Yale University

Proxy reconstructions and model simulations of precipitation during Earth's glacial periods suggest that the locations and mechanisms of atmospheric moisture transport have changed considerably during Earth's past. We investigate the hydroclimate of the Last Glacial Maximum (LGM) using simulations with the Community Earth System Model, with a focus on the extratropics and the influence of atmospheric rivers (ARs), a key driver of modern‐day moisture transport globally. Mean and extreme precipitation increase significantly over southwestern Patagonia, Iberia, and southwestern North America—mid‐latitude regions affected by ARs in the modern climate—despite overall decreases elsewhere. In each, the associated moisture transport changes are different, with increased transport and AR activity mainly occurring in the North Atlantic. The overall LGM response is dominated by the response to ice sheets, with other forcings causing additional cooling and drying over the extratropics and a strong decrease of moisture transport over the subpolar North Atlantic.

Obesity is the main driving factor for comorbidities in Prader–Willi syndrome (PWS) patients due to overeating behaviors. The gut microbiota has been implicated in the etiology of obesity and associated comorbidities. The purpose of the present study was to characterize the fecal microbiota in Chinese patients with PWS and compare it to that of patients with obesity as well as healthy controls. We conducted a cross-sectional study with 35 PWS patients (PWS), 35 patients with obesity (OB), and 35 healthy controls (HC). Metagenomic sequencing was performed in stool samples. The composition of the fecal microbiota in PWS patients differed from that of participants in the OB and HC groups. It was characterized by increased Akkermansia Eubacterium, Eubacterium rectale, and Roseburia intestinalis and decreased Parabacteroides and Phascolarctobacterium. Additionally, the homeostatic model assessment of insulin resistance (HOMA-IR) was lower in PWS patients than in patients with obesity. Spearman rank correlation analysis showed that Achromobacter, Acidiphilium, Xylophilus, and Frisingicoccus were significantly negatively correlated with HOMA-IR. The composition of the gut microbiota in Chinese PWS patients differed from that in patients with obesity, which might contribute to higher insulin sensitivity in PWS patients.

There are approximately 5 million pregnancies per year in the USA, with 1 million ending in miscarriage (a loss occurring prior to 20 weeks of gestation) and over 20,000 ending in stillbirth at or beyond 20 weeks of gestation. As many as 50% of these losses are unexplained. Our objective was to evaluate the effect of expanding the placental pathology diagnostic categories to include the explicit categories of (1) dysmorphic chorionic villi and (2) small placenta in examining previously unexplained losses. Using a clinical database of 1256 previously unexplained losses at 6–43 weeks of gestation, the most prevalent abnormality associated with each loss was determined through examination of its placental pathology slides. Of 1256 cases analyzed from 922 patients, there were 878 (69.9%) miscarriages and 378 (30.1%) antepartum stillbirths. We determined the pathologic diagnoses for 1150/1256 (91.6%) of the entire series, 777/878 (88.5%) of the miscarriages (< 20 weeks’ gestation), and 373/378 (98.7%) of the stillbirths (≥ 20 weeks’ gestation). The most common pathologic feature observed in unexplained miscarriages was dysmorphic chorionic villi (757 cases; 86.2%), a marker associated with genetic abnormalities. The most common pathologic feature observed in unexplained stillbirths was a small placenta (128 cases; 33.9%). Our classification system reinforced the utility of placental examination for elucidating potential mechanisms behind pregnancy loss. The improved rate of diagnosis appeared to be the result of filling a gap in previous pregnancy loss classification systems via inclusion of the categories of dysmorphic chorionic villi and small placenta.

