#Zuckerman STEM Leadership Program

[9jacompass]

MPOWER Women in STEM Scholarship For International Students - Apply Now

MPOWER Women in STEM Scholarship For International Students – Apply Now

Are you a woman in science, technology, engineering and mathematics? Do you want to advance your educational career as a woman? Then apply for the MPOWER Women in STEM Scholarship 2023 aimed at addressing inequality in education. In recognition of the extraordinary potential of women in the sciences, Women in STEM Scholarship was created by MPOWER Financing to equip women. The scholarship focues…

[eretzyisrael]

Calm or irate, alert or distracted, wide awake or asleep in bed: Each state causes us to learn and remember differently. The information from external sensory perceptions and our internal states are conveyed through separate neural pathways; yet together they determine how our brain processes and stores information. New research at the Weizmann Institute of Science has uncovered a cellular mechanism that integrates these two streams in the uppermost layer of the outermost part of the brain – layer 1 of the cortex.  This mechanism appears to play a pivotal role in controlling the plasticity the brain needs in order to learn.

Dr. Ivo Spiegel’s laboratory of the Weizmann Institute of Science’s Neurobiology Department studies “adult education” – that is, how various types of neurons in the cortex regulate the plasticity of cortical circuits in the adult brain. Although researchers had previously assumed the external/internal integration that affects learning and plasticity takes place in the cortex, they have had few clues as to how this happens. One way to approach the issue, says Spiegel, is to identify the various players and then figure out how they all work together. “It is a bit like trying to reverse-engineer a very complex watch,” he says.

In a new study recently published in Neuron, Spiegel, his research group and colleagues focused on particular nerve cells in layer 1 of the cortex. Researchers divide neurons in the cortex into two broad types – excitatory and inhibitory.  While most nerve cells in the cortex are excitatory, the research team wanted to investigate the idea that the inhibitory neurons there are essential to the integration process. But in order to investigate how these neurons function in animal models, they first needed to find genes expressed in these cells alone, so that they then could be manipulated selectively with genetic engineering techniques in the lab.

Spiegel, together with his research students Daniella Apelblat and Dahlia Kushinsky, and with the research group of Dr. Johannes Letzkus at the Max Planck Institute for Brain Research in Frankfurt, Germany, identified such a gene, called Ndnf. Their findings showed that Ndnf expression in the layer-1 inhibitory neurons is unique among the inhibitory neuron subtypes. Next, Spiegel and his colleagues created mice in which they manipulated the Ndnf gene so that the Ndnf-expressing neurons could be controlled and their activities tracked. Using these mice, the team then tested whether NDNF neurons in layer 1 of the auditory cortex play a role in a standard learning experiment in which the mice associate a tone with a mild foot shock.

Of course, all neurons work through their connections to other neurons, and the NDNF neurons are no different. The researchers traced their closest connections, finding that they link to excitatory neurons lower down in the cortex through branched extensions called dendrites that reach into layer 1. By analyzing the connections, the team found that another type of inhibitory cell, the Martinotti cells, were acting on the NDNF neurons. Further investigation showed that the two were mutually exclusive – when one was “on” the other was “off,” and vice versa. This pathway had not been seen before.  Spiegel: “We found this connection particularly interesting, since Martinotti cells are thought to modulate the dendrites of excitatory neurons during learning.”

Proper inhibition might be key to our ability to learn and experience new things

Next, the team asked to what extent each of these inhibitory cell types – Martinotti cells and NDNF neurons – is involved in learning: That is, do these cells change their responsiveness to the tone during the learning experiment? Surprisingly, the responses of Martinotti cells did not change, but the responses of NDNF neurons became much stronger. In fact, they found that the better the mouse learned to fear the tone, the more responsive the NDNF neurons were upon hearing it. This suggests that NDNF neurons may play a role in encoding the strength of the learned experience.

Ultimately, the team’s findings suggest that NDNF neurons and Martinotti cells split the job between them: The NDNF neurons preferentially mediate the response to internal stimuli, Martinotti cells respond more to the external. Since these two cell types also seem to be connected via a third type of inhibitory neuron, there appear to be complex feedback mechanisms acting on these cortical inhibitory neurons as learning takes place. Spiegel says that inhibitory neurons are thought to be more flexible than the excitatory ones and thus might contribute much more to plasticity. In other words, proper inhibition might be key to our ability to learn and experience new things.

