A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy.

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells.

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-ß (TGF-ß) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

Dithieno[3,2-b:2',3'-d]pyrrole Cored p-Type Semiconductors Enabling 20 % Efficiency Dopant-Free Perovskite Solar Cells.

Organic p-type semiconductors with tunable structures offer great opportunities for hybrid perovskite solar cells (PVSCs). We report herein two dithieno[3,2-b:2',3'-d]pyrrole (DTP) cored molecular semiconductors prepared through π-conjugation extension and an N-alkylation strategy. The as-prepared conjugated molecules exhibit a highest occupied molecular orbital (HOMO) level of -4.82 eV and a hole mobility up to 2.16×10-4  cm2 V-1 s-1 . Together with excellent film-forming and over 99 % photoluminescence quenching efficiency on perovskite, the DTP based semiconductors work efficiently as hole-transporting materials (HTMs) for n-i-p structured PVSCs. Their dopant-free MA0.7 FA0.3 PbI2.85 Br0.15 devices exhibit a power conversion efficiency over 20 %, representing one of the highest values for un-doped molecular HTMs based PVSCs. This work demonstrates the great potential of using a DTP core in designing efficient semiconductors for dopant-free PVSCs.

The eIF2α Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen Trafficking.

The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that the eukaryotic initiation factor 2α (eIF2α) kinases heme-regulated inhibitor (HRI) and protein kinase R (PKR) control distinct cellular and immune-related activities in response to diverse bacterial pathogens. Specifically for Listeria monocytogenes, there was reduced translocation of the pathogen to the cytosolic compartment in HRI-deficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that Hri-/- mice, as well as wild-type mice treated with an HRI inhibitor, are more susceptible to listeriosis. In the first few hours of L. monocytogenes infection, there was much greater pathogen proliferation in the liver of Hri-/- mice than in the liver of Hri+/+ mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in Hri+/+ mice in the first few hours of infection whereas the increase in IL-6 levels in Hri-/- mice was notably delayed. Consistent with these in vivo findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected Hri-/- macrophages and fibroblasts was significantly higher than the rate seen with infected Hri+/+ cells. Treatment of cells with an eIF2α kinase activator enhanced both the HRI-dependent and PKR-dependent infection phenotypes, further indicating the pharmacologically malleability of this signaling pathway. Collectively, these results suggest that HRI mediates the cellular confinement and killing of virulent L. monocytogenes in addition to promoting a system-level cytokine response and that both are required to limit pathogen replication during the first few hours of infection.

Who's holding the baby? A prospective diary study of the contact patterns of mothers with an infant.

BACKGROUND: Models of infectious disease are increasingly utilising empirical contact data to quantify the number of potentially infectious contacts between age groups. While a growing body of data is being collected on contact patterns across many populations, less attention has been paid to the social contacts of young infants. We collected information on the social contacts of primary carers of young infants and investigated their potential for use as a proxy for contacts made by their infant. METHODS: We recruited primary carers of infants under one year of age residing in two geographically, demographically and socioeconomically distinct local government areas of Melbourne, Australia - Boroondara and Hume - including a sub-group of Turkish-speaking participants. Participants recorded their own contacts in a paper diary and noted whether their infant was present or absent. Information collected included times at an address; description of location; and details on people contacted at the location. Descriptive summary measures and distributions of contacts by location type, intensity, day of contact and by age are reported. RESULTS: Of the 226 participants recruited, 220 completed diaries were returned. Participant contact patterns were similar across all groups, with respect to the types of locations, intensity and day of contact, with some variation in the number of unique daily contacts. The infant was present at around 85% of locations at which the primary carer contacted other individuals. The majority of contacts occurring when the infant was present were in Own Home (32%), Retail and Hospitality (18%) and Transport (18%) settings. The mean daily number of unique contacts by infants was estimated as 9.1, 8.7 and 6.5 in Boroondara, Hume (English) and Hume (Turkish), respectively, with a similar age distribution across each of our surveyed groups. CONCLUSIONS: Our demonstration that contact patterns of mothers with infants are reasonably robust to socioeconomic and cultural differences is a step forward in modelling infectious disease transmission. With infants spending most of their time in the company of their mother, contact patterns of mothers are a useful proxy measure of infant contact patterns. The age distribution of contacts made by infants estimated in this study may be used to supplement population-wide contact information commonly used in infectious disease transmission models.

Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen.