In the analysis of data with a censored survival outcome and high-dimensional covariates, when a single data source has a limited sample size/power, integrative analysis of data from multiple sources can effectively increase sample size and improve estimation and variable selection performance. Under certain circumstances, for example when it is desirable to preserve data privacy, only summary statistics, as opposed to raw data, can be pooled for integrative analysis. In this study, we consider summary statistics-based integrative analysis of multi-source data with a censored survival outcome and high-dimensional covariates under the Cox model. This data setting can be more challenging than many in the literature. We further consider the scenario where some (but not all) covariates have homogeneous effects, and note that properly identifying such homogeneity can lead to more efficient estimation and a deeper understanding of the underlying data generation mechanisms. To this end, we propose a privacy-preserving penalized integrative analysis method, which can simultaneously achieve regularized estimation, variable selection, and homogeneity pursuit. An effective computational algorithm is developed, and asymptotic consistency and distributional properties are rigorously established. Numerical studies, including simulation and the analysis of a bladder cancer data set, convincingly demonstrate the practical effectiveness of the proposed method.

The name of Raymond Aron is often strangely missing from the canon of the twentieth-century’s great philosophers. He is sometimes thought of as a “Cold War intellectual,” but not as a philosopher of the first rank. This would be a mistake. Aron helped to articulate a distinctively French style of liberal political theory. Unlike Anglophone liberalism that has been a doctrine of rights, Aron’s exemplified a certain ideal of human character—rational, skeptical, open-minded—that defines liberalism at its best. His heroes were Montesquieu, Tocqueville, and Weber. Aron articulated these views when liberalism was under attack from the combination of Marxism and Existentialism that dominated the post-World War II period in France. His example will be useful today when liberalism is once more under attack from both the extreme Right and the extreme Left.

In Kenya similar to other countries in Eastern and Southern Africa There is a disproportionately high burden of the global HIV incidence among youth ages 15–24 years, and where adolescent girls and young women account for up to a third of all incident HIV infections and more than double the burden of HIV compared to their male peers. Previous work has shown early sexual debut as entry point into risks to sexual and reproductive health among young people including STI/HIV acquisition. This was a formative assessment of the local context of three sexual risk behaviors among youth ages of 15–24 years: early sexual debut, multiple sexual partnerships, and age-mixing /intergenerational sex for purposes of informing comprehensive combination HIV intervention program design. We conducted a cross-sectional formative qualitative study in four sub-counties within Homabay county a high HIV prevalence region of Kenya. Participants were recruited through youth groups, schools, government offices and, community gatekeepers using approved fliers, referred to a designated venue for focus group discussion (FGD). After oral informed consent, twelve FGDs of 8–10 participants were carried out. Transcripts and field notes were uploaded to Atlas.ti qualitative data analysis and research software (version 8.0, 2017, ATLAS.ti GmbH). Open coding followed by grouping, categorization of code groups, and thematic abstraction was used to draw meaning for the data. A total of 111 youth participated in the FGD, 65 males and 46 females. The main findings were that youth engaged in early sex for fear of being labeled ‘odd’ by their peers, belief (among both male and female) that ‘practice makes perfect’, curiosity about sex, media influence, need to prove if one can father a child (among male), the notion that sex equals love with some of the youth using this excuse to coerce their partners into premature sex, and the belief that sex is a human right and parents/guardians should not intervene. Male youth experienced more peer-pressure to have sex earlier. Female youths cited many reasons to delay coitarche that included fear of pregnancy, burden of taking care of a baby, and religious doctrines. Having multiple sexual partners and intergenerational sexual relationships were common among the youth driven by perceived financial gain and increased sexual prowess. HIV prevention strategies need to address gender vulnerabilities, as well as promoting a protective environment, hence application of combination prevention methods is a viable solution to the HIV pandemic. Trial registration number: The study was approved by the KNH/UoN Ethics review committee (KNH/UoN ERC-P73/03/2011) and New York University (NYU Reg no.–00000310).

White matter connectivity supports diverse cognitive demands by efficiently constraining dynamic brain activity. This efficiency can be inferred from network controllability, which represents the ease with which the brain moves between distinct mental states based on white matter connectivity. However, it remains unclear how brain networks support diverse functions at birth, a time of rapid changes in connectivity. Here, we investigate the development of network controllability during the perinatal period and the effect of preterm birth in 521 neonates. We provide evidence that elements of controllability are exhibited in the infant’s brain as early as the third trimester and develop rapidly across the perinatal period. Preterm birth disrupts the development of brain networks and altered the energy required to drive state transitions at different levels. In addition, controllability at birth is associated with cognitive ability at 18 months. Our results suggest network controllability develops rapidly during the perinatal period to support cognitive demands but could be altered by environmental impacts like preterm birth.

