Database resources of the National Center for Biotechnology Information.

The National Center for Biotechnology Information (NCBI) provides online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for most of these databases. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, SciENcv, the NIH Comparative Genomics Resource (CGR), NCBI Virus, SRA, RefSeq, foreign contamination screening tools, Taxonomy, iCn3D, ClinVar, GTR, MedGen, dbSNP, ALFA, ClinicalTrials.gov, Pathogen Detection, antimicrobial resistance resources, and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

Database resources of the National Center for Biotechnology Information in 2023.

The National Center for Biotechnology Information (NCBI) provides online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for most of these databases. New resources include the Comparative Genome Resource (CGR) and the BLAST ClusteredNR database. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, IgBLAST, GDV, RefSeq, NCBI Virus, GenBank type assemblies, iCn3D, ClinVar, GTR, dbGaP, ALFA, ClinicalTrials.gov, Pathogen Detection, antimicrobial resistance resources, and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.

timsTOF HT Improves Protein Identification and Quantitative Reproducibility for Deep Unbiased Plasma Protein Biomarker Discovery.

Mass spectrometry (MS) is a valuable tool for plasma proteome profiling and disease biomarker discovery. However, wide-ranging plasma protein concentrations, along with technical and biological variabilities, present significant challenges for deep and reproducible protein quantitation. Here, we evaluated the qualitative and quantitative performance of timsTOF HT and timsTOF Pro 2 mass spectrometers for analysis of neat plasma samples (unfractionated) and plasma samples processed using the Proteograph Product Suite (Proteograph) that enables robust deep proteomics sampling prior to mass spectrometry. Samples were evaluated across a wide range of peptide loading masses and liquid chromatography (LC) gradients. We observed up to a 76% increase in total plasma peptide precursors identified and a >2-fold boost in quantifiable plasma peptide precursors (CV < 20%) with timsTOF HT compared to Pro 2. Additionally, approximately 4.5 fold more plasma peptide precursors were detected by both timsTOF HT and timsTOF Pro 2 in the Proteograph analyzed plasma vs neat plasma. In an exploratory analysis of 20 late-stage lung cancer and 20 control plasma samples with the Proteograph, which were expected to exhibit distinct proteomes, an approximate 50% increase in total and statistically significant plasma peptide precursors (q < 0.05) was observed with timsTOF HT compared to Pro 2. Our data demonstrate the superior performance of timsTOF HT for identifying and quantifying differences between biologically diverse samples, allowing for improved disease biomarker discovery in large cohort studies. Moreover, researchers can leverage data sets from this study to optimize their liquid chromatography-mass spectrometry (LC-MS) workflows for plasma protein profiling and biomarker discovery. (ProteomeXchange identifier: PXD047854 and PXD047839).

High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester†.

The placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal-fetal health. The normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes (SEGs) not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background. Placenta expresses 14,979 polyadenylated genes above sequencing noise (transcripts per million > 0.66), with 10.7% SEGs across gestation. Differentially expressed genes (DEGs) account for 86.7% of genes in the full cohort [false discovery rate (FDR) < 0.05]. Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR < 0.001, fold change > 1.5), there remains 50.1% DEGs (3353 upregulated in first and 4155 upregulated in third trimester). This is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and SEGs may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers for maternal-fetal health.

Database resources of the national center for biotechnology information.

The National Center for Biotechnology Information (NCBI) produces a variety of online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for the most of these databases. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, RefSeq, SRA, Virus, dbSNP, dbVar, ClinicalTrials.gov, MMDB, iCn3D and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.

Improved magnetic delivery of cells to the trabecular meshwork in mice.

Glaucoma is the leading cause of irreversible blindness worldwide and its most prevalent subtype is primary open angle glaucoma (POAG). One pathological change in POAG is loss of cells in the trabecular meshwork (TM), which is thought to contribute to ocular hypertension and has thus motivated development of cell-based therapies to refunctionalize the TM. TM cell therapy has shown promise in intraocular pressure (IOP) control, but existing cell delivery techniques suffer from poor delivery efficiency. We employed a novel magnetic delivery technique to reduce the unwanted side effects of off-target cell delivery. Mesenchymal stem cells (MSCs) were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) and after intracameral injection were magnetically steered towards the TM using a focused magnetic apparatus ("point magnet"). This technique delivered the cells significantly closer to the TM at higher quantities and with more circumferential uniformity compared to either unlabeled cells or those delivered using a "ring magnet" technique. We conclude that our point magnet cell delivery technique can improve the efficiency of TM cell therapy and in doing so, potentially increase the therapeutic benefits and lower the risk of complications such as tumorigenicity and immunogenicity.

