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Both parasympathetic nervous system regulation and receipt of social support from close relationships contribute to prosocial development, although few studies have examined their combined influences in adolescence and particularly within racially and ethnically minoritized populations. In this longitudinal study of 229 U.S. Mexican-origin adolescents (48% female-identifying), youths reported on receipt of social support from family and friends from 10 to 16 years, had their baseline respiratory sinus arrhythmia (RSA) measured at 17 years, reported their prosocial behavior and completed the Mind in the Eyes test to assess cognitive empathy at 17 and 19 years, and reported their prosocial civic behavior (i.e., community activity) at 19 years. Family social support predicted prosocial behavior at 17 years, and friend social support predicted prosocial civic behavior at 19 years. Compared to youths with lower or higher baseline RSA, youths with moderate RSA reported more prosocial civic behavior, had greater cognitive empathy, and tended to report more general prosocial behavior at 19 years. The quadratic association between baseline RSA and cognitive empathy was stronger for youths with greater family social support. These findings are the first to extend the evidence that moderate baseline parasympathetic nervous system activity supports prosocial development into late adolescence and with the U.S. Mexican-origin community, and these findings address calls for more integrative biopsychosocial studies of prosociality.

Responses are slower in two-choice tasks when either a previous stimulus feature or the previous response repeats than when all features repeat or all features change. Current views of action control posit that such partial repetition costs (PRCs) index the time to update a prior "binding" between a stimulus feature and the response or to resolve processing conflicts between retrieved and current features. However, violating a heuristic that stimulus feature repetitions and changes "signal" repetitions or changes of the previous response, respectively, may also contribute to such costs. To determine whether such relational codes affect performance, we compared PRCs in two- and four-choice tasks. While a stimulus feature repetition signals a response repetition in both tasks, a stimulus feature change signals a specific alternative response only in a two-choice task. Consistent with the signaling hypothesis, we observed similar complete repetition benefits in the two- and four-choice tasks but smaller complete change benefits in the four-choice task. We also investigated whether the smaller complete change benefit in the four-choice task--that is, the signaling effect--varies with the validity of the signal in the previous trial. In all four experiments, we observed a larger signaling effect after trials in which stimulus changes or repetitions corresponded to response changes or repetitions, respectively, than after trials in which stimulus changes did not correspond with response changes. We conclude that signaling contributes to PRCs, which indicates that bindings include relational codes.

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.

Long noncoding RNAs (lncRNAs) account for the largest portion of RNA from the transcriptome, yet most of their functions remain unknown. Here, we performed two independent high-throughput CRISPRi screens to understand the role of lncRNAs in monocyte function and differentiation. The first was a reporter-based screen to identify lncRNAs that regulate TLR4-NFkB signaling in human monocytes and the second screen identified lncRNAs involved in monocyte to macrophage differentiation. We successfully identified numerous noncoding and protein-coding genes that can positively or negatively regulate inflammation and differentiation. To understand the functional roles of lncRNAs in both processes, we chose to further study the lncRNA LOUP [lncRNA originating from upstream regulatory element of SPI1 (also known as PU.1)], as it emerged as a top hit in both screens. Not only does LOUP regulate its neighboring gene, the myeloid fate-determining factor SPI1, thereby affecting monocyte to macrophage differentiation, but knockdown of LOUP leads to a broad upregulation of NFkB-targeted genes at baseline and upon TLR4-NFkB activation. LOUP also harbors three small open reading frames capable of being translated and are responsible for LOUPs ability to negatively regulate TLR4/NFkB signaling. This work emphasizes the value of high-throughput screening to rapidly identify functional lncRNAs in the innate immune system.

The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.