“We are just at the start of unraveling the workings of these circuits, but there has already been quite a bit of interest in the mice that we generated, as they provide a new tool for studying learning, memory and plasticity in the cortex. We are now designing several new experiments that will take this research in new directions,” he says.

Among these is research into the way that plasticity in this part of the brain is reduced as we age. “Signals about our internal state are conveyed by acetylcholine – a neurotransmitter that often declines in the elderly. We think that this substance might play a role in maintaining the plasticity of the cortical neurons, and we intend to explore the possible connection between these signals and Alzheimer’s,” says Spiegel.

Dr. Ivo Spiegel's research is supproted by the Zuckerman STEM Leadership Program; the Dan Andreae Laboratory; the Irwin Green Alzheimer's Research Fund; and the Leff Family. Dr. Spiegel is the incumbent of the Friends of Linda and Richard Price Career Development Chair.

[evoldir]

Postdoc: TelAvivU.FloralDiversity

I am recruiting post-doctoral fellow through the Zuckerman STEM Leadership Program for outstanding USA or Canada citizens ( http://bit.ly/2NMFnoa). The scholarship is for two years with option for one year extension. Zuckerman Postdoctoral Scholars receive a scholarship of $50,000 per academic year, with $36,000 each year for living expenses and $14,000 each year for research ($10,000) and travel ($4,000) expenses. The research subject is drivers and consequences of floral diversity, from the genetic basis of floral traits to pollination networks. Specific study system and research question are open to discussion, and should fit to the candidate's skills and interests. The lab of plant evolutionary ecology is part of School of Plant Sciences and Food Security in Tel Aviv University, and is located in the Botanical Garden. Major research projects in the lab include: molecular basis and evolution of floral colour variation in irises, ecological speciation in irises, adaptation and evolution of plants along climate gradients, conservation biology, and plant mating systems. Tel Aviv is coastal city with an excellent beaches, and is highly liberal, vibrant and international. Israel is small enough to travel from Tel Aviv to either mountains or desert (or desert mountains) in only a couple of hours drive. Israel flora is among the most diverse ones outside the tropics, with about 3,000 species in an area of 1/6 of the state of Indiana. Candidates must be citizens of United States or Canada, or have a documented status that allows them to study and work in the US. Candidates must hold a Ph.D. degree from a premier university, or if still studying for a Ph.D., must submit their Ph.D. thesis before October 1, 2018. Interested candidates should send a CV and a cover letter including brief ideas for research and names of at least two referees to sapiry@post.tau.ac.il . Applications are considered when received, but should be submitted before 1 October 2018. via Gmail

[scienceblogtumbler]

Why Young and Female Patients Don’t Respond as Well to Cancer Immunotherapy

Cancer immunotherapy — empowering a patient’s own immune system to clear away tumors on its own — holds great promise for some patients. But for other patients, immunotherapy just doesn’t work.

Researchers at University of California San Diego School of Medicine have found evidence that helps explain why patients who are young and/or female have especially low response rates to some types of cancer immunotherapy.

Their findings suggest that since the typically robust immune systems of young and female patients are better at getting rid of tumor cells, the cells left behind are not as readily visible to the immune system to begin with, rendering some types of immunotherapy ineffective.

The study is published August 17, 2020, in Nature Communications.

“Now that we know why some patients don’t respond as well to immunotherapy, we can begin developing more informed approaches to treatment decisions — for instance, developing predictive algorithms to determine a person’s likely response before initiating immunotherapies that may have a high probability of not working or working poorly for them,” said senior author Hannah Carter, PhD, associate professor of medicine at UC San Diego School of Medicine.

Cancerous or infected cells wave molecular flags that tell the immune system to clear them away before the problem gets out of control. The flag poles — molecules of the Major Histocompatibility Complexes (MHC) — are displayed at the surface of most cells in the body. MHCs hold up antigen flags — bits of just about everything from inside the cells — and display them to immune cell surveyors that are constantly checking for damaged or infected cells. Since tumor cells carry a lot of mutations, they show up frequently among these flags, allowing the immune system to detect and eliminate them.

But some tumor cells evade the immune system by also throwing up a stop sign molecule that keeps the immune system from recognizing the MHC flags. And here’s where immune checkpoint inhibitors come in: This type of cancer immunotherapy uses antibodies to make the tumor cell once again visible to the patient’s immune system.

