No evidence for an up-regulation of female immune function in response to elevated risk of sexual conflict.

Sexual conflict is widespread among sexually reproducing organisms. Phenotypic plasticity in female resistance traits has the potential to moderate the harm imposed by males during mating, yet female plasticity has rarely been explored. In this experiment, we investigated whether female seed beetles invest more in immunocompetence, measured as phenoloxidase (PO) capacity, when exposed to cues signalling a greater risk of sexual conflict. Risk perception was manipulated by housing focal individuals alone or with a companion as developing larvae, followed by exposure to a mating-free male- or female-biased social environment when adults. We predicted that females exposed to cues of increased sexual conflict would have increased PO capacity. However, PO capacity did not differ between either larval or adult social treatments. Our results suggest that females may not perceive a risk to their fitness on the basis of increased male presence or are unable to adjust this aspect of their phenotype in response to that risk.

Radiography managers' perceptions on skills required in public health institutes in Gauteng.

Background: Management of radiography departments requires skilled and competent managers. This task becomes complex if there is no management development and collaborative performance monitoring. Aim: The study aimed to explore and describe the radiography managers' perceptions regarding management training and skills required. Setting: The research was conducted in public health institutions of Gauteng, South Africa. Methods: Qualitative, exploratory and descriptive approach was adopted, and a purposive sampling method was used to select twenty-three (23) managers from the radiography departments; however, data saturation guided the sample size. Data were collected through online focus group discussions (FGDs). Ethical approval was obtained through Departmental Research Committee (DRC) of Medical Imaging and Radiation Sciences (MIRS) department, Higher Degrees Committee (HDC), Research Ethics Committee and Gauteng Department of Health Research Committees. Data trustworthiness was obtained through member checking, data verification and an independent coder to verify the accuracy of the data. Thematic data analysis method was used to analyse the data. Results: Five themes emerged from the thematic analysis and centred on: difficulties in transitioning into management, lack of management support, the need for postgraduate management qualification, coaching and mentoring and required skills for radiography managers. Conclusion: Public health institutions continuously face transitions in service delivery frameworks. This requires competent and skilled radiography managers to survive in this environment. The study revealed that new managers experience difficulties and require management support to succeed in their roles. Contribution: Awareness of managers developmental needs relative to the real-life dynamics of radiography management in Gauteng public health environment.

The role of autophagy in the progression of HIV infected cardiomyopathy.

Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 ß light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.

A data harmonization project of three large prospective cardiovascular health-focused cohorts.

Few prospective studies examine multilevel resilience resources and psychosocial factors in relation to cardiovascular health and disease. Recent research indicates that resilience resources are associated with a reduction in the incidence of cardiovascular disease-related events, but few studies have examined this relationship across different racial/ethnic populations or in large cohorts. Harmonization may address these limitations because it allows data from several cohorts to be analyzed together, potentially increasing sample size and in turn power overall and in minority populations. This paper describes the process involved in combining three cardiovascular health-focused cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America Study. Using a systematic process, we identified appropriate data harmonization techniques to use in harmonizing variables across cohorts. Variables included exposures (e.g., resilience resources), outcomes (e.g., American Heart Association's Life's Simple 7), and covariates (e.g., race and ethnicity). Post harmonization examinations included psychometric analyses of the harmonized variables. A total of 13,284 participants were included in the final harmonized dataset. This project provides opportunities for future research in resilience resources and informs future studies that need to harmonize data. Results based on the harmonized dataset could inform interventions and policies.

Laterality Targeting in Graded Inferior Rectus Tenotomy Corrects Lateral Incomitance of Hypertropia in Sagging Eye Syndrome.