The Impact of Collaboration Between Science and Religious Education Teachers on Their Understanding and Views of Argumentation.

Teachers' understanding and teaching of argumentation is gaining more attention in science education research. However, little is known about how science teachers engage in argumentation with teachers of different subject taking an interdisciplinary perspective that may inspire new pedagogical ideas or strategies. In particular, the positioning of argumentation at the juncture of science and religion is rare. This paper reports an empirical study involving science and religious education (RE) teachers who collaborated on teaching argumentation in three secondary schools in England. Their interdisciplinary collaboration was sustained by a series of professional development sessions over 18 months. Analysis of the interview data unfolds how the teachers' collaboration impacted their understanding of argumentation and views of teaching their subject. Through working relationally in exploring and teaching argumentation, the science teachers reflected more notable changes than their RE counterparts. Science teachers came to appreciate student voice in the learning process and the role of argumentation in fostering students' scientific reasoning. The paper is a salient step to researching argumentation in a cross-curricular terrain, particularly in relation to RE. It also sheds light on how collaborating with teachers of another subject bolstered science teachers' professional development and broke subject barriers.

Sex differences in microRNA expression in first and third trimester human placenta†.

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences.

Correlation between hand grip strength and regional muscle mass in older Asian adults: an observational study.

BACKGROUND: Previous research has demonstrated a correlation between hand grip strength (HGS) and muscle strength. This study aims to determine the relationship between HGS and muscle mass in older Asian adults. METHODS: We retrospectively reviewed the dual-energy X-ray absorptiometry (DXA) records of 907 older adults (239 (26.4%) men and 668 (73.6%) women) at one medical institution in Taipei, Taiwan, from January 2019, to December 2020. Average age was 74.80 ± 9.43 and 72.93 ± 9.09 for the males and females respectively. The inclusion criteria were: 1) aged 60 and older, 2) underwent a full-body DXA scan, and 3) performed hand grip measurements. Patients with duplicate results, incomplete records, stroke history, and other neurological diseases were excluded. Regional skeletal muscle mass was measured using DXA. HGS was measured using a Jamar handheld dynamometer. RESULTS: Total lean muscle mass (kg) averaged 43.63 ± 5.81 and 33.16 ± 4.32 for the males and females respectively. Average HGS (kg) was 28.81 ± 9.87 and 19.19 ± 6.17 for the males and females respectively. In both sexes, HGS and regional muscle mass consistently declined after 60 years of age. The rates of decline per decade in upper and lower extremity muscle mass and HGS were 7.06, 4.95, and 12.30%, respectively, for the males, and 3.36, 4.44, and 12.48%, respectively, for the females. In men, HGS significantly correlated with upper (r = 0.576, p < 0.001) and lower extremity muscle mass (r = 0.532, p < 0.001). In women, the correlations between HGS and upper extremity muscle mass (r = 0.262, p < 0.001) and lower extremity muscle mass (r = 0.364, p < 0.001) were less strong, though also statistically significant. CONCLUSION: Muscle mass and HGS decline with advancing age in both sexes, though the correlation is stronger in men. HGS measurements are an accurate proxy for muscle mass in older Asian adults, particularly in males.

Incidence of pulmonary embolism in COVID-19 infection in the ED: ancestral, Delta, Omicron variants and vaccines.

