The rockefeller university

Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened similar to 200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor. Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.

The growth of the global terrestrial sink of carbon dioxide has puzzled scientists for decades. We propose that the role of land management practices-from intensive forestry to allowing passive afforestation of abandoned lands-have played a major role in the growth of the terrestrial carbon sink in the decades since the mid twentieth century. The Forest Transition, a historic transition from shrinking to expanding forests, and from sparser to denser forests, has seen an increase of biomass and carbon across large regions of the globe. We propose that the contribution of Forest Transitions to the terrestrial carbon sink has been underestimated. Because forest growth is slow and incremental, changes in the carbon density in forest biomass and soils often elude detection. Measurement technologies that rely on changes in two-dimensional ground cover can miss changes in forest density. In contrast, changes from abrupt and total losses of biomass in land clearing, forest fires and clear cuts are easy to measure. Land management improves over time providing important present contributions and future potential to climate change mitigation. Appreciating the contributions of Forest Transitions to the sequestering of atmospheric carbon will enable its potential to aid in climate change mitigation.

The Gulf of Mexico (GoM) region is prone to disasters, including recurrent oil spills, hurricanes, floods, industrial accidents, harmful algal blooms, and the current COVID-19 pandemic. The GoM and other regions of the U.S. lack sufficient baseline health information to identify, attribute, mitigate, and facilitate prevention of major health effects of disasters. Developing capacity to assess adverse human health consequences of future disasters requires establishment of a comprehensive, sustained community health observing system, similar to the extensive and well-established environmental observing systems. We propose a system that combines six levels of health data domains, beginning with three existing, national surveys and studies plus three new nested, longitudinal cohort studies. The latter are the unique and most important parts of the system and are focused on the coastal regions of the five GoM States. A statistically representative sample of participants is proposed for the new cohort studies, stratified to ensure proportional inclusion of urban and rural populations and with additional recruitment as necessary to enroll participants from particularly vulnerable or under-represented groups. Secondary data sources such as syndromic surveillance systems, electronic health records, national community surveys, environmental exposure databases, social media, and remote sensing will inform and augment the collection of primary data. Primary data sources will include participant-provided information via questionnaires, clinical measures of mental and physical health, acquisition of biological specimens, and wearable health monitoring devices. A suite of biomarkers may be derived from biological specimens for use in health assessments, including calculation of allostatic load, a measure of cumulative stress. The framework also addresses data management and sharing, participant retention, and system governance. The observing system is designed to continue indefinitely to ensure that essential pre-, during-, and post-disaster health data are collected and maintained. It could also provide a model/vehicle for effective health observation related to infectious disease pandemics such as COVID-19. To our knowledge, there is no comprehensive, disaster-focused health observing system such as the one proposed here currently in existence or planned elsewhere. Significant strengths of the GoM Community Health Observing System (CHOS) are its longitudinal cohorts and ability to adapt rapidly as needs arise and new technologies develop.

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARSCoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation. This Review discusses how the disease biology of many sarcomas is driven by chromatin pathway alterations ranging from dysregulation of DNA methylation, histone modifications and nucleosome remodelling to disruption of higher-order, 3D chromatin structure, with a view to use this knowledge to better develop targeted therapies for patients with sarcoma.

Mammalian SWI/SNF complexes are ATP-dependent chromatin remodeling complexes that regulate genomic architecture. Here, we present a structural model of the endogenously purified human canonical BAF complex bound to the nucleosome, generated using cryoelectron microscopy (cryo-EM), cross-linking mass spectrometry, and homology modeling. BAF complexes bilaterally engage the nucleosome H2A/H2B acidic patch regions through the SMARCB1 C-terminal alpha-helix and the SMARCA4/2 C-terminal SnAc/post-SnAc regions, with disease-associated mutations in either causing attenuated chromatin remodeling activities. Further, we define changes in BAF complex architecture upon nucleosome engagement and compare the structural model of endogenous BAF to those of related SWI/SNF-family complexes. Finally, we assign and experimentally interrogate cancer-associated hot-spot mutations localizing within the endogenous human BAF complex, identifying those that disrupt BAF subunit-subunit and subunit-nucleosome interfaces in the nucleosome-bound conformation. Taken together, this integrative structural approach provides important biophysical foundations for understanding the mechanisms of BAF complex function in normal and disease states.

Background. Diffuse intrinsic pontine glioma (DIPG) is a highly lethal malignancy that occurs predominantly in children. DIPG is inoperable and post-diagnosis survival is less than 1 year, as conventional chemotherapy is ineffective. The intact blood-brain barrier (BBB) blocks drugs from entering the brain. Convection-enhanced delivery (CED) is a direct infusion technique delivering drugs to the brain, but it suffers from rapid drug clearance. Our goal is to overcome the delivery barrier via CED and maintain a therapeutic concentration at the glioma site with a payload-adjustable peptide nanofiber precursor (NFP) that displays a prolonged retention property as a drug carrier. Methods. The post-CED retention of Zr-89-NFP was determined in real time using PET/CT imaging. Emtansine (DM1), a microtubule inhibitor, was conjugated to NIP The cytotoxicity of the resulting DM1-NFP was tested against patient-derived DIPG cell lines.The therapeutic efficacy was evaluated in animals bearing orthotopic DIPG, according to glioma growth (measured using bioluminescence imaging) and the long-term survival. Results. DM1-NFP demonstrated potency against multiple glioma cell lines. The half-maximal inhibitory concentration values were in the nanomolar range. NFP remained at the infusion site (pons) for weeks, with a clearance half-life of 60 days. DM1-NFP inhibited glioma progression in animals, and offered a survival benefit (median survival of 62 days) compared with the untreated controls (28 days) and DM1-treated animal group (26 days). Conclusions. CED, in combination with DM1-NFP, complementarily functions to bypass the BBB, prolong drug retention at the fusion site, and maintain an effective therapeutic effect against DIPG to improve treatment outcome.

Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.