Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Biomechanical Activation of Keloid Fibroblasts Promotes Lysosomal Remodeling and Exocytosis.

Keloids are a severe form of scarring for which the underlying mechanisms are poorly understood, and treatment options are limited or inconsistent. Although biomechanical forces are potential drivers of keloid scarring, the direct cellular responses to mechanical cues have yet to be defined. The aim of this study was to examine the distinct responses of normal dermal fibroblasts and keloid-derived fibroblasts (KDFs) to changes in extracellular matrix stiffness. When cultured on hydrogels mimicking the elasticity of normal or scarred skin, KDFs displayed greater stiffness-dependent increases in cell spreading, F-actin stress fiber formation, and focal adhesion assembly. Elevated actomyosin contractility in KDFs disrupted the normal mechanical regulation of extracellular matrix deposition and conferred resistance on myosin inhibitors. Transcriptional profiling identified mechanically regulated pathways in normal dermal fibroblasts and KDFs, including the actin cytoskeleton, Hippo signaling, and autophagy. Further analysis of the autophagy pathway revealed that autophagic flux was intact in both fibroblast populations and depended on actomyosin contractility. However, KDFs displayed marked changes in lysosome organization and an increase in lysosomal exocytosis, which was mediated by actomyosin contractility. Together, these findings demonstrate that KDFs possess an intrinsic increase in cytoskeletal tension, which heightens the response to extracellular matrix mechanics and promotes lysosomal exocytosis.

Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria.

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

Care or Complicity? Medical Personnel in Prisons.

Imprisonment may sometimes be a justified form of punishment. Yet the U.S. carceral system suffers from appalling problems of justice-in who is put into prisons, in how imprisoned people are treated, and in downstream personal and community health impacts. Medical personnel working in prisons and jails take on risky work for highly vulnerable and underserved patients. They are to be lauded for their professional commitments. Yet at the same time, prison care undercuts the ability of medical personnel to uphold their own professional standards and sometimes fails in even basic health protection. Doctors in prisons are stuck between their commitment to vulnerable patients and complicity in a system that requires their participation to uphold its constitutionality. Medical ethics is frayed in prisons, and the problem deserves our attention.

Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.

Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.

To Be or Not To Be Polar: The Ferroelectric and Antiferroelectric Nematic Phases.

We report two new series of compounds that show the ferroelectric nematic, NF, phase in which the terminal chain length is varied. The longer the terminal chain, the weaker the dipole-dipole interactions of the molecules are along the director and thus the lower the temperature at which the axially polar NF phase is formed. For homologues of intermediate chain lengths, between the non-polar and ferroelectric nematic phases, a wide temperature range nematic phase emerges with antiferroelectric character. The size of the antiparallel ferroelectric domains critically increases upon transition to the NF phase. In dielectric studies, both collective ("ferroelectric") and non-collective fluctuations are present, and the "ferroelectric" mode softens weakly at the N-NX phase transition because the polar order in this phase is weak. The transition to the NF phase is characterized by a much stronger lowering of the mode relaxation frequency and an increase in its strength, and a typical critical behavior is observed.

Lectin-Seq: A method to profile lectin-microbe interactions in native communities.

Soluble human lectins are critical components of innate immunity. Genetic models suggest that lectins influence host-resident microbiota, but their specificity for commensal and mutualist species is understudied. Elucidating lectins' roles in regulating microbiota requires an understanding of which microbial species they bind within native communities. To profile human lectin recognition, we developed Lectin-Seq. We apply Lectin-Seq to human fecal microbiota using the soluble mannose-binding lectin (MBL) and intelectin-1 (hItln1). Although each lectin binds a substantial percentage of the samples (10 to 20%), the microbial interactomes of MBL and hItln1 differ markedly in composition and diversity. MBL binding is highly selective for a small subset of species commonly associated with humans. In contrast, hItln1's interaction profile encompasses a broad range of lower-abundance species. Our data uncover stark differences in the commensal recognition properties of human lectins.