Aim Consolidate and synthesize evidence on working nurse‐parent experiences of parenthood. Background Demands in healthcare strain the workforce, causing burnout and high turnover rates, especially among nurses. Balancing work and family responsibilites is even more challenging for nurse‐parents. Introduction Nursing is highly stressful, and the experiences of nurse‐parents are under‐researched highlighting the need to better understand and support nurse‐parents in their dual roles. Methods Seven databases (PubMed, Embase, CINAHL, PsycINFO, ProQuest, Scopus, and Web of Science) were systematically searched for published and unpublished primary qualitative studies. Extracted data were meta‐summarized and synthesized using Sandelowski and Barroso's approach. Findings Twelve peer‐reviewed studies, conducted between 2007 and 2022, investigated the challenges faced by 339 female nurse‐parents across various countries. The meta‐synthesis revealed two main themes: (a) Clashes of dual roles, and (b) Accept, adapt, and compromise, which were supported by six subthemes. Nurse‐parents struggled with dual roles, often neglected self‐care, and experienced work–family conflicts. However, they learned to accept their situations, adapt by seeking help from family, friends, and colleagues, and compromise on career aspirations to prioritize their families. The importance of organizational support and flexibility in accommodating their dual roles was emphasized. Discussion Female nurse‐parents face challenges in balancing their dual roles, resulting in fatigue, compromised self‐care, and limited social interactions. The culture of self‐sacrifice in nursing contributes to these challenges, impacting patient safety. Supportive interventions like mindfulness programs and exercise classes can promote well‐being. Staffing shortages and shift work further affect the work–life balance for nurse‐parents. Conclusion and implications for nursing and health policy Creating a supportive work environment for nurse‐parents is crucial. Family‐friendly shifts revised parental leave policies, and improved childcare support are needed. Supporting nurse‐parents benefits their well‐being and enhances patient care. Collaboration between healthcare organizations and policymakers is essential to address workforce shortages and implement changes.

Calcium signaling is critical for successful fertilization. In spermatozoa, calcium influx into the sperm flagella mediated by the sperm-specific CatSper calcium channel is necessary for hyperactivated motility and male fertility. CatSper is a macromolecular complex and is repeatedly arranged in zigzag rows within four linear nanodomains along the sperm flagella. Here, we report that the Tmem249 -encoded transmembrane (TM) domain–containing protein, CATSPERθ is essential for the CatSper channel assembly during sperm tail formation. CATSPERθ facilitates the channel assembly by serving as a scaffold for a pore-forming subunit CATSPER4. CATSPERθ is specifically localized at the interface of a CatSper dimer and can self-interact, suggesting its potential role in CatSper dimer formation. Male mice lacking CATSPERθ are infertile because the sperm lack the entire CatSper channel from sperm flagella, rendering sperm unable to hyperactivate, regardless of their normal expression in the testis. In contrast, genetic abrogation of any of the other CatSper TM subunits results in loss of CATSPERθ protein in the spermatid cells during spermatogenesis. CATSPERθ might act as a checkpoint for the properly assembled CatSper channel complex to traffic to sperm flagella. This study provides insights into the CatSper channel assembly and elucidates the physiological role of CATSPERθ in sperm motility and male fertility.

