-led research team has described a new species of nematode found inside bark beetles that emerged from a dead log of a fir tree.

Nematodes, also known as roundworms, are a diverse phylum (category) of unsegmented worm-like animals that live in a wide variety of habitats and have diverse life habits. Many nematodes, including this previously unknown species, are either parasitic or live inside a host organism for the duration of a particular life stage.

The log from the trunk of a fallen Veitch's fir tree (Abies veitchii) was collected from the experimental forest of the Sugadaira Montane Research Center of the University of Tsukuba, Nagano, in June 2018. This log was found to be infected with bark beetles, including the species Cryphalus piceae. These beetles were dissected and their microbial contents cultured to allow the nematodes they contained to propagate. Nematodes were also isolated from the bark of the log. Although several other nematode species were identified, their cultures did not propagate, so only the new species was examined in detail for this study.

Principal investigator of the biodiversity project Professor Yousuke Degawa describes the novel nematode: "Members of the genus Cryptaphelenchus commonly lack a functional rectum and anus, which is a typical characteristic of predator/entemoparasitic species. This suggests that this mycophagous genus has retained this ancestral character. The female of the newly described species can be identified based on its long and slender tail, and the male has a cuticular extension surrounding its tail. We named the species Cryptaphelenchus abietis, for the name of the tree from which it was isolated."

Molecular genetic sequencing clarified the phylogenetic position of this new species in relation to other nematode species. It was clearly a member of the genus Cryptaphelenchus, a group of nematodes that usually feed on fungi when they are not inside their associated insect hosts.

As Senior Researcher Natsumi Kanzaki, the study's first author, explains, "Most similar nematodes have been found to be quite difficult to culture. Because of how easily Cryptaphelenchus abietis can be cultivated in a laboratory setting, this new species may be particularly useful for future studies of the physiological and ecological evolution of nematodes in relation to their genomic characters."

Thousands of years ago, archaic humans such as Neanderthals and Denisovans went extinct. But before that, they interbred with the ancestors of present-day humans, who still to this day carry genetic mutations from the extinct species.

Over 40 percent of the Neanderthal genome is thought to have survived in different present-day humans of non-African descent, but spread out so that any individual genome is only composed of up to two percent Neanderthal material. Some human populations also carry genetic material from Denisovans - a mysterious group of archaic humans that may have lived in Eastern Eurasia and Oceania thousands of years ago.

The introduction of beneficial genetic material into our gene pool, a process known as adaptive introgression, often happened because it was advantageous to humans after they expanded across the globe. To name a few examples, scientists believe some of the mutations affected skin development and metabolism. But many mutations are yet still undiscovered.

Now, researchers from GLOBE Institute at the University of Copenhagen have developed a new method using deep learning techniques to search the human genome for undiscovered mutations.

"We developed a deep learning method called 'genomatnn' that jointly models introgression, which is the transfer of genetic information between species, and natural selection. The model was developed in order to identify regions in the human genome where this introgression could have happened," says Associate Professor Fernando Racimo, GLOBE Institute, corresponding author of the new study.

"Our method is highly accurate and outcompetes previous approaches in power. We applied it to various human genomic datasets and found several candidate beneficial gene variants that were introduced into the human gene pool," he says.

The new method is based on a so-called convolutional neural network (CNN), which is a type of deep learning framework commonly used in image and video recognition.

Using hundreds of thousands of simulations, the researchers at the University of Copenhagen trained the CNN to identify patterns in images of the genome that would be produced by adaptive introgression with archaic humans.

Besides confirming already suggested genetic mutations from adaptive introgression, the researchers also discovered possible mutations that were not known to be introgressed.

"We recovered previously identified candidates for adaptive introgression in modern humans, as well as several candidates which have not previously been described," says postdoc Graham Gower, first author of the new study.

Some of the previously undescribed mutations are involved in core pathways in human metabolism and immunity.

"In European genomes, we found two strong candidates for adaptive introgression from Neanderthals in regions of the genome that affect phenotypes related to blood, including blood cell counts. In Melanesian genomes, we found candidate variants introgressed from Denisovans that potentially affected a wide range of traits, such as blood-related diseases, tumor suppression, skin development, metabolism, and various neurological diseases. It's not clear how such traits are affected in present-day carriers of the archaic variants, e.g. neutrally, positively or negatively, although historically the introgressed genetic material is assumed to have had a positive effect on those individuals carrying them," he explains.

The next stage for the research team is to adapt the method to more complex demographic and selection scenarios to understand the overall fate of Neanderthal genetic material. Graham Gower points out that the team aims to follow up on the function of the candidate variants in the genome that they found in this study.

Looking forward, it remains a challenge to search the human genome for genetic material from as yet unsampled populations, so-called ghost populations. However, the researchers are hopeful that they can further train the neural network to recognize mutations from these unsampled populations.

"Future work could also involve developing a CNN that can detect adaptive introgression from a ghost population, for cases in which genomic data from the source is unavailable," says Graham Gower.

"Boomers" and "millennials" who go to church are more likely to trust their neighbours and donate to charity, according to a new study.

Religious beliefs and participation help close the gaps in civic participation between millennials and their elders, researchers have found.

