The rockefeller university

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.

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.

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.

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

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.

Objectives: We describe the clinical, mycological, immunological, and genetic characteristics of six HIV-negative patients presenting with invasive cryptococcosis.& nbsp;Methods: Patients with cryptococcosis without any of the classical risk factors, such as HIV infection, followed at Cayenne Hospital, were prospectively included. An immunologic and genetic assessment was performed.& nbsp;Results: Five male patients and one female patient, 5 adults and one child, were investigated. All presented a neuromeningeal localization. Cryptococcus neoformans var. gattii and C. neoformans var. grubii were isolated in two and three patients, respectively, whereas one patient could not be investigated. Overall, we did not observe any global leukocyte defect. Two patients were found with high levels of circulating autoantibodies against Granulocyte macrophage-colony stimulating factor (GM-CSF), and none had detectable levels of autoantibodies against Interferon gamma (IFN-gamma) Sequencing of STAT1 exons and flanking regions performed for four patients was wild type.& nbsp;Conclusion: To better understand cryptococcosis in patients with cryptococcosis but otherwise healthy, further explorations are needed with repeated immune checkups and strain virulence studies.

Previously published digital autoradiography of H-3-labeled capecitabine reveals a near-uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to C-14-labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro-drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing H-3 capecitabine to the gemcitabine analog F-18-FAC. The metabolism of capecitabine in this model was studied through LC-MS of tumor tissue. The autoradiographs confirmed that the H-3 label from capecitabine was much more uniformly distributed through the tumor than the F-18 from the gemcitabine analog. LC-MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre-5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog F-18-FAC. In a human xenograft model, (BxPC3), the H-3 label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post-administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species.

The photoreceptor rhodopsin (Rho) becomes active when a tethered inverse agonist ligand (11CR) is photoconverted to an agonist (ATR). The ligand-binding pocket of inactive rhodopsin is completely enclosed, whereas active rhodopsin displays pores accessible from the lipid bilayer. Stabilization of active rhodopsin impedes 11CR binding and photoreceptor dark adaptation. Here, we used genetic code expansion and bioorthogonal labeling to engineer Rho mutants that serve as FRET sensors for measuring 11CR binding kinetics and energetics. We found that mutations that alter a channel between transmembrane helices 5 and 6 (TM5/6) dramatically affect 11CR binding kinetics but not agonist release kinetics. Our data provide direct experimental evidence for 11CR entry between TM5/6 in Rho that involves dynamic allosteric control of the ligand entry channel. Our findings provide a conceptual framework for understanding the function of G protein-coupled receptors with hydrophobic ligands that are hypothesized to enter their binding pockets through transmembrane pores.

Background: Previous research has detailed the impor-tance of a racially and ethnically diverse physician workforce in improving access to care, communication, patient satisfaction, and health outcomes, particularly for underserved and systemi-cally marginalized patients (1). Despite this need, disparities in representation within medicine, including internal medicine (IM), persist. Many identities fall under the umbrella of diversity; here, references to diversity pertain to race/ethnicity. Objective: To elucidate trends in representation for IM resi-dency applicants and matriculants who identify as underrepre-sented in medicine (UIM). Methods and Findings: Data about applicants and matriculants to Accreditation Council for Graduate Medical Education IM resi-dency programs between July 2010 and July 2018 were acquired from the Association of American Medical Colleges. Institutional review board review was not required for the deidentified, publicly available data. Analysis was performed using Prism (version 9.2.0; GraphPad Software) and Excel (version 16.43; Microsoft). Between 2010 and 2018, a total of 214656 unique persons applied to IM residency programs and 87489 matriculated; 28222 of the applicants (13.2%) and 9269 of the matriculants (10.6%) identified as a UIM race/ethnicity (Figure, A). The proportion of aggregate UIM applicants grew minimally but significantly (slope, 0.34 [95% CI, 0.29 to 0.39]; Figure, B). On stratified analysis, a statistically significant increase was seen only for applicants who were Black or African American (slope, 0.11 [CI, 0.05 to 0.17]) and those who were Hispanic, Latino, or of Spanish origin (slope, 0.22 [CI, 0.15 to 0.29]). Trends for the proportion of aggregate UIM matriculants similarly had minimal but significant growth (slope, 0.11 [CI, 0.02 to 0.20]; Figure, C). In examining disaggregated UIM matriculant data, only the proportion of matriculants who were Hispanic, Latino, or of Spanish origin significantly changed (slope, 0.13 [CI, 0.05 to 0.21]).

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG(+) plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin alpha v beta 6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis. Multi-modal profiling reveals major alterations in colonic B cells in patients with ulcerative colitis, including reduced clonal diversity of plasma cells, and suggests that circulating gut-homing plasmablasts could serve as a biomarker for disease activity.