PURPOSE: This retrospective review examines the incidence of pulmonary embolism (PE) during computed tomography pulmonary angiography (CTPA) exams performed in the emergency room setting of a tertiary care center over dominant periods of the ancestral, Delta, and Omicron variants of COVID-19. MATERIALS/METHODS: Demographic information, patient comorbidities and risk factors, vaccination status, and COVID-19 infection status were collected from patient's charts. Incidence of PE in COVID positive patients was compared between variant waves. Subgroup analysis of vaccination effect was performed. RESULTS: CTPA was ordered in 18.3% of COVID-19 positive patients during the ancestral variant period, 18.3% during the Delta period and 17.3% during the Omicron wave. PE was seen in 15.0% of the ancestral COVID-19 variant cohort, 10.6% in the Delta COVID cohort and 9.23% of the Omicron cohort, reflecting a 41% and 60% increased risk of PE with ancestral variants compared to Delta and Omicron periods respectively. The study however was underpowered and the difference in rate of PE did not reach statistically significance (p = 0.43 and p = 0.22). Unvaccinated patients had an 2.75-fold increased risk of COVID-associated PE during the Delta and Omicron periods (p = .02) compared to vaccinated or recovered patients. CONCLUSION: Vaccination reduces the risk of COVID-19 associated PE. Patients infected with the Delta and Omicron COVID-19 variants may have a lower incidence of pulmonary embolism, though a larger or multi-institution study is needed to prove definitively.

Enantioselective Synthesis of N-Alkylamines through ß-Amino C-H Functionalization Promoted by Cooperative Actions of B(C6F5)3 and a Chiral Lewis Acid Co-Catalyst.

We disclose a catalytic method for ß-C(sp3)-H functionalization of N-alkylamines for the synthesis of enantiomerically enriched ß-substituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg- or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,ß-unsaturated compounds. An array of δ-amino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage ß-C-H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.

Clinical utility of the endometrial receptivity analysis in women with prior failed transfers.

PURPOSE: To determine the utility of the endometrial receptivity analysis (ERA) in women with prior failed embryo transfers (ET). METHODS: This was a retrospective study of patients who underwent an ERA test with a subsequent frozen ET. Women were classified based on their indication for an ERA test: (1) ≥ 1 prior failed ET (cases), or (2) as a prophylactic measure (controls). A subset analysis of women with ≥ 3 prior failed transfers was performed. Pregnancy outcomes of the subsequent cycle were examined, including conception, clinical pregnancy, and ongoing pregnancy/live birth. RESULTS: A total of 222 women were included, 131 (59%) women with ≥ 1 prior failed ET and 91 (41%) controls. Among the 131 women with ≥ 1 prior failed ET, 20 women (9%) had ≥ 3 prior failed ETs. The proportion of non-receptive ERA tests in the three groups were the following: 45% (≥ 1 prior failed ET), 40% (≥ 3 prior failed ETs), and 52% (controls). The results did not differ between cases and controls. The pregnancy outcomes did not differ between women with ≥ 1 prior failed ET and controls. In women with ≥ 3 prior failed ETs, there was a lower ongoing pregnancy/live birth rate (28% vs 54%, P = 0.046). CONCLUSION: Women with ≥ 1 prior failed ET and ≥ 3 prior failed ETs had a similar prevalence of non-receptive endometrium compared to controls. Women with ≥ 3 prior failed ETs had a lower ongoing pregnancy/live birth rate despite a personalized FET, suggesting that there are additional factors in implantation failure beyond an adjustment in progesterone exposure.

Direct Conversion of N-Alkylamines to N-Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.

An efficient catalytic method to convert an α-C-H bond of N-alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of N-alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.

Access to radiotherapy among circumpolar Inuit populations.

Cancer is a substantial health burden for Inuit populations, an Indigenous peoples who primarily inhabit the circumpolar regions of Alaska, Canada, Greenland, and Russia. Access to radiotherapy is lacking or absent in many of these regions, despite it being an essential component of cancer treatment. This Review presents an overview of factors influencing radiotherapy delivery in each of the four circumpolar Inuit regions, which include population and geography, health-systems infrastructure, and cancer epidemiology. This Review also provides insight into the complex patient pathways needed to access radiotherapy, and on radiotherapy use. The unique challenges in delivering radiotherapy to circumpolar Inuit populations are discussed, which, notably, include geographical and cultural barriers. Recommendations include models of care that have successfully addressed these barriers, and highlight the need for increased collaboration between circumpolar referral centres in Alaska, Canada, Greenland, and Russia to ultimately allow for better delivery of cancer treatment.