Experts have measured the social "capital" religion gives people of all ages. They found those in their 20s and 30s were less likely to join groups and associations, and less likely to be religious, but being involved with the church gave them more "religious capital" than older people who also attended services.

The study shows boomers often have more social capital than millennials and are more likely to be religious. Religious millennials may be more likely to encounter and interact with boomers, and this could "boost" the value of their religious capital. Religious boomers, in contrast, are likely to encounter others of the same age with similar social lives, so their church-based interactions have less of a social benefit.

The research, by Stuart Fox from Brunel University, Ekaterina Kolpinskaya, from the University of Exeter, Jennifer Hampton and Esther Muddiman, from the Wales Institute of Social and Economic Research and Data (WISERD) based at Cardiff University and Ceryn Evans from Swansea University, is published in The Sociological Review.

Researchers used data from the UK's Household Longitudinal Study (UKHLS). The sample included information about all those born between 1946 and 1958, and those born after 1982. They measured religious participation through self-reported frequency of attendance at religious services.

Researchers found participating in religion gave boomers and millennials more social trust, despite how often they attended church. Those who participated at least once a year were more likely to trust their neighbours - by around four to five percentage points.

Millennials who said their religious belief made "some" difference to their daily life were around four percentage points more likely to donate to charity than those who said it didn't make difference, while those who said it made ""much" difference are seven percentage points more likely.

Boomers who attended religious services at least once a week were the most likely to donate to charity, and around eight percentage points more likely than those of a similar age who didn't attend church. The same is true for millennials, although the difference between those who participate weekly and who do not participate at all is 12 points.

Dr Fox said: "While lower levels of religious capital are contributing to lower levels of social capital among millennials, religious activity is also a more effective source of social capital for millennials than their elders.

"We found millennials are less likely to join groups or associations than boomers, regardless of their religious participation, so have less social capital."

Researchers found the effect of religion on membership of community associations is limited, apart from older Baptists and Methodists, who were around eight per cent and four per cent respectively more likely to join community associations than their peers who are involved in other religions, or none.

Millennials who said religious beliefs made a big difference to their daily lives were significantly more likely to join community associations - by around 13 points. The research shows millennials who participated in religious services at least once a year - or once a month, or once a week - is around 10 points more likely to join a community association than one who does not. For boomers the same difference is 3 points.

Dr Kolpinskaya said: "We found religious participation increases associational membership for both generations regardless of its intensity: what matters is the difference between boomers or millennials who participate in religious activity at all, and boomers or millennials who do not."

An international survey by the University of Münster's Cluster of Excellence "Religion and Politics" provides the first empirical evidence of an identity-related political cleavage of European societies that has resulted in the emergence of two entrenched camps of substantial size. "We see two distinct groups with opposing positions, which we call 'Defenders' and 'Explorers'", says psychologist Mitja Back, spokesperson of the interdisciplinary research team that conducted the most comprehensive survey of identity conflicts in Europe to date. "Who belongs to our country, who threatens whom, who is disadvantaged? Across all such questions of identity, the initial analyses of the survey reveal a new line of conflict between the two groups, which have almost diametrically opposite opinions. In debates over identity, these opinions have hardened into seemingly irreconcilable conflicts. The study could open up new avenues to tackle these conflicts".

The two camps together account for a significant proportion of citizens in all countries: more than one-third in Germany (Fig. 3.1) and almost three-quarters in Poland (Fig. 3.4). In liberal democratic states like Germany, the proportion of 'Defenders' is 20% and that of 'Explorers', 14%. In France and Sweden, 14% and 29% 'Defenders', and 11% and 15% 'Explorers', respectively, were observed. In a semi-authoritarian country like Poland, where according to the researchers the government provides populist support to the 'Defenders' opinions, the proportion of both groups combined is 72%. "This shows how much the conflict can escalate in a country: the polarized positions can grow to form the majority", says Mitja Back. "The degree to which a population becomes polarized and how far feelings of threat and narrow ideas of identity also entail feelings of disadvantage and mistrust therefore vary depending on the political system. This suggests that identity conflicts are open to political influence".

Who are 'Explorers' and 'Defenders'?

5,011 respondents in Germany, France, Poland and Sweden took part in the survey, which the Cluster of Excellence conducted with "Kantar Deutschland" at the end of 2020. Its authors are the sociologists Detlef Pollack and Olaf Müller, the psychologists Mitja Back and Gerald Echterhoff, and the political scientist Bernd Schlipphak. Their Working Report, "Of Defenders and Explorers: An identity conflict over belonging and threat" (http://go.wwu.de/izpgb), provides initial results. Drawing on the detailed results on more than 20 questions examined, they used cluster analyses to form groups comprising people with very similar attitudes and displaying strong differences one from the other. This yielded the patterns of 'Explorers' and 'Defenders' across all questions.

In all countries, the 'Defender' group largely endorse a narrow definition of who belongs to their country, with only those belonging who were born in the country, have ancestors of the ethno-national majority, and/or belong to the dominant religion. They therefore defend traditional criteria such as ethnic and religious homogeneity. At the same time, 'Defenders' feel rather threatened by foreigners such as Muslims and refugees, and consider themselves rather disadvantaged. They are also more dissatisfied with democracy and more distrustful of political institutions.