Ferroelectric Nematic-Isotropic Liquid Critical End Point.

A critical end point above which an isotropic phase continuously evolves into a polar (ferroelectric) nematic phase with an increasing electric field is found in a ferroelectric nematic liquid crystalline material. The critical end point is approximately 30 K above the zero-field transition temperature from the isotropic to nematic phase and at an electric field of the order of 10 V/µm. Such systems are interesting from the application point of view because a strong birefringence can be induced in a broad temperature range in an optically isotropic phase.

Effects of California's New Patient Homelessness Screening and Discharge Care Law in an Emergency Department.

Introduction California State Bill 1152 (SB1152) mandated all non-state-operated hospitals meet specific criteria when discharging patients identified as experiencing homelessness. Little is known about SB1152's effect on hospitals or compliance statewide. We studied the implementation of SB1152 in our emergency department (ED). Methods We analyzed our suburban academic ED's institutional electronic medical record for one year before (July 1, 2018-June 20, 2019) and one year after (July 1, 2019-June 30, 2020) implementation of SB1152. We identified individuals by lack of address during registration, International Classification of Diseases, Tenth Revision (ICD-10) code of homelessness, and/or the presence of an SB1152 discharge checklist. Demographics, clinical information, and repeat visit data were collected. Results ED volumes were constant during the pre- and post-SB1152 periods (approximately 75,000 annually); however, ED visits by people experiencing homelessness more than doubled (630 (0.8%) to 1530 (2.1%) in the pre- and post-implementation periods. Age and sex distributions were similar with approximately 80% of patients aged 31-65 years and less than 1% under 18. Visits by females comprised less than 30% of the population. Visits by people of the White race decreased from 50% to 40% pre- and post-SB1152. Visits by people of the Black, Asian, and Hispanic races experiencing homelessness increased by 18% to 25%, 1% to 4%, and 19% to 21%, respectively. Acuity was unchanged with 50% of visits classified as "urgent." Discharges increased from 73% to 81% and admissions halved from 18% to 9%. Visits by patients with only one ED visit decreased (28% to 22%); those with four or more visits increased (46% to 56%). The most common primary diagnoses pre- and post-SB1162 were alcohol use (6.8% and 9.3%, respectively), chest pain (3.3% and 4.5%, respectively), convulsions (3.0%, and 2.46%, respectively), and limb pain (2.3% and 2.3%, respectively). The primary diagnosis of suicidal ideation doubled from the pre- to post-implementation periods (1.3% to 2.2%, respectively). Checklists were completed for 92% of identified patients discharged from the ED. Conclusion Implementation of SB1152 in our ED resulted in identifying an increased number of persons experiencing homelessness. We identified opportunities for further improvement since pediatric patients were missed. Further analysis is warranted, especially with the coronavirus disease 2019 (COVID-19) pandemic, which has significantly affected healthcare-seeking behavior in EDs.

Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain.

Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders.

Intrinsically Chiral Twist-Bend Nematogens: Interplay of Molecular and Structural Chirality in the NTB Phase.

The front cover artwork is provided by Dr Rebecca Walker of the Liquid Crystals Group at the University of Aberdeen. The image is a cartoon depiction of the formation of the heliconical chiral twist-bend nematic phase (N*TB ) from its constituent bent molecules. The presence of a single enantiomer of the chiral, lactate-based liquid crystal dimers biases the formation of helices with only one handedness, unlike in the conventional NTB phase, observed for achiral molecules, for which the left- and right-handed helices are doubly degenerate. Read the full text of the Research Article at 10.1002/cphc.202200807.

Outbreaks of SARS-CoV-2 Infections in Nursing Homes during Periods of Delta and Omicron Predominance, United States, July 2021-March 2022.