Catalytic Deuterium Incorporation within Metabolically Stable ß-Amino C-H Bonds of Drug Molecules.

An efficient deuteration process of ß-amino C-H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C6F5)3 and Brønsted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d6 to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of ß-deuterated bioactive amines with up to 99% deuterium incorporation.

Provision of comprehensive, culturally competent palliative care in the Qikiqtaaluk region of Nunavut: Health care providers' perspectives.

OBJECTIVE: To explore health care providers' perceptions of the provision of palliative care in the Qikiqtaaluk (formerly known as Baffin) region of Nunavut. DESIGN: An exploratory, qualitative, cross-sectional design using in-depth, semistructured interviews. SETTING: Qikiqtaaluk region of Nunavut. PARTICIPANTS: Seven physicians and 6 registered nurses who worked in Iqaluit or other northern Inuit communities in the Qikiqtaaluk region of Nunavut. METHODS: Thirteen health care providers participated in in-person or telephone semistructured interviews, which were audiorecorded and transcribed verbatim. MAIN FINDINGS: Interviews with the participating health care providers in the Qikiqtaaluk region of Nunavut revealed 5 complex and interwoven themes that influence the provision of comprehensive, culturally competent palliative care services to Indigenous patients: respecting Inuit culture, end-of-life care planning, and the role of family; recognizing the importance of the northern community (sense of home); being aware of the limited health care resources; recognizing the critical role of medical interpreters; and improving the quality of palliative care programs and resources, as well as health care provider training in palliative care and Inuit end-of-life care. CONCLUSION: Health care providers in the Qikiqtaaluk region of Nunavut have identified several important themes that influence the provision of culturally sensitive and comprehensive palliative care, most notably the need to develop palliative care resources and programs. It is hoped that the results of this study can be used to help guide palliative care strategies including program development and educational initiatives for health care providers. These initiatives can help build community capacity within a currently underserviced population and improve end-of-life care services available to Nunavut patients and their families. Further studies are required to determine the perspectives of medical interpreters, as well as palliative care patients and their families.

C-H Functionalization of Amines via Alkene-Derived Nucleophiles through Cooperative Action of Chiral and Achiral Lewis Acid Catalysts: Applications in Enantioselective Synthesis.

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,ß-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg-PyBOX complex. Thus, a wide variety of ß-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells.

Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1.

Mode of conception does not affect fetal or placental growth parameters or ratios in early gestation or at delivery.

PURPOSE: Ratio of fetal weight to placenta size varies by mode of conception (fertility treatments utilized) in animals. Our objective was to assess whether fertility treatments also affect these ratios in humans. METHODS: In this retrospective study, we assessed two cohorts: (a) early gestation cohort, women with singleton pregnancies who underwent first trimester vaginal ultrasound and (b) delivered cohort, women who delivered a live-born, singleton infant with placenta disposition to pathology. Crown rump length (CRL) and estimated placental volume (EPV) were calculated from first trimester ultrasound images using a validated computation. Infant birth weight (BW), pregnancy data, placental weight (PW), and placental histopathology were collected. Fetal growth-to-placental weight ratios (CRL/EPV; BW/PW) and placentas were compared by mode of conception. Linear regression was used to adjust for confounding variables. RESULTS: Two thousand one hundred seventy patients were included in the early gestation cohort and 1443 in the delivered cohort. Of the early gestation cohort (a), 85.4% were spontaneous conceptions, 5.9% Non-IVF Fertility (NIFT), and 8.7% IVF. In the delivered cohort (b), 92.4% were spontaneous, 2.1% NIFT, and 80 5.5% IVF. There were no significant differences between fetal growth-to-placental weight parameters, ratios, and neonatal birth measurements based on mode of conception. Placenta accreta was significantly higher in the patients receiving fertility treatments (1.2 versus 3.6%, p < 0.05). CONCLUSIONS: Mode of conception does not appear to influence fetal growth-to-placental weight ratios throughout gestation. In addition, findings in animal models may not always translate into human studies of infertility treatment outcomes.