The 'Explorer' group, on the other hand, reject a narrow definition of belonging based on ethno-religious criteria. Its members do not feel threatened by foreigners, but instead see immigration and growing diversity as an opportunity, and they also advocate a society with many notions of life oriented towards equality. They see themselves as being well represented by the political system, are more satisfied with democracy, and are more likely to trust political institutions. In semi-authoritarian Poland, however, where the government provides populist support to 'Defenders' positions on ethno-religious homogeneity and protection against foreigners, the 'Explorers' also feel disadvantaged and are dissatisfied with democracy and government.

The two groups also differ strongly in cultural, religious, psychological and social terms (Figs. 3.6 and 3.7), with 'Defenders' in all countries being far more attached to home and religious than 'Explorers'. The former also have a stronger preference for social hierarchies and trust other people less, while the reverse is true of the latter. 'Explorers' also tend to be quite young, highly educated, more likely to live in a city, and less likely to be affected by socio-economic hardship. Except in Poland, 'Defenders' are more likely than 'Explorers' to be found among the elderly and the low educated. They tend to live in rural areas and, again with the exception of Poland, consider themselves to have a lower social status.

Political effects and recommendations

The cultural conflict also has strong political effects: 'Defenders' favour populist parties and believe much more in the concept of a "strong leader"; they are also prone to conspiracy theories and advocate elements of direct democracy. 'Explorers' hold diametrically opposed views. For example, 26% of 'Defenders' in Germany and 57% in Poland are likely to vote for a populist party (Fig. 6.6), while 'Explorers' tend not to.

According to the researchers, this can represent fundamentally different concepts of politics: 'Defenders' favour concepts more in line with anti-pluralist ideas that claim that political regulations should express a single popular will; 'Explorers', in contrast, share attitudes more compatible with pluralist ideas that claim that politics is a process of negotiation and compromise between different interests. Mitja Back: "A person's positioning in the conflict as 'Explorer' or 'Defender' can have a strong impact on the form of democracy desired. Cultural conflicts over identity have therefore become very entrenched politically, and now structure the population's social and political views to a significant extent".

By linking their results to other insights from current research, the authors see the polarized positions as being rooted in fundamental and rather stable psychological needs of varying strength, such as security and stability ('Defenders'), or openness and change ('Explorers'). According to the report, this implies that societies are always composed of a mixture of 'Explorers' and 'Defenders'. In contrast to more material conflicts, the identity conflict is therefore more difficult to negotiate, and especially so when ideas of identity are framed in religious or fundamentalist terms. Identity conflict is also exacerbated by the effects of globalization, such as migration, increasingly supranational instead of national policies, and crises such as the financial crisis and the Covid 19 pandemic. "This makes questions of identity - who belongs to the country, or who triggers feelings of threat - all the more urgent".

The researchers therefore urge politicians to refrain from taking one of the two sides. Neither in liberal democracies nor in authoritarian countries has this led to movement in entrenched conflicts, as at least one group always feels excluded. Rather, it is important to take the underlying psychological needs on both sides seriously, and to understand them as social resources, while tracing the sometimes widely divergent demands of both groups back to their functional core. "In this way, it is possible to filter out which positions are not acceptable to each group, and which are open to negotiation. Only by doing so can we find a basis for compromise that currently seems impossible, as well as space for dialogue without one side devaluing the other". (vvm/sca)

RUDN University doctors found alterations in serum amino acid profile in children with attention deficit hyperactivity disorder (ADHD). The findings will help to understand the mechanism of the disorder and develop new treatment strategies. The study is published in the journal Biomedical Reports.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests itself in childhood. Children with ADHD find it difficult to concentrate and manage their impulsivity. It is known that ADHD is also manifested at the neurochemical level -- for example, the work of dopamine and norepinephrine is disrupted. However, there is still no definitive data on how the responsible for brain function amino acids profile changes in ADHD. Although drugs consisting of amino acids are often used for the treatment of ADHD. Scientists of the RUDN University detected the alterations of the amino acid profile in blood serum in children with ADHD.

"Amino acids serve a significant role in brain development and functioning. In particular, certain amino acids or their precursors are well-established to be involved in neuronal signaling as neurotransmitters. Correspondingly, disruption of amino acid metabolism results in significant neurological disorders, particularly in children. Therefore, unraveling the potential underlying mechanisms implicated in ADHD pathogenesis is essential for improving our understanding of the disorder and further development of management strategies", Anatoly Skalny, DSc, Head of RUDN Department of medical elements studies

102 children aged 7 to 14 years were involved in the study. 71 of them were diagnosed with ADHD, the rest of the participants were neurotypical (without diagnosed disorders). The level of amino acids in the blood serum was measured using liquid chromatography. Then scientists compared the data obtained in children with ADHD and neurotypical children using statistical methods.

It turned out that the serum amino acid profile in children with ADHD differs from neurotypical children. Histidine, glutamine, and proline levels were found to be 29%, 10%, and 20% lower, respectively. Aspartic acid and glutamate were found to be 7% higher, and hydroxyproline-42% higher. Accordingly, the ratio of glutamine to glutamate in children with ADHD is 28% lower than normal, and the ratio of proline to hydroxyproline is 29% lower. The first ratio is one of the indicators of the transmission of nerve impulses, and the second can be a marker of disorders of collagen metabolism and connective tissue. Related diseases are sometimes considered to be associated with ADHD.