This study leverages six years of public prekindergarten (pre-K) and kindergarten data (N = 22,469) from the Boston Public Schools (BPS) to examine enrollment in BPS pre-K from 2012-2017 for students from different racial/ethnic, socioeconomic, and linguistic groups. The largest differences in enrollment emerged with respect to race and ethnicity--and for enrollment in programs in higher-quality schools (defined as schools scoring in the top quartile on third-grade standardized tests)--with disparities increasing over time. Although there were no differences across groups in proximity to BPS pre-K programs in general, Black students lived about a quarter of a mile farther than their White peers from the nearest program in a higher-quality school, with gaps widening over time. Closer proximity was associated with a higher likelihood of enrollment in a program in a higher-quality school. Implications for future research and policy are discussed.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Abstract Influenza viruses cause substantial morbidity and mortality every year despite seasonal vaccination. mRNA-based vaccines have the potential to elicit more protective immune responses, but for maximal breadth and durability, it is desirable to deliver both the viral hemagglutinin and neuraminidase glycoproteins. Delivering multiple antigens individually, however, complicates manufacturing and increases cost, thus it would be beneficial to express both proteins from a single mRNA. Here, we develop an mRNA genetic configuration that allows the simultaneous expression of unmodified, full-length NA and HA proteins from a single open reading frame. We apply this approach to glycoproteins from contemporary influenza A and B viruses and, after vaccination, observe high levels of functional antibodies and protection from disease in female mouse and male ferret challenge models. This approach may further efforts to utilize mRNA technology to improve seasonal vaccine efficacy by efficiently delivering multiple viral antigens simultaneously and in their native state.

Abstract Nucleoside-modified mRNA-LNP vaccines have revolutionized vaccine development against infectious pathogens due to their ability to elicit potent humoral and cellular immune responses. In this article, we present the results of the first norovirus vaccine candidate employing mRNA-LNP platform technology. The mRNA-LNP bivalent vaccine encoding the major capsid protein VP1 from GI.1 and GII.4 of human norovirus, generated high levels of neutralizing antibodies, robust cellular responses, and effectively protected human enteroids from infection by the most prevalent genotype (GII.4). These results serve as a proof of concept, demonstrating that a modified-nucleoside mRNA-LNP vaccine based on norovirus VP1 sequences can stimulate an immunogenic response in vivo and generates neutralizing antibodies capable of preventing viral infection in models of human gastrointestinal tract infection.

Abstract Background Anesthesiologists provide crucial anesthesiology services in the operating room and non-operating room locations. Combined with an aging and growing Israeli population, there is an increasing demand for anesthesiology services. A previous study performed in 2005 showed that most anesthesiologists are immigrant physicians with few Israeli medical school graduates. Since then, physician immigration decreased, many have retired and demand for anesthesia services has increased while insufficient numbers of new anesthesiologists were trained, leading to a shortage, limiting surgeries and other procedures in many hospitals. The present study examined the composition of the Israeli anesthesiology workforce in 2021and compared it to the 2005 workforce. Methods A cross-sectional survey of demographic and professional information about each Israeli hospital anesthesiologists was solicited from 34 anesthesiology department chairs responsible for 36 Israeli acute care hospitals. Results There are 1313 anesthesiologists in the 36 hospitals, resulting in a ratio of 14.2 anesthesiologists per 100,000 population. 22.6% of anesthesiologists will reach retirement age over the next ten years. The proportion of female anesthesiologists was 28.7%. While Israeli medical school graduates increased to 18.1% from 12.2% in 2005, non-Israeli citizens and non-permanent residents comprised 8.5% of the workforce. Conclusions Despite growth in the ratio of anesthesiologists per population, a workforce shortage is expected to worsen over the next ten years due to retirements, shortened call hours, and the Yatziv reform which bans graduates of certain overseas medical schools from obtaining Israeli Medical Licenses. The current workforce has compensated for the existing shortage of anesthesiologists by enlisting non-Israeli trainees from overseas. Yet, it is crucial to maintain and enlarge the local Israeli workforce to forestall a worsening shortage.