SARS-CoV-2 infections among vaccinated nursing home residents increased after the Omicron variant emerged. Data on booster dose effectiveness in this population are limited. During July 2021-March 2022, nursing home outbreaks in 11 US jurisdictions involving >3 infections within 14 days among residents who had received at least the primary COVID-19 vaccine(s) were monitored. Among 2,188 nursing homes, 1,247 outbreaks were reported in the periods of Delta (n = 356, 29%), mixed Delta/Omicron (n = 354, 28%), and Omicron (n = 536, 43%) predominance. During the Omicron-predominant period, the risk for infection within 14 days of an outbreak start was lower among boosted residents than among residents who had received the primary vaccine series alone (risk ratio [RR] 0.25, 95% CI 0.19-0.33). Once infected, boosted residents were at lower risk for all-cause hospitalization (RR 0.48, 95% CI 0.40-0.49) and death (RR 0.45, 95% CI 0.34-0.59) than primary vaccine-only residents.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) outbreaks in nursing homes involving residents who had completed a primary coronavirus disease 2019 (COVID-19) vaccine series-13 US jurisdictions, July-November 2021.

Among nursing home outbreaks of coronavirus disease 2019 (COVID-19) with ≥3 breakthrough infections when the predominant severe acute respiratory coronavirus virus 2 (SARS-CoV-2) variant circulating was the SARS-CoV-2 δ (delta) variant, fully vaccinated residents were 28% less likely to be infected than were unvaccinated residents. Once infected, they had approximately half the risk for all-cause hospitalization and all-cause death compared with unvaccinated infected residents.

Mission Creep or Mission Lapse? Scientific Review in Research Oversight.

BACKGROUND: The ethical use both of human and non-human animals in research is predicated on the assumption that it is of a high quality and its projected benefits are more significant than the risks and harms imposed on subjects. Yet questions remain about whether and how IRBs and IACUCs should consider the scientific value of proposed research studies. METHODS: We draw upon 45 interviews with IRB and IACUC members and researchers with oversight experience about their perceptions of their own roles in reviewing the quality and value of scientific protocols. Interview transcripts were memoed to highlight specific findings, which were then used to identify key themes through an iterative process. RESULTS: IRB and IACUC members expressed broad trust in the need for and value of research, and they often assumed that protocols had social value or that prior review, especially when associated with funding, affirmed both the rigor and merit of those protocols. Some oversight members also took an explicit stance against scientific review by stating that such review is not within the regulatory mandates governing their parts in the oversight system. Yet other interviewees expressed uneasiness about the current paradigm for evaluating the quality and overall value of science, suggesting that IRB and IACUC members perceive gaps in the oversight systems. CONCLUSIONS: These findings reveal many similarities in how IRB and IACUC members understand the roles and limitations of their respective oversight committees. We conclude with a discussion of how the lack of a clear mandate regarding scientific review within US federal regulations may undermine ethical engagement of whether human and animal research is scientifically justified, resulting in a "mission lapse" wherein no organizational body is clearly responsible for ensuring that the research being conducted has the potential to advance science and benefit society.

Management of Bipolar Disorder During the Perinatal Period.

Bipolar disorder (BPD) is a lifelong mental health condition characterized by symptoms of mania, depression, and often anxiety. BPD can have detrimental consequences for individuals during pregnancy and the postpartum period, as well as for their offspring. This is often due to underdiagnosis and/or misdiagnosis as unipolar depression. There is a high incidence of first episodes of BPD in pregnant and postpartum persons. Perinatal care providers need to routinely screen for BPD and assess for relapse among those with a previous diagnosis during the pregnancy and postpartum periods. Medication management is complex and must be considered in the context of an individual's risk factors and perceptions about treatment as well as the limited evidence regarding fetal safety, using a shared decision-making model. Collaboration, consultation, and/or referral to mental health care providers are essential for managing acute and chronic BPD symptoms.

Intrinsically Chiral Twist-Bend Nematogens: Interplay of Molecular and Structural Chirality in the NTB Phase.