&laquoThe observed alterations in Pro/Hypro and Gln/Glu levels and ratios are likely associated with the coexisting connective tissue pathology and alterations in glutamatergic neurotransmission in ADHD, respectively. However, further in vivo and in vitro studies are required in order to investigate the detailed mechanisms linking amino acid metabolism with ADHD", Anatoly Skalny, DSc, Head of RUDN Department of medical elements studies

Testicular cancer is the most common cancer among men under 40 in Europe and the USA. National statistics from the Cancer League indicate 471 new cases and 12 deaths in Switzerland. In general, the prospects for successful treatment of testicular cancer are good over time and, especially with early diagnosis, even further improved. Even if metastases are already present, testicular cancer can be successfully treated with appropriate therapy in the majority of cases.

New classification enables even more targeted treatment

The primary treatment for testicular cancer is the removal of the affected testicle. However, the disease is often only discovered at a stage where metastases are already present and then, after the primary surgical procedure, follow-up drug or radiological treatment is necessary. The new data have been used to make a more detailed classification of metastatic disease stages, making it possible to plan and carry out therapy in an even more targeted manner. Prof. Dr. med. Jörg Beyer, co-initiator of the study project and first author of one of the two publications of the «IGCCCG Update Consortium» estimates: "In many cases, we may be able to administer medication a little more selectively. At the same time, we have an increased certainty that we will not miss any case with an aggressive progression. And with the new classification, the benefits for the patient are twofold: a reduced treatment burden with respect to chemotherapy and increased certainty in terms of outcome."

International research consortium conducts extensive study

Previous treatment guidelines were based on data from 1975 to 1990 involving a total of 5862 patients. The new study compared these results with more recent data from 1990 to 2013 and a larger number of patients. The International Germ-Cell Cancer Collaborative Group Update research consortium (IGCCCG Update Consortium) examined data from 30 medical centers in 17 countries (Australia, Europe, Russia and America). The study included documentation of 12 149 patients with metastatic testicular cancer. Particular attention was paid to potential criteria that could help refine classification.

And another piece of good news: better prognosis for testicular cancer patients

Compared with the original data, the new study results revealed that the prognosis has improved significantly in all cases. In the "good prognosis" classification, 5-year survival increased from 86% to a new 95%. And in the "intermediate prognosis" group, this value increased from 72% to 88%. The improvement was most impressive in the group with widely metastasized disease and the poorest prognosis: 5-year survival increased from 48% to 67%. Prof. Dr. med. Daniel Aebersold, Chairman of the Board of UCI University Cancer Center Inselspital, adds: "The study impressively demonstrates the progress made in cancer therapy. In just well over twenty years, it has been possible to significantly improve the prospects of a long-term tumor-free life after a testicular cancer diagnosis."

Prospects

The next step will be to incorporate the consortium's findings into treatment guidelines and reduce the burden of cancer therapy. In addition, new approaches to the treatment of metastatic testicular cancer need to be considered, such as those currently being investigated in a SAKK study which aim to combine radio- and chemotherapy. It can be assumed that optimized therapies for testicular cancer will lead to a further improved prognosis with reduced treatment intensity in the coming years.

In the mid-14th century Europe was devastated by a major pandemic - the Black Death - which killed between 40 and 60 per cent of the population. Later waves of plague then continued to strike regularly over several centuries.

Plague kills so rapidly it leaves no visible traces on the skeleton, so archaeologists have previously been unable to identify individuals who died of plague unless they were buried in mass graves.

Whilst it has long been suspected that most plague victims received individual burial, this has been impossible to confirm until now.

By studying DNA from the teeth of individuals who died at this time, researchers from the After the Plague project, based at the Department of Archaeology, University of Cambridge, have identified the presence of Yersinia Pestis, the pathogen that causes plague.

These include people who received normal individual burials at a parish cemetery and friary in Cambridge and in the nearby village of Clopton.

Lead author Craig Cessford of the University of Cambridge said, "These individual burials show that even during plague outbreaks individual people were being buried with considerable care and attention. This is shown particularly at the friary where at least three such individuals were buried within the chapter house. Cambridge Archaeological Unit conducted excavations on this site on behalf of the University in 2017."

"The individual at the parish of All Saints by the Castle in Cambridge was also carefully buried; this contrasts with the apocalyptic language used to describe the abandonment of this church in 1365 when it was reported that the church was partly ruinous and 'the bones of dead bodies are exposed to beasts'."

The study also shows that some plague victims in Cambridge did, indeed, receive mass burials.

Yersinia Pestis was identified in several parishioners from St Bene't's, who were buried together in a large trench in the churchyard excavated by the Cambridge Archaeological Unit on behalf of Corpus Christi College.

This part of the churchyard was soon afterwards transferred to Corpus Christi College, which was founded by the St Bene't's parish guild to commemorate the dead including the victims of the Black Death. For centuries, the members of the College would walk over the mass burial every day on the way to the parish church.

Cessford concluded, "Our work demonstrates that it is now possible to identify individuals who died from plague and received individual burials. This greatly improves our understanding of the plague and shows that even in incredibly traumatic times during past pandemics people tried very hard to bury the deceased with as much care as possible."