The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen Listeria monocytogenes Within a few hours of systemic infection, the massive proliferation of L. monocytogenes in Perforin-2(-/-)mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured Perforin-2(-/-)cells that the vacuole-to-cytosol transitioning of L. monocytogenesis greatly accelerated. Unexpectedly, we found that in Perforin-2(-/-)macrophages,Listeria-containing vacuoles quickly (≤ 15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of L. monocytogenes to its replicative niche in the cytosol. This hypothesis was supported by our finding that aL. monocytogenes strain expressing virulence factors at a constitutively high level replicated equally well in Perforin-2(+/+)and Perforin-2(-/-)macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of Listeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.

Fabrication of Efficient Low-Bandgap Perovskite Solar Cells by Combining Formamidinium Tin Iodide with Methylammonium Lead Iodide.

Mixed tin (Sn)-lead (Pb) perovskites with high Sn content exhibit low bandgaps suitable for fabricating the bottom cell of perovskite-based tandem solar cells. In this work, we report on the fabrication of efficient mixed Sn-Pb perovskite solar cells using precursors combining formamidinium tin iodide (FASnI3) and methylammonium lead iodide (MAPbI3). The best-performing cell fabricated using a (FASnI3)0.6(MAPbI3)0.4 absorber with an absorption edge of ∼1.2 eV achieved a power conversion efficiency (PCE) of 15.08 (15.00)% with an open-circuit voltage of 0.795 (0.799) V, a short-circuit current density of 26.86(26.82) mA/cm(2), and a fill factor of 70.6(70.0)% when measured under forward (reverse) voltage scan. The average PCE of 50 cells we have fabricated is 14.39 ± 0.33%, indicating good reproducibility.

Eukaryotic initiation factor 2 (eIF2) signaling regulates proinflammatory cytokine expression and bacterial invasion.

In eukaryotic cells, there are two well characterized pathways that regulate translation initiation in response to stress, and each have been shown to be targeted by various viruses. We recently showed in a yeast-based model that the bacterial virulence factor YopJ disrupts one of these pathways, which is centered on the α-subunit of the translation factor eIF2. Here, we show in mammalian cells that induction of the eIF2 signaling pathway occurs following infection with bacterial pathogens and that, consistent with our yeast-based findings, YopJ reduces eIF2 signaling in response to endoplasmic reticulum stress, heavy metal toxicity, dsRNA, and bacterial infection. We demonstrate that the well documented activities of YopJ, inhibition of NF-κB activation and proinflammatory cytokine expression, are both dependent on an intact eIF2 signaling pathway. Unexpectedly, we found that cells with defective eIF2 signaling were more susceptible to bacterial invasion. This was true for pathogenic Yersinia, a facultative intracellular pathogen, as well as for the intracellular pathogens Listeria monocytogenes and Chlamydia trachomatis. Collectively, our data indicate that the highly conserved eIF2 signaling pathway, which is vitally important for antiviral responses, plays a variety of heretofore unrecognized roles in antibacterial responses.

Burden of chronic kidney disease in Nepal: An analysis of the burden of disease from 1990 to 2019.

Chronic kidney disease (CKD) has emerged as one of the major public health concerns. The increasing prevalence of its correlates such as obesity, diabetes, and hypertension has been, due in part responsible for the increased burden. However, very few studies have presented the comprehensive data on burden of disease particularly in developing countries like Nepal. In this study, we have performed an analysis on prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs) and disability-adjusted life years (DALYs) attributable to CKD in Nepal using Global Burden of Disease (GBD) Study 2019. The GBD 2019 study provides estimation of the prevalence, mortality rates, YLDs, YLLs and DALYs due to 369 different disease and 87 risk factors for 204 countries and territories across the world. In this study, we present Nepal specific data on prevalence, mortality, YLDs, YLLs and DALYs related to CKD. In 2019, there were 1,895,080 prevalent cases of CKD with 5,108 deaths, and a total of 168,900 DALYs were attributable to CKD. Age-standardized prevalence rate of CKD increased from 5,979.1 cases per 100,000 population (95% UI: 5539.7, 6400.4) in 1990 to 7,634.1 cases per 100,000 population (95% UI: 7138.8, 8119.4) in 2019 with higher prevalence in males. Similarly, the age-standardized mortality due to CKD increased for both sexes from 0.8 deaths per 100,000 population (95% UI: 0.6, 1.0) in 1990 to 2.6 deaths per 100,000 population (95% UI: 2.0, 3.3) in 2019. The burden of CKD as a percentage of total DALYs was 0.5% (95% UI: 0.4, 0.6) in 1990 and increased to 1.8% (95% UI: 1.4, 2.2%) in 2019. Kidney dysfunction, high systolic blood pressure, high fasting plasma glucose, high body mass index, low temperature, lead exposure, diet high in sodium, and high temperature were found to be the major risk factors for CKD. The study reveals that Nepal has a high and rising burden of CKD. Innovative strategies for prevention of CKD including health system preparedness for treatment services are required to respond to the rising burden of CKD.