Abstract Background The COVID-19 pandemic was an unprecedented public health emergency that heavily affected the healthcare workforce. Although the Military Health System (MHS) has robust capabilities and was able to deploy medical staff to support civilian hospitals during the crisis, it too was adversely impacted by personnel issues. We aimed to identify and address gaps in understanding the impact of the COVID-19 pandemic on healthcare personnel in the MHS. Methods We conducted semi-structured key informant interviews with 28 MHS stakeholders, including policymakers, program managers, and healthcare providers. We recruited respondents using purposive and snowball sampling until we reached thematic saturation. Interviews were conducted virtually from December 2022 to March 2023 and coded by deductive thematic analysis using NVivo. Results Burnout and mental health concerns across the workforce increased during the pandemic, although some felt military culture facilitated resilience. Reduction in personnel was noted and slow hiring processes and noncompetitive wages hindered hiring, contributing to staffing shortages. Initial disruptions occurred in training and skills readiness, although these issues were reduced over time. Concerns remain about newer trainees’ preparedness and teaching staff’s availability in the MHS. Conclusion This study uniquely assessed the impact of the COVID-19 pandemic response on the MHS healthcare workforce through in-depth key informant interviews. Multi-pronged strategies are needed to promote personnel well-being in complex healthcare systems like the MHS.

Abstract Phylogenomic data are revolutionizing the field of insect phylogenetics. One of the most tenable and cost-effective methods of generating phylogenomic data is target enrichment, which has resulted in novel phylogenetic hypotheses and revealed new insights into insect evolution. Orthoptera is the most diverse insect order within polyneoptera and includes many evolutionarily and ecologically interesting species. Still, the order as a whole has lagged behind other major insect orders in terms of transitioning to phylogenomics. In this study, we developed an Orthoptera-specific target enrichment (OR-TE) probe set from 80 transcriptomes across Orthoptera. The probe set targets 1828 loci from genes exhibiting a wide range of evolutionary rates. The utility of this new probe set was validated by generating phylogenomic data from 36 orthopteran species that had not previously been subjected to phylogenomic studies. The OR-TE probe set captured an average of 1037 loci across the tested taxa, resolving relationships across broad phylogenetic scales. Our detailed documentation of the probe design and bioinformatics process is intended to facilitate the widespread adoption of this tool.

Abstract While first-generation, spike (S)-based COVID-19 vaccines were effective against early SARS-CoV-2 strains, the rapid evolution of novel Omicron subvariants have substantially reduced vaccine efficacy. As such, broadly protective vaccines against SARS-CoV-2 are needed to prevent future viral emergence. In addition, it remains less clear whether peripheral immunization, especially with mRNA vaccines, elicits effective respiratory immunity. Our group has developed a nucleoside-modified mRNA vaccine expressing the nucleocapsid (N) protein of the ancestral SARS-CoV-2 virus and has tested its use in combination with the S-based mRNA vaccine (mRNA-S). In this study, we examined efficacy of mRNA-N alone or in combination with mRNA-S (mRNA-S+N) against more immune evasive Omicron variants in hamsters. Our data show that mRNA-N alone induces a modest but significant protection against BA.5 and that dual mRNA-S+N vaccination confers complete protection against both BA.5 and BQ.1, preventing detection of virus in the hamster lungs. Analysis of respiratory immune response in mice shows that intramuscular mRNA-S+N immunization effectively induces respiratory S- and N-specific T cell responses in the lungs and in bronchoalveolar lavage (BAL), as well as antigen-specific binding IgG in BAL. Together, our data further support mRNA-S+N as a potential pan-COVID-19 vaccine for broad protection against current and emerging SARS-CoV-2 variants.

The paper describes an array of optical cones as a potential configuration for tracker-less daylighting, without using an electro-mechanical tracker. Subsequently, a single optical cone is analyzed, mainly in terms of sunlight collection efficiency and acceptance angle, as a function of the cone's geometrical dimensions. The cones were fabricated and illuminated, with the results compared with those of the theoretical analysis. We then consider the feasibility of a cone array as a sunlight collector, for low light intensity daylighting applications, particularly in the context of indoor plant growing.