Non-symmetric lactate-based chiral liquid crystal dimers containing an odd-membered spacer are shown to exhibit a chiral twist-bend nematic phase which is stable on cooling to room temperature. A comparison of racemic and optically pure materials reveals that the pitch length in the N*TB phase is not influenced by molecular chirality, whereas the nematic-twist-bend nematic transition temperature is increased.

The effect of a lateral alkyloxy chain on the ferroelectric nematic phase.

The synthesis and characterisation of two series of low molar mass liquid crystals, the 4-[(4-nitrophenoxy)carbonyl]phenyl 2-alkoxy-4-methoxybenzoates (series 5-m) and the 4-[(3-fluoro-4-nitrophenoxy)carbonyl]phenyl 2-alkoxy-4-methoxybenzoates (series 6-m) are reported in order to explore the effects of a lateral alkyloxy chain on the formation and stability of the recently discovered ferroelectric nematic phase. In both series m, the number of carbon atoms in the lateral chain, is varied from one to nine. The two series differ by the addition of a fluorine substituent in the 6-m series. 5-1 is the extensively studied ferroelectric nematogen RM734. All the members of the 5-m series exhibited both a conventional nematic, N, and ferroelectric nematic, NF, phase, whereas all the members of the 6-m series exhibit a direct NF-I transition with the exception of 6-1 that also exhibits a N phase. The replacement of a hydrogen atom by a fluorine atom reduces the nematic-isotropic transition temperature, T NI, whereas the ferroelectric nematic-nematic, or isotropic, transition temperature, T NFN/I, increases. This is interpreted in terms of the reduced structural anisotropy associated with the larger fluorine atom whereas the increase in the stability of the NF phase reflects changes in polarity and polarizability. The dependence of T NI and T NFN/I on m in both series is similar, and these initially decrease on increasing m but converge to limiting values on further increasing m. This suggests that the lateral alkyloxy chain may adopt conformations in which it lies along the major axis of the mesogenic unit.

Ten Years of the Nepal Ambulance Service: Successful and Sustainable Efforts.

We describe the evolution of the nonprofit Nepal Ambulance Service (NAS) in a narrative of its 10-y history, presenting geographical, social, cultural, and financial considerations that permeated the development of NAS. We gathered narrative information from the NAS leadership and partners to detail key organizational considerations regarding the implementation and maintenance of the prehospital system in Nepal. We describe the response of NAS to the 2015 earthquake and summarize transport data for 6 mo before and 6 mo after the event. The data collected included the date and time of calls received, time to ambulance dispatch, on-scene time, time to arrival at the hospital, time until the ambulance crew was back in service, patient age and sex, chief complaints, and work shift time of the ambulance crew. To characterize the time to response and transport after the 2015 earthquake, we present the means and standard deviations of the time intervals. There was an overall increase in calls and, specifically, trauma-related calls after the 2015 earthquake. The time from a call placed to dispatch was stable, approximately 2 min, throughout the period, whereas the time from dispatch to the scene and arrival at the scene varied widely. We discuss the response to coronavirus disease 2019 (COVID-19). The NAS provided care to 1230 patients with COVID-19. The descriptive data show how well NAS responded to a major national disaster and the recent pandemic.

Ethical Criteria for Improved Human Subject Protections in Phase I Healthy Volunteer Trials.

Phase I healthy volunteer trials test the safety and tolerability of investigational pharmaceuticals. In them, participants are exposed to study-drug risks without the possibility of direct medical benefit and typically must spend days or weeks in a residential research facility. Monetary payments are used to incentivize enrollment and compensate participants for their time. Together, these features of phase I healthy volunteer trials create a research context that differs markedly from most other clinical research, including by enrolling disproportionate numbers of economically disadvantaged people of color as participants. Due to these unique trial features and participation patterns, traditional biomedical research oversight offers inadequate ethical and policy guidance for phase I healthy volunteer research. This article details five ethical criteria crafted to be responsive to the particularities of this type of research: translational science value, fair opportunity and burden sharing, fair compensation for service, experiential welfare, and enhanced voice and recourse.