Lugano, Switzerland, 17 June 2021 - Adding an immune checkpoint inhibitor to anti-HER2 treatment in breast cancer does not improve pathological complete response (pCR), according to the primary analysis of the IMpassion050 trial presented today during the ESMO Virtual Plenary. (1) The phase III trial is the first to report data comparing a neoadjuvant anti-HER2 based regimen with or without the anti-PD-L1 antibody atezolizumab in patients with high-risk, HER2-positive early breast cancer.

The standard treatment for high-risk, HER2-positive early breast cancer is dual anti-HER2 blockade plus chemotherapy. While antibody therapy may enhance innate and adaptive immunity and activate cellular cytotoxicity, there is evidence that combination with a checkpoint inhibitor may further enhance the immune response. (2) IMpassion050 evaluated the efficacy and safety of neoadjuvant atezolizumab versus placebo in patients receiving dose-dense anthracycline and taxane-based chemotherapy as a sequential treatment in combination with the antibodies pertuzumab and trastuzumab.

The trial enrolled 454 patients with high-risk HER2-positive early breast cancer, meaning they had a primary breast tumour size of >2 cm, and pathologic confirmation of nodal involvement. Patients were randomly allocated in a 1:1 ratio to the two treatment arms and received six months of neoadjuvant therapy. Following surgery, patients resumed their allocated treatment with atezolizumab versus placebo. Patients with pCR continued pertuzumab and trastuzumab while those with residual disease could switch to trastuzumab emtansine (T-DM1). (3)

The co-primary endpoints were pCR in the intention to treat (ITT) and PD-L1 positive populations. Event-free survival (EFS), overall survival and safety were secondary endpoints. The trial was stopped prematurely when the Independent Data Monitoring Committee judged that there was an unfavourable benefit-risk profile with the intervention. The data were analysed early, with three patients still to undergo surgery.

In the ITT population, pCR was achieved by 62.4% of the atezolizumab arm and 62.7% of the placebo arm (p= 1.0). In the PD-L1 positive population, pCR was achieved by 64.2% of the atezolizumab arm and 72.5% of the placebo arm (p= 0.2). Regarding safety, there were higher rates of grade 3/4 adverse events (AEs; 51.8% versus 43.6%) and serious AEs (19.5% versus 13.3%) in the neoadjuvant phase with atezolizumab versus placebo, respectively. During neoadjuvant treatment, four patients in the atezolizumab group died compared to no patient in the placebo group. Of the four deaths, two fatal events were assigned to study treatment- - one due to alveolitis and one due to septic shock, although it is not clear whether these were immune-related.

Lead author Prof Jens Huober, professor?of gynaecologic oncology at the Breast Centre St. Gallen, Switzerland, said: "Overall, the safety profile was consistent with other combination studies with atezolizumab, with no new side-effects. It is important to note that this was a selected population of high-risk HER2-positive patients to justify the potential toxicity of the additional drug and because patients with HER2-positive, node negative, smaller tumours do well with standard treatment."

Huober added: "The additional immunotherapy in this setting did not enhance the pCR rate in the overall population or in any subgroup. However, what counts for patients are EFS and overall survival (OS), which were secondary endpoints and we need longer follow-up for those results. In addition, there is some evidence in triple negative breast cancer that pCR may not be the best endpoint for measuring the efficacy of immunotherapy."

Commenting on the study, Dr Carmen Criscitiello, scientist and senior physician at the European Institute of Oncology in Milan, Italy said: "At trial level pCR is not a robust and validated endpoint for efficacy so the findings should be interpreted with caution until there are long-term results on EFS. In triple negative breast cancer, immune checkpoint inhibition added to standard neoadjuvant therapy modestly increased pCR rate in the GeparNUEVO (4) and KEYNOTE-522 studies (5) - yet EFS was significantly improved in both studies."

Criscitiello added: "In the metastatic setting, the benefit of adding an immune checkpoint inhibitor to chemotherapy is largely confined to the PD-L1 positive population. In the neoadjuvant setting, benefit in patients with triple negative breast cancer has been observed in the overall population and in both PD-L1 positive and negative subgroups. In the IMpassion050 PD-L1 positive group, the pCR rate was numerically inferior in the experimental arm compared to the control arm, suggesting a numerical opposite trend in PD-L1 negative tumours. This indicates the need to better investigate biological differences on the impact of PD-L1 by disease setting."

Criscitiello said the findings on safety should be examined carefully given the curative setting. She said: "Toxicity is more or less in line with what has been reported with similar combinations in other settings. There is a need to investigate if there is any link between atezolizumab and the treatment-related deaths, although - except alveolitis - they were not typical immune-related side-effects. In the curative setting we should be even more conservative and cautious when we look at the toxicity that may be induced by a new treatment. So far, this combination has not demonstrated an improvement in pCR rate, so the balance between risk and benefit should be carefully monitored before considering this therapeutic strategy."

A study performed by researchers at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) from the Spanish National Research Council (CSIC) in collaboration with Stony Brook University (USA) proposes a new strategy for the development of new drugs based on the inhibition of tyrosine kinase enzymes, molecules that activate and trigger many cellular processes. The results have been published in the Chemistry - A European Journal.

The new approach is based on the regulation of the signaling cascade of tyrosine kinases, and could lead to the development of improved and more selective tools for research, diagnosis or treatment of some diseases.