The shape of cells is the outcome of the balance of inner forces produced by the actomyosin network and the resistive forces produced by cell adhesion to their environment. The specific contributions of contractile, anchoring and friction forces to network deformation rate and orientation are difficult to disentangle in living cells where they influence each other. Here, we reconstituted contractile actomyosin networks in vitro to study specifically the role of the friction forces between the network and its anchoring substrate. To modulate the magnitude and spatial distribution of friction forces, we used glass or lipids surface micropatterning to control the initial shape of the network. We adapted the concentration of Nucleating Promoting Factor on each surface to induce the assembly of actin networks of similar densities and compare the deformation of the network toward the centroid of the pattern shape upon myosin-induced contraction. We found that actin network deformation was faster and more coordinated on lipid bilayers than on glass, showing the resistance of friction to network contraction. To further study the role of the spatial distribution of these friction forces, we designed heterogeneous micropatterns made of glass and lipids. The deformation upon contraction was no longer symmetric but biased toward the region of higher friction. Furthermore, we showed that the pattern of friction could robustly drive network contraction and dominate the contribution of asymmetric distributions of myosins. Therefore, we demonstrate that during contraction, both the active and resistive forces are essential to direct the actin network deformation.

Fast, high-fidelity operations between microwave resonators are an important tool for bosonic quantum computation and simulation with superconducting circuits. An attractive approach for implementing these operations is to couple these resonators via a nonlinear converter and actuate parametric processes with RF drives. It can be challenging to make these processes simultaneously fast and high fidelity, since this requires introducing strong drives without activating parasitic processes or introducing additional decoherence channels. We show that in addition to a careful management of drive frequencies and the spectrum of environmental noise, leveraging the inbuilt symmetries of the converter Hamiltonian can suppress unwanted nonlinear interactions, preventing converter-induced decoherence. We demonstrate these principles using a differentially-driven DC-SQUID as our converter, coupled to two high-Q microwave cavities. Using this architecture, we engineer a highly-coherent beamsplitter and fast (~100 ns) swaps between the cavities, limited primarily by their intrinsic single-photon loss. We characterize this beamsplitter in the cavities’ joint single-photon subspace, and show that we can detect and post-select photon loss events to achieve a beamsplitter gate fidelity exceeding 99.98%, which to our knowledge far surpasses the current state of the art.

The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.

Physical forces are prominent during tumor progression. However, it is still unclear how they impact and drive the diverse phenotypes found in cancer. Here, we apply an integrative approach to investigate the impact of compression on melanoma cells. We apply bioinformatics to screen for the most significant compression-induced transcriptomic changes and investigate phenotypic responses. We show that compression-induced transcriptomic changes are associated with both improvement and worsening of patient prognoses. Phenotypically, volumetric compression inhibits cell proliferation and cell migration. It also induces organelle stress and intracellular oxidative stress and increases pigmentation in malignant melanoma cells and normal human melanocytes. Finally, cells that have undergone compression become more resistant to cisplatin treatment. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution.

Aim: To determine if electrocardiogram (EKG) findings may be a useful tool to predict changes in repeat transthoracic echocardiogram (TTE). Methods: We evaluated patients who underwent TTE during hospitalization and their EKGs, and whether findings differed between studies. Results: Of 229 hospitalized patients who underwent repeat TTE, 183 (80%) were abnormal. Each minor and major EKG abnormality resulted in a 1.8 (1.2 to 2.6; p = 0.002) and 2.1 (1.3 to 3.3; p < 0.001) increased odds of abnormal imaging on TTE, respectively. The negative likelihood ratio for an unchanged EKG to predict an unchanged TTE was 0.68 (95% CI = 0.62 to 0.73). Conclusion: Among hospitalized patients with prior imaging results, an unchanged EKG predicts an unchanged TTE.