Factors that determine women's autonomy to make decisions about sexual and reproductive health and rights in Nepal: A cross-sectional study.

Women's autonomy on sexual and reproductive health issues is critical to women's health and well-being. Women have the right to decide on their fertility and sexuality, be free from coercion and violence, and achieve well-being. This study has identified women's autonomy regarding decision and exercise of their sexual reproductive health and rights and its association with determining factors in Nepal. Descriptive and analytical statistics such as bivariate and multivariate regression analysis were performed using data from Nepal Demographic and Health Survey 2016. The survey collected data from 12,862 women of reproductive age groups i.e. 15-49 years. However, for this study, we analyzed the data of only ever-married women and they were 9,875 in total. The analysis showed that women's autonomy in exercising their sexual reproductive health rights is highly associated with media exposure after controlling demographic variables. The frequency of exposure to media (i. less than a week: adjusted odds ratio (AOR):1.383; confidence interval (CI):1.145-1.670, p<0.001, ii. at least once a week: AOR:1.657; CI:1.359-2.021, p<0.001) is positively associated with women's autonomy. Furthermore, factors like women from Janajati (AOR:1.298; CI:1.071-1.576, p<0.01) and other Terai ethnic groups (AOR:1.471; CI:1.160-1.866, p<0.01), higher education attainment (AOR:1.482; CI:1.164-1.888, p<0.01), richest wealth quintile (AOR:1.527; CI:1.151-2.026, p<0.01), paid work (AOR:1.277; CI:1.045-1.561, p<0.05) and living in Lumbini Province (AOR:0.622; CI:0.486-0.797, p<0.001) and Sudur Paschim Province (AOR:0.723; CI:0.554-0.944, p<0.05) were found to be significantly associated with women's autonomy in sexual and reproductive health decision making. Similarly, women's autonomy is also increased with their increased age. In conclusion, women's exposure to media, improved socio-economic status and increased age influence their autonomy to make decisions about sexual and reproductive health rights in Nepal. Therefore, this study underscores the need to address socio-economic barriers and improve women's exposure to the media to enhance their autonomy further.

Burden of Cardiovascular Diseases in Nepal from 1990 to 2019: The Global Burden of Disease Study, 2019.

Cardiovascular diseases (CVDs) have emerged as the leading cause of deaths worldwide in 2019. Globally, more than three-quarters of the total deaths due to CVDs occur in low- and middle-income countries like Nepal. Although increasing number of studies is available on the prevalence of CVDs, there is limited evidence presenting a complete picture on the burden of CVDs in Nepal. In this context, this study aims to provide comprehensive picture on the burden of CVDs in the country. This study is based on the Global Burden of Disease (GBD) study 2019, which is a multinational collaborative research covering 204 countries and territories across the world. The estimations made from the study are publicly available in the GBD Compare webpage operated by the Institute for Health Metrics and Evaluation (IHME), University of Washington. This article makes use of those data available on the GBD Compare page of IHME website to present the comprehensive picture of the burden of CVDs in Nepal. Overall, in 2019, there were an estimated 1,214,607 cases, 46,501 deaths, and 1,104,474 disability-adjusted life years (DALYs) due to CVDs in Nepal. The age-standardized mortality rates for CVDs witnessed a marginal reduction from 267.60 per 100,000 population in 1990 to 245.38 per 100,000 population in 2019. The proportion of deaths and DALYs attributable to CVDs increased from 9.77% to 24.04% and from 4.82% to 11.89%, respectively, between 1990 and 2019. Even though there are relatively stable rates of age-standardized prevalence, and mortality, the proportion of deaths and DALYs attributed to CVDs have risen sharply between 1990 and 2019. Besides implementing the preventive measures, the health system also needs to prepare itself for the delivery of long-term care of patients with CVDs which could have significant implications on resources and operations.

A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice.

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases.

Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice.

Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-ß and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet ß cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro-inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single-nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell-cycle, and senescence-associated pathways in naturally aged mice. Long-term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.

Burden of Diabetes Mellitus in Nepal: An Analysis of Global Burden of Disease Study 2019.