So why would a person’s age or sex influence how well immune checkpoint inhibitors work?

Sex and age differences have long been observed when it comes to immune response. For example, females have twice the antibody response to flu vaccines and are far more susceptible to autoimmune diseases. Similarly, human immune systems tend to weaken as we age. But if females and younger people have stronger immune responses in most cases, you might expect cancer immunotherapy to work better for them, not worse.

To get to the bottom of this conundrum, Carter’s team looked at genomic information for nearly 10,000 patients with cancer available from the National Institutes of Health’s The Cancer Genome Atlas, and another 342 patients with other tumor types available from the International Cancer Genome Consortium database and published studies. They found no age or sex-related differences in MHC function.

What they did find was that, compared to older and male patients with cancer, younger and female patients tend to accumulate more cancer-causing genetic mutations of the sort that MHCs can’t present to the immune system as efficiently. Carter said this is likely because robust immune systems of the young and female are better at getting rid of cells displaying well-presented mutant self-antigens, leaving behind tumor cells that rely more heavily on the poorly presented mutations. This selective pressure is known as immuno-editing.

“So if a tumor cell doesn’t present highly visible, mutated self antigens to begin with, checkpoint inhibitor drugs can’t help reveal them to the immune system,” she said.

“This shows an important thing, that the interplay between the cancer genome and the adaptive arm of the immune system is not a static one,” said co-author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center. “Two simple but important variables, age and sex, influence this interplay. The study also emphasizes the master role of the MHC in dictating the outcome of this interplay, reaffirming its central role in the evolution of disease, cancer included, at the level of the individual and population.”

Carter cautions that their findings for “younger” patients don’t necessarily apply to children since, genetically speaking, pediatric tumors are very different from adult tumors. In addition, she noted that, like most genomics databases, those used in this study contain data primarily from people of Caucasian descent, and more diversity is needed to confirm that the findings can be generalized to all populations.

“Cancer isn’t just one disease, and so the way we treat it can’t be one-size-fits-all,” she said. “All checkpoint inhibitors can do is remove the generic block that tumors put up to hide from the immune system. The more we learn about how interactions between tumors and immune systems might vary, the better positioned we are to tailor treatments to each person’s situation.”

Co-authors of the study also include: Andrea Castro, Rachel Marty Pyke, Xinlian Zhang, Wesley Kurt Thompson, Ludmil B. Alexandrov, Maurizio Zanetti, UC San Diego; and Chi-Ping Day, National Institutes of Health.

The study was funded, in part, by the National Institutes of Health (grants T15LM011271, DP5-OD017937, RO1CA220009, P41GM103504, 5R01CA155010-02, 5R01HL103532-03, 2P50CA101942-11A1, R50RCA211482A, R35CA197633, P01CA168585, 5P50CA168536, GM08042, 1RO1CA155010-02, 5R01HL103532-03, R21CA216772-01A1, T32HL007627, P50CA165962, P01CA163205, K08CA188615), National Science Foundation (graduate fellowship 2015205295), Mark Foundation for Cancer Research (grant 18-022-ELA), CIFAR Fellowship, Blavatnik Family Foundation, Broad Institute SPARC Program, BroadIgnite, BroadNext10, Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund, Faircloth Family Research Fund, DFCI Center for Cancer Immunotherapy, Leukemia and Lymphoma Society, American Association for Cancer Research, Geoffrey Beene Cancer Research Center, Society for Memorial Sloan Kettering Cancer Center, Lung Cancer Research Foundation, Frederick Adler Chair Fund, One Ball Matt Memorial Golf Tournament, Queen Wilhelmina Cancer Research Award, STARR Foundation, Ludwig Trust, Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant, Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant SU2C-AACR-DT17-15), Ben and Catherine Ivy Foundation, Zuckerman STEM Leadership Program, Benoziyo Endowment Fund for the Advancement of Science, DFCI Center for Cancer Immunotherapy Research fellowship, Howard Hughes Medical Institute and American Cancer Society (grant PF-17-042-01–LIB).

Disclosure: Co-author Rachel Marty Pyke is an employee and holds stock in Personalis.

source https://scienceblog.com/517987/why-young-and-female-patients-dont-respond-as-well-to-cancer-immunotherapy/