Importance Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors’ knowledge. Objective To investigate outcomes in people with PSS compared with people without PSS. Data Sources MEDLINE, Embase, PsycInfo, Cochrane, LILACS, LIPECS, and Web of Science, with years searched from 1951 to January 30, 2023. Study Selection Observational studies that reported PSS outcomes. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used for abstracting data, and the Joanna Briggs Institute tool was used for risk-of-bias assessment. Data were reported as odds ratio (OR) and standardized mean difference (SMD) with a 95% CI using a random-effects meta-analysis. Publication bias was assessed using funnel plots and the Egger test. Outlier and meta-regression analyses were performed to explore the source of heterogeneity. Data were analyzed from November 2022 to January 2023. Main Outcomes and Measures Measured outcomes were mortality, poor functional outcome (modified Rankin scale [mRS] score 3-6), disability (mean mRS score), recurrent stroke, and dementia at patient follow-up. Results The search yielded 71 eligible articles, including 20 110 patients with PSS and 1 166 085 patients without PSS. Of the participants with PSS, 1967 (9.8%) had early seizures, and 10 605 (52.7%) had late seizures. The risk of bias was high in 5 studies (7.0%), moderate in 35 (49.3%), and low in 31 (43.7%). PSSs were associated with mortality risk (OR, 2.1; 95% CI, 1.8-2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8-2.8), greater disability (SMD, 0.6; 95% CI, 0.4-0.7), and increased dementia risk (OR, 3.1; 95% CI, 1.3-7.7) compared with patients without PSS. In subgroup analyses, early seizures but not late seizures were associated with mortality (OR, 2.4; 95% CI, 1.9-2.9 vs OR, 1.2; 95% CI, 0.8-2.0) and both ischemic and hemorrhagic stroke subtypes were associated with mortality (OR, 2.2; 95% CI, 1.8-2.7 vs OR, 1.4; 95% CI, 1.0-1.8). In addition, early and late seizures (OR, 2.4; 95% CI, 1.6-3.4 vs OR, 2.7; 95% CI, 1.8-4.1) and stroke subtypes were associated with poor outcomes (OR, 2.6; 95% CI, 1.9-3.7 vs OR, 1.9; 95% CI, 1.0-3.6). Conclusions and Relevance Results of this systematic review and meta-analysis suggest that PSSs were associated with significantly increased mortality and severe disability in patients with history of stroke. Unraveling these associations is a high clinical and research priority. Trials of interventions to prevent seizures may be warranted.

We present the application of Angiopep-2 as a molecular degrader of extracellular proteins (MoDE) promoting target protein removal by both transcytosis and lysosomal degradation mechanisms in brain endothelial cells. The accumulation of pathogenic proteins is a hallmark of many neurodegenerative diseases, and removal of these species is a promising avenue for the development of novel therapies. Targeted protein degradation technologies are emerging as efficacious therapeutic strategies in a wide range of diseases. However, there are no existing methods for the degradation of extracellular proteins in the central nervous system (CNS). Angiopep-2, a brain-targeting peptide derived from aprotinin, has previously been employed as a covalent tag to facilitate receptor-mediated transcytosis of therapeutics across the blood brain barrier (BBB). MoDEs/LyTACs consisting of Angiopep-2 modified with biotin or a chloroalkane ligand triggered endocytosis of streptavidin and HaloTag protein, respectively. Interestingly, uptake occurred independently of LRP-1, which is the reported receptor for Angiopep-2. MoDE-mediated endocytosis of streptavidin in a bEnd.3 BBB model resulted in two mechanisms of protein removal: both bi-directional transcytosis and lysosomal degradation. This study demonstrates that Angiopep-2-based MoDEs can recruit, endocytose, and degrade proteins of interest in CNS cells, supporting their further development as molecular degraders of pathogenic neuroproteins.

Human action recognition aims at extracting features on top of human skeletons and estimating human pose. It has received increasing attention in recent years. However, existing methods capture only the action information while in a real world application such as cognitive assessment, we need to measure the executive functioning that helps psychiatrists to identify some mental disease such as Alzheimer, Schizophrenia and ADHD. In this paper, we propose a skeleton-based action recognition named Mind-In-Action (MIA) for cognitive assessment. MIA integrates a pose estimator to extract the human body joints and then automatically measures the executive functioning employing the distance and elbow angle calculation. Three score functions were designed to measure the executive functioning: the accuracy score, the rhythm score and the functioning score. We evaluate our model on two different datasets and show that our approach significantly outperforms the existing methods.