Globally, the number of people living with diabetes mellitus (DM) increased by 62% between 1990 and 2019, affecting 463 million people in 2019, and is projected to increase further by 51% by 2045. The increasing burden of DM that requires chronic care could have a considerable cost implication in the health system, particularly in resource constraint settings like Nepal. In this context, this study attempts to present the burden of DM in terms of prevalence, mortality, and disability adjusted life years (DALYs). The study is based on the Global Burden of Disease Study 2019, a multinational collaborative research, led by the Institute for Health Metrics and Evaluations. In the study, the overall prevalence of DM was estimated using DisMod MR-2.1, a Bayesian metaregression model. DALYs were estimated summing years of life lost due to premature death and years lived with disability. There were a total of 1,412,180 prevalent cases of DM, 3,474 deaths and 189,727 DALYs, due to DM in 2019. All-age prevalence rate and the age-standardized prevalence rate of DM stood at 4,642.83 (95% uncertainty interval (UI): 4,178.58-5,137.74) and 5,735.58 (95% UI: 5,168.74-6327.73) cases per 100,000 population, respectively, in 2019. In 2019, 1.8% (95% UI: 1.54, 2.07) of total deaths were from DM, which is a more than three-fold increase from the proportion of deaths attributed in 1990 (0.43%, 95% UI: 0.36, 0.5) with most of these deaths being from DM type 2. In 2019, a total of 189,727 disability adjusted life years (DALYs) were attributable to DM of which 105,950 DALYs were among males, and the remaining 83,777 DALYs were among females. Overall, between 1990 and 2019, the DALYs, attributable to Type 1 and 2 DM combined and for Type 2 DM only, have increased gradually across both sexes. However, the DALYs per 100,000 attributable to DM have slightly reduced across both sexes in that time. There is a high burden of DM in Nepal in 2019 with a steep increase in the proportion of deaths attributable to DM in Nepal which could pose a serious challenge to the health system. Primary prevention of DM requires collaborative efforts from multiple sectors. Meanwhile, the current federal structure could be an opportunity for integrated, locally tailored public health and clinical interventions for the prevention of the disease and its consequences.

Progress in Reducing Inequalities in Reproductive, Maternal, Newborn and Child Health Services in Nepal.

BACKGROUND: Equity has emerged as a cross-cutting theme in the health sector, and countries across the world are striving to ensure that all people have access to the health services they need without undue financial hardship and educational, social, cultural and geographical barriers. In this context, this analysis has attempted to analyse Nepal's progress in reducing inequalities in reproductive, maternal, newborn and child health services based on economic status and place of residence. METHODS: In this analysis, we have used data available from the web version of the Health Equity Assessment Toolkit, a data visualisation tool developed by the World Health Organisation. We have analysed the inequalities in terms of a composite coverage index which combines eight reproductive, maternal, newborn and child health interventions along the continuum of care. RESULTS: Composite coverage of reproductive, maternal, newborn and child health services was 43% in 2001 which increased to 65% in 2016. The absolute difference in composite coverage of the services between the lowest and highest wealth quintiles decreased from 28-percentage points in 2001 to 8-percentage points in 2016. The difference in service coverage between the urban and rural settings reduced from 21-percentage points to six percentage points in the period. Among the eight various services, births attended by skilled birth attendants is the indicator with the highest scope for improvement.   Conclusions: Inequalities based on wealth quintiles and residence places have narrowed from 2001 to 2016. Additional efforts in expanding skilled birth attendants and antenatal care service coverage among the poorest quintile and rural residents could further improve the coverage of the indicators at the national level and narrow down the inequalities.

Factors associated with physical and sexual violence among school-going adolescents in Nepal: Findings from Global School-based Student Health Survey.

BACKGROUND: Globally violence is a matter of public health concern with severe physical and mental health implications and social consequences. Evidence suggest that adolescents have an elevated risk of exposure to physical and sexual violence. However, there is a lack of nationally representative research on violence and its associated factors in Nepal to inform interventions. This paper attempts to find the factors associated with various forms of physical and sexual violence among school-going adolescents in Nepal. METHODS: We analysed the cross-sectional data from the Global School-based Student Health Survey (GSHS) 2015. The GSHS survey applied a two-stage cluster sampling process to select a representative sample of 7 to 11 grade students from 74 schools across the country. We applied logistic regression analysis to identify the factors associated with physical and sexual violence. RESULTS: Out of the total 6,529 participants, 45.24% of them faced a physical attack, 39.25% were involved in a physical fight, and 11.65% were victims of sexual violence in the survey administered between 7 August 2015 to 14 March 2016. In a multiple regression analysis, the age of participants, parental supervision, feeling unsafe at school, and the number of close friends were found to be associated with a physical attack. Participants who were bullied, had multiple sex partners, and had received corporal punishment in school had a higher engagement in a physical fight. Likewise, school grade, having parents who understand the problems, having multiple sex partners, and corporal punishment at school were associated with instances of sexual violence. CONCLUSION: The study identified multiple factors associated with experiences of physical attacks, involvement in a physical fight, and sexual violence among school-going adolescents. This study results can have important implications for school administration, parents, and policymakers alike to plan appropriate anti-violence strategies and interventions. Since various forms of violence share some common risk factors, a comprehensive strategy could be worth considering to prevent such acts of violence.