Tyrosine kinases are a set of enzymes that are essential for communication between the cells of our body, which trigger biochemical reactions that are important for life. "The dysfunction of these enzymes is related to serious diseases such as diabetes, some neurological disorders and many types of cancer," explains Ignacio Alfonso, a researcher at the IQAC-CSIC.

They activate different signaling pathways

Cell signaling is the process by which cells communicate. In the cell there are many types of receptors or specific proteins that recognize the proteins synthesized by the body and make the cell respond to them. One of the most important are tyrosine kinases.

"Cells receive signals from the environment when a molecule (a hormone, for example) binds to one of these receptors. The receptor recognizes the molecule and triggers a series of chemical reactions", explains Alfonso. This allows cells to work to control vital functions of the body, such as cell multiplication or destruction. Each process has its own signaling path. After the first molecule in the signaling pathway receives the signal, another molecule is activated, then another and another, and so on throughout the signaling cascade until cellular function is fulfilled. "The abnormal activation of signaling pathways can lead to diseases, such as cancer", says the researcher.

Kinases are a family of molecules that activate many different signaling pathways, which implies that they themselves participate in all of these processes. "When you want to avoid any of these processes, a research strategy is to inhibit kinases, blocking them with synthetic molecules. But this strategy is not very selective, since other important pathways may be inhibiting," warns Alfonso. In fact, the similarity between kinases and their functional versatility (the same kinase acts on different molecules and is involved in different processes) has made it difficult to design specific inhibitors to modulate pathological situations or dissect different functions in basic research.

Target: the place where kinases act

It is here where this work proposes an alternative strategy: not to inhibit the kinases, but to cover and block the molecules on which the kinases act. The tool for this would be artificial synthetic receptors, that is, synthetic molecules that would protect the place where the kinases exert their action. "Our group has designed molecules that interact with the substrates of the kinase, and not with the kinase" explains Alfonso. "We have prepared artificial molecular 'cages', made up of pseudopeptides, that are able to modulate the activity of these enzymes" clarifies the researcher.

"This complementary approach paves the way for selective modulation of an individual kinase-stimulated signaling pathway, without interfering with other functions of the kinase," explains Todd Miller from Stony Brook University. "This technology would enable investigators to dissect the contributions of specific signaling pathways in cellular function".

Despite being a proof-of-concept study, the results of this study could lead to more selective modulators/inhibitors of these kinases that would be used as research tools for the full understanding of this complex communication network. "This approach generates basic knowledge, which could be essential to better understand key biological functions and the origin of many diseases", concludes Dr. Alfonso.

The German National Academy of Sciences Leopoldina and the German Council for Sustainable Development (RNE) have published a joint position paper presenting paths to climate neutrality by 2050. In it, the Leopoldina and the RNE highlight options for action to effect the changes needed within society, at political level and in the business world, in view especially of the urgency and the historic dimensions of the transformation we face. With the paper, the Leopoldina and the RNE are consciously not seeking to engage in a race to set the most ambitious target. They are instead offering an options paper for setting the right course and covering the key implementation steps. The position paper was presented at the RNE's 20th annual conference and was handed over to the Federal Chancellor, Dr Angela Merkel.

"The opportunities presented by the European Green Deal, the new US administration and additional climate commitments made by, for example, China and the G7 must now be exploited to expand and reinforce international climate protection alliances," says Prof. (ETHZ) Dr Gerald Haug, President of the German National Academy of Sciences Leopoldina. "In addition to a global carbon price, what's needed are foresighted, cross-sector investments in infrastructure expansion and in new climate-friendly technologies," Haug continues.

Dr Werner Schnappauf, Chairman of the RNE, points to the importance of the project often being underestimated: "Action on an entirely different scale is needed to bring about a real transformation. A fundamental change in direction is necessary in order to achieve climate neutrality. The decarbonisation of industry alone will require up to four times the current volume of energy from renewable sources." This illustrates how quickly renewable energies and the related networks need to be expanded in the years to come, he says. "As much green electricity as possible being made available as quickly and as affordably as possible will be crucial here," Schnappauf emphasises. The citizens need to be involved and their engagement promoted to achieve the changes this entails, he says. "This challenge of the century calls for swift action that does justice to our responsibility towards the young and future generations," says Schnappauf.

The authors focus on carbon emissions trading as the lead instrument with which to realise the transformation, embedded in an overall climate policy strategy that includes regulatory framework, funding and governance policy. A broad mobilisation of private capital will also be needed, they argue, which in turns requires long-term security of investment.

Another key assertion of the position paper is that climate protection can only unfold the necessary impact if pursued at the European level as part of the European Green Deal and ultimately also globally. In addition to options in the area of market policy action, the authors address the issues of financing, foreign policy, international solidarity, social equity and education.

The joint position paper can be found here: http://www.leopoldina.org/en/climate-neutrality

Abu Dhabi, UAE: Trans-Neptunian Objects (TNOs), small objects that orbit the sun beyond Neptune, are fossils from the early days of the solar system which can tell us a lot about its formation and evolution.

