The rockefeller university

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

The mass of the W boson, a mediator of the weak force between elementary particles, is tightly constrained by the symmetries of the standard model of particle physics. The Higgs boson was the last missing component of the model. After observation of the Higgs boson, a measurement of the W boson mass provides a stringent test of the model. We measure the W boson mass, M-W, using data corresponding to 8.8 inverse femtobarns of integrated luminosity collected in proton-antiproton collisions at a 1.96 tera-electron volt center-of-mass energy with the CDF II detector at the Fermilab Tevatron collider. A sample of approximately 4 million W boson candidates is used to obtain M-W = 80,433.5 +/- 6.4(stat) +/- 6.9(syst) = 80,433.5 +/- 9.4MeV/c(2), the precision of which exceeds that of all previous measurements combined (stat, statistical uncertainty; syst, systematic uncertainty; MeV, mega-electron volts; c, speed of light in a vacuum). This measurement is in significant tension with the standard model expectation.

The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of approximate to 1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD. METHODS: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03 x 10(-11)), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures.

When New York City (NYC) became an epicenter of the COVID-19 pandemic in the spring of 2020, statistical consulting centers at academic medical institutions in the area were immediately inundated with requests from hospital leadership and researchers for methodological support to address different aspects of the outbreak. Statisticians suddenly had to pivot from their usual responsibilities to focus entirely on COVID-19 work, and consulting centers had to devise innovative strategies to restructure their workflow and develop new infrastructure to address the acute demand for support. As statisticians from seven NYC-area institutions, we share our experiences and lessons learned during the pandemic, with the hope that this will lead not only to better preparedness for future public health crises when the skills and expertise of statisticians are critically needed, but also to lasting improvements to the structure and practice of statistical consulting centers.

Females and males often migrate at different rates. Official data on sex-specific international migration flows are missing for most countries, prohibiting comparative measures to identify and address inequalities. Here we use six methods to estimate male and female five-year bilateral migration flows between 200 countries from 1990 to 2020. We validate the estimates from each method through correlations of several migration measures with equivalent reported statistics in countries that collect flow data. We find that the Pseudo-Bayesian demographic accounting method performs consistently better than the other estimation methods for both female and male estimated flows. The estimates from all methods indicate a decline in the share of female migration flows from 1990-1995 to 2005-2010 followed by a recovery over the decade since 2010.

Purpose: Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. Experimental Design: We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177. [Lu-177]Lu-DTPA-CHX-A"-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. Results: [Lu-177]Lu-DTPA-CHX-A"-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [Lu-177]Lu-DTPA-CHX-A"-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 mu Ci and 750 mu Ci doses of [Lu-177]Lu-DTPA-CHX-A"-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [Lu-177]Lu-DTPA-CHX-A"-SC16 had pathologically confirmed complete responses (CR). In the patient-derived xenograft model Lu149, all doses of [Lu-177]Lu-DTPA-CHX-A"-SC16 markedly prolonged survival. At the 250 mu Ci and 500 mu Ci doses, 5 of 10 and 7 of 9 mice demonstrated pathologically confirmed CRs, respectively. Four of 10 mice that received 750 mu Ci of [Lu-177]Lu-DTPA-CHX-A"-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining 6 mice demonstrated pathologically confirmed CRs. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. Conclusions: Together, the compelling antitumor efficacy, pathologic CRs, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [Lu-177]Lu-DTPA-CHX-A"-SC16.

Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile pre clinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9-a cancer target whose clinical development has been hampered by compounds with poorly understood target specific-ity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve signifi- cant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.

Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.

RNA detection is important in diverse diagnostic and analytical applications. RNAs can be rapidly detected usingmolecular beacons, whichfluoresce upon hybridizing to a target RNA but require oligonucleotides with complexfluorescent dye andquencher conjugations. Here, we describe a simplified method for rapidfluorescence detection of a target RNA using simpleunmodified DNA oligonucleotides. To detect RNA, we developed Lettuce, afluorogenic DNA aptamer that binds and activates thefluorescence of DFHBI-1T, an otherwise nonfluorescent molecule that resembles the chromophore found in greenfluorescentprotein. Lettuce was selected from a randomized DNA library based on binding to DFHBI-agarose. We further show that Lettucecan be split into two separate oligonucleotide components, which are nonfluorescent on their own but becomefluorescent whentheir proximity is induced by a target RNA. We designed several pairs of split Lettuce fragments that contain an additional 15-20nucleotides that are complementary to adjacent regions of the SARS-CoV-2 RNA, resulting in Lettucefluorescence only in thepresence of the viral RNA. Overall, these studies describe a simplified RNA detection approach using fully unmodified DNAoligonucleotides that reconstitute the Lettuce aptamer templated by RNA