Effects of Cu Precursor on the Performance of Efficient CdTe Solar Cells.

Copper (Cu) incorporation is a key process for fabricating efficient CdTe-based thin-film solar cells and has been used in CdTe-based solar cell module manufacturing. Here, we investigate the effects of different Cu precursors on the performance of CdTe-based thin-film solar cells by incorporating Cu using a metallic Cu source (evaporated Cu) and ionic Cu sources (solution-processed cuprous chloride (CuCl) and copper chloride (CuCl2)). We find that ionic Cu precursors offer much better control in Cu diffusion than the metallic Cu precursor, producing better front junction quality, lower back-barrier heights, and better bulk defect property. Finally, outperforming power conversion efficiencies of 17.2 and 17.5% are obtained for devices with cadmium sulfide and zinc magnesium oxide as the front window layers, respectively, which are among the highest reported CdTe solar cells efficiencies. Our results suggest that an ionic Cu precursor is preferred as the dopant to fabricate efficient CdTe thin-film solar cells and modules.

A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.

Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.

The activities of the Yersinia protein kinase A (YpkA) and outer protein J (YopJ) virulence factors converge on an eIF2alpha kinase.

The Yersinia protein kinase A (YpkA) and outer protein J (YopJ) are co-expressed from a single transcript and are injected directly into eukaryotic cells by the plague bacterium Yersinia pestis. When overexpressed in vertebrate or yeast cells, YpkA disrupts the actin-based cytoskeletal system by an unknown mechanism, whereas YopJ obstructs inductive chemokine expression by inhibiting MAPK and NF-kappaB signaling. Previously, we showed that the fission yeast Schizosaccharomyces pombe was sensitive to the kinase activity of YpkA. Here, we screened yeast for cellular processes important for YpkA activity and found that the eIF2alpha kinases mollify the toxicity imparted by the kinase activity of YpkA. Specifically, strains lacking the eIF2alpha kinase Hri2 were particularly sensitive to YpkA. Unexpectedly, the activity of YopJ, which conferred a phenotype consistent with its inhibitory effect on MAPK signaling, was also found to be dependent on Hri2. When expressed in S. pombe, YopJ sensitized cells to osmotic and oxidative stresses through a Hri2-dependent mechanism. However, when co-expressed with YpkA, YopJ protected cells from YpkA-mediated toxicity, and this protection was entirely dependent on Hri2. In contrast, YopJ did not confer protection against the toxic effects of the Yersinia virulence factor YopE. These findings are the first to functionally link YpkA and YopJ and suggest that eIF2alpha kinases, which are critically important in antiviral defenses and protection against environmental stresses, also play a role in bacterial virulence.

A potential role for complement in immune evasion by Mycobacterium leprae.

Lepromatous leprosy is a model of immune evasion wherein pathogen-specific IL-10-secreting T cells and concomitant failure of Th-1 immunity permit uncontrolled proliferation of the intracellular pathogen, Mycobacterium leprae (M. leprae). The mechanism of this immune escape is unknown. Here, the authors report that phenolic glycolipid-1 (PGL-1), a major and distinguishing feature of the M. leprae cell wall, is expressed in the cell membrane of M. leprae-infected human dendritic cells, where it can activate complement in human serum. The authors demonstrate that PGL-1 and the C3 component of complement colocalize in lipid rafts in the dendritic cell membrane, and enter the immune synapse upon co-culture of M. leprae-infected DCs and T cells. Hence, activated C3 is strategically located to costimulate naïve T cells via the complement regulatory protein, CD46, a process known to stimulate the differentiation of IL-10-secreting regulatory T cells. These observations suggest a potential novel mechanism of immune evasion, wherein M. leprae may subvert host natural immunity to provoke an adaptive response that favors bacillary survival.