A new study led by Mohamad Ali-Dib, a research scientist at the NYU Abu Dhabi Center for Astro, Particle, and Planetary Physics, reports the significant discovery that two groups of TNOs with different surface colors also have very different orbital patterns. This new information can be compared to models of the solar system to provide fresh insights into its early chemistry. Additionally, this discovery paves the way for further understanding of the formation of the Kuiper Belt itself, an area beyond Neptune comprised of icy objects, that is also the source of some comets.

In the paper, The rarity of very red TNOs in the scattered disk, published in The Astronomical Journal, the researchers explain how they studied the chemical composition of TNOs in order to understand the dynamical history of the Kuiper Belt. TNOs are either deemed "Less Red" (often referred to as Gray), or "Very Red" (often referred to as Red) based on their surface colors. By re-analyzing a 2019 data set, the researchers discovered that gray and red TNOs have vastly different orbital patterns. Through additional calculations, the researchers determined that the two groups of TNOs formed in different locations, and this led to the dichotomy in both their orbits and colors.

Many models of the solar system have been designed to show how the Kuiper Belt has evolved, but these models only study the origins of its orbital structure or colors, not both simultaneously.

"With more data, our team's work could be applied to more detailed solar system models and has the potential to reveal new insights about the solar system and how it has changed over the course of time," said Ali-Dib.

(Boston)--An intrauterine fracture is a rare finding during routine prenatal imaging. This condition can be due to maternal trauma, genetic disorders of the skeleton, as well as other predisposing maternal metabolic and vascular disorders. Genetic disorders that have previously been reported to cause intrauterine fracture include brittle bone disease (osteogenesis imperfecta or OI), osteopetrosis, hypophosphatasia and Ehlers-Danlos syndrome (EDS).

Now for the first time, researchers from Boston University School of Medicine (BUSM) report a new genetic cause, unrelated to OI, for the 23 fractures that occurred in-utero to a mother with EDS hypermobility type.

EDS is a disease that weakens the bones and connective tissues of your body. It can make joints loose and skin thin and easily bruised. It also can weaken blood vessels and organs. There are 13 types of EDS. The most common, and generally considered the least severe, is hypermobile EDS (hEDS). While there are genetic tests for some subtypes of EDS, no genetic test has been developed for diagnosing hEDS.

Following the birth, the mom, infant and dad were enrolled in BUSM's Ehlers-Danlos Clinical Research Program. After evaluation of the family, including documenting medical history and physical findings, DNA samples were taken from each of them. The DNA was evaluated and confirmed that the infant had no pathologic genetic mutations associated with OI. However, several new gene mutations including one gene, CCDC134, that has been identified as causing bone fragility, was identified in the infant.

According to the researchers, this case report clearly demonstrates that there is at least one other genetic cause for infantile fractures other than OI and child abuse (non-accidental trauma) that is associated with EDS. "Therefore we are recommending that the additional gene we identified as being the likely cause for this infant's fractures, be included in the genetic panel for bone fragility and that careful consideration be given for other causes of infantile fractures other than OI and non-accidental trauma," said corresponding author, Michael F. Holick, PhD, MD, professor of medicine, physiology and biophysics and molecular medicine at BUSM.

While acknowledging that child abuse is a serious problem that needs to be dealt with appropriately, Holick believes misdiagnosing child abuse can also have devastating long-term consequences for both the child and the parents. "If this infant were brought into the hospital with an upper respiratory tract infection at eight weeks of age, an x-ray of his chest would have revealed healing fractures of his arms and multiple healing fractures of his ribs. A skeletal survey would have revealed the healing fractures in both his legs. He would have been tested and found not to have OI, and therefore the diagnosis for the fractures would have been that they were caused by non-accidental trauma. The child would have been immediately removed from the care of his parents and the parents would have been accused of felony child abuse. It is hoped that this case report will now give reconsideration for diagnosing child abuse solely based on x-ray findings of a fracture or fractures with a negative genetic test for OI," he said.

Holick stresses that by better understanding how this pathologic genetic mutation affects the skeleton to cause fractures provides the scientific community with the ability to develop new strategies for treatment. "We will be able to develop new approaches not only for treating bone fragility in infants with this genetic disorder, but also for treating bone brittleness associated with osteoporosis, which is associated with enormous cost both in terms of quality of life and medical expenses," Holick said.

New study challenges long-standing assumptions about disease severity in infants, and suggests that standard qPCR interpretations underestimate the true burden of other highly contagious diseases, such as COVID-19 and influenza.

Pertussis, also known as "whooping cough," remains a significant cause of death in infants and young children around the world and, despite global vaccination programs, many countries are experiencing a resurgence of this highly contagious disease.

A new study by Boston University School of Public Health and the University of Georgia's Odum School of Ecology presents evidence that could help explain this resurgence: asymptomatic individuals. Lots of them.

Published in the journal eLife, the study suggests that most adults and many children who contract pertussis display no symptoms at all--a reversal of what many experts have long believed about an infection that can cause months of violent coughing fits and "whooping" sounds.

The paper builds upon a 2015 study in which the researchers discovered a series of weakly positive pertussis infections after collecting nasal swab samples from 2,000 mother/infant pairs in Zambia every 2-3 weeks for several months, using quantitative PCR (qPCR) diagnosis. In a standard qPCR analysis, these low-intensity signals would be discounted as false-positive results. But the repeated clusters of mother/infant cases, which illustrated a natural arc of infection as the infection ran its course, suggested that these weak PCR signals provided important information about disease.

"The fact that we found concordance within the mother/infant pairs told us that, in all likelihood, even the weakly affected mothers are contagious at close range, and are probably infecting their babies," says Dr. Christopher Gill, co-lead author of the study and associate professor of global health at BUSPH. Asymptomatic spread is not a unique phenomenon with infectious diseases, he says, but as the world has seen with COVID-19, the ability to detect asymptomatic infections early and accurately through qPCR can provide vital information about the epidemiology and burden of diseases.

"This was a quest to understand weakly positive qPCR and then determine what proportion of pertussis transmissions are coming from asymptomatic people," Gill says.

To confirm that these weak signals were accurate and relevant, the researchers conducted a closer analysis for the eLife study, and discovered additional evidence supporting the likelihood of asymptomatic transmission. The cluster of weak signals aligned with stronger signals, indicating that they occurred during an outbreak; the clusters reflected the natural rise and fall of an epidemic; signals were strongly clustered within mother/infant pairs; and the stronger the qPCR signal, the more likely individuals were to experience symptoms.

Confident in their findings, the researchers then compared the symptomatic cases to the asymptomatic cases and discovered that about 70% of infected mothers displayed no symptoms, and about 25% of infected babies displayed no symptoms. And infants with only mild symptoms (cough or runny nose) comprised over 50% of infections.

"We expected this in mothers, since pertussis becomes less severe with age and repeat exposure," says co-lead author Dr. Christian Gunning, post-doctoral researcher at UGA's School of Ecology. "But mild and asymptomatic infection in infants was assumed to be quite rare. And what we see here is the opposite--severe pertussis in infants is the exception rather than the rule."

The findings underscore the need for a shift in the way qPCR tests are interpreted, Gill says.

"Using a 'line in the sand' approach to interpret results is too simplistic and leads us to discard true and useful information," he says. "If one were trying to map a flu season, it would make more sense to use the weakly positive PCR results as an early warning of impending flu outbreaks, rather than waiting for symptomatic patients with very strong PCR results to start showing up in the ER."

Gunning agrees, saying disease surveillance plays an important role in preventing and responding to disease outbreaks. "Our results differ from traditional approaches that medical doctors use to diagnose and treat patients," he says. "When we tested many people many times, we could 'peer under the hood' and see a lot of hidden infections in this population."

Gunning says that a similar approach could help monitor for outbreaks of COVID. "To control disease outbreaks, we need to know when and where the disease has spread. New strategies like wastewater monitoring could leverage weak qPCR signals to give us a better, fasteridea of who's at risk, and allow us to more quickly intervene. And if you only look at sick people, you're going to miss a lot."

UTICA, NY -- More than 2 million coronary artery stents are implanted each year to help protect or restore normal blood flow to the heart, to treat patients suffering from angina or a heart attack due to coronary artery disease (CAD). While stents are highly effective and safe devices, scarring or clotting of unhealed stents can occur in a small percentage of subjects, leading to complications such as stent restenosis or thrombosis, which can be life-threatening. At present, approaches to understand stent healing based on their biological clotting status is unavailable in patients.

To devise a potential solution to this problem, Dr. Jason McCarthy, an Associate Professor at the Masonic Medical Research Institute (MMRI), and his team have developed a fluorescent probe that binds to activated platelets, one of the main cell types involved in the clotting and scarring process of improperly healed stents. "By using a new platelet-targeted molecular imaging agent coupled with fluorescence imaging, in particular intravascular catheter-based imaging, we are enabling a new approach to localize and visualize platelets during or after coronary stent implantation. This tool has the potential to enable clinicians to proactively treat patients before the development of occlusive stent clotting or scarring, as opposed to reactively, when the patient is symptomatic," said Dr. Jason McCarthy, co-senior author on the manuscript.

In a collaboration with Dr. Farouc A. Jaffer, an Interventional Cardiologist at Massachusetts General Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School, the team modified a drug called tirofiban, an FDA-approved compound known to bind to activated platelets, to enable a fluorescence-based strategy for the detection of platelet-rich clots in experimental subjects.

Stent implantation is a routine invasive procedure in which a stent is delivered over a coronary wire to the target lesion location. Given that clinicians already have intracoronary wire access during this procedure, performing imaging of platelet deposition using fluorescence-based catheters can be readily accomplished (fluorescence catheters have already been tested in patients). "Once the interventional cardiologist is ready to image platelet deposition on stents, a small amount of our new platelet-targeted imaging agent will be intravenously administered. After a few minutes, a fluorescence imaging catheter will be delivered down the coronary over the same wire, followed by an imaging pullback to visualize whether there are any platelets adhered to the stent, which may indicate that it is prone to further development of clots. This will give the clinician the option at the point-of-care to change pharmacological or interventional management of the patient to optimize their outcomes," said Dr. McCarthy.

The manuscript details the process by which the team created and tested the novel imaging agent. "This new agent provides tools that open up numerous possibilities for translational cardiovascular imaging, especially at the point-of-care," said Dr. Khanh Ha, co-author on the paper, and postdoctoral fellow at the MMRI, "With the imaging catheters already approved for clinical use, the goal was to create an imaging agent that would hopefully also prove clinically translatable."