PURPOSE: To determine if laterally selective graded vertical rectus tenotomy (GVRT) of the inferior rectus (IR) can correct the lateral incomitance of hypertropia (HT) commonly encountered in sagging eye syndrome (SES), comparing it with inferior oblique (IO) recession. DESIGN: Retrospective comparative interventional clinical study. METHODS: We reviewed 73 consecutive patients undergoing GVRT of the IR for correction of horizontally incomitant HT due to SES from July 2012 to October 2023. Confounding diagnoses were excluded. Using topical anesthesia, GVRT was initiated from the nasal versus temporal side corresponding to greater HT, with dosing adjusted intraoperatively until cover testing in central gaze indicated orthotropia. We compared 8 cases of IO recession to 4mm posterior and 3mm lateral to the IR insertion. RESULTS: Nasal GVRT was performed in 41 patients (standard deviation), and temporal GVRT on 32 patients. Mean nasal GVRT was 69±15% and mean temporal GVRT was 62±17%. Mean HT in central gaze was reduced by nasal GVRT from 3.9±1.7Δ to 0.3±1.4Δ, and from 4.0±1.6Δ to 0.2±1.1Δ by temporal GVRT. Nasal GVRT corresponding to the side of the tenotomy had greater effect in contralateral gaze at 3.2±2.2Δ than ipsilateral gaze at 2.1±2.0Δ (p=0.0250), whereas temporal GVRT had greater effect in ipsilateral gaze at 4.9±2.7D than contralateral gaze at 2.9±2.9D (p=0.0002). Inferior oblique recession in 8 patients reduced lateral incomitance from 13±5.0Δ to 0.5±1.4Δ (p<0.0001). CONCLUSION: Nasal GVRT corrects about 1Δ and temporal GVRT 2Δ horizontal incomitance of HT, while IO recession corrects about 12.5Δ. Selection of GVRT laterality improves outcomes without additional risk or operating time.

Signature Analysis of High-Throughput Transcriptomics Screening Data for Mechanistic Inference and Chemical Grouping.

High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in in vitro cell-based test systems. As an extension of a previous study testing 44 chemicals, HTTr was used to screen an additional 1751 unique chemicals from the EPA's ToxCast collection in MCF7 cells using eight concentrations and an exposure duration of 6 hours. We hypothesized that concentration-response modeling of signature scores could be used to identify putative molecular targets and cluster chemicals with similar bioactivity. Clustering and enrichment analyses were conducted based on signature catalog annotations and ToxPrint chemotypes to facilitate molecular target prediction and grouping of chemicals with similar bioactivity profiles. Enrichment analysis based on signature catalog annotation identified known mechanisms-of-action (MeOAs) associated with well-studied chemicals and generated putative MeOAs for other active chemicals. Chemicals with predicted MeOAs included those targeting estrogen receptor (ER), glucocorticoid receptor (GR), retinoic acid receptor (RAR), the NRF2/KEAP/ARE pathway, AP-1 activation and others. Using reference chemicals for ER modulation, the study demonstrated that HTTr in MCF7 cells was able to stratify chemicals in terms of agonist potency, distinguish ER agonists from antagonists, and cluster chemicals with similar activities as predicted by the ToxCast ER Pathway model. Uniform manifold approximation and projection (UMAP) embedding of signature-level results identified novel ER modulators with no ToxCast ER Pathway model predictions. Finally, UMAP combined with ToxPrint chemotype enrichment was used to explore the biological activity of structurally-related chemicals. The study demonstrates that HTTr can be used to inform chemical risk assessment by determining in vitro points-of-departure, predicting chemicals' molecular mechanism(s)-of-action (MeOA) and grouping chemicals with similar bioactivity profiles.

High-Throughput Transcriptomics Screen of ToxCast Chemicals in U-2 OS Cells.

New approach methodologies (NAMs) aim to accelerate the pace of chemical risk assessment while simultaneously reducing cost and dependency on animal studies. High Throughput Transcriptomics (HTTr) is an emerging NAM in the field of chemical hazard evaluation for establishing in vitro points-of-departure and providing mechanistic insight. In the current study, 1201 test chemicals were screened for bioactivity at eight concentrations using a 24-h exposure duration in the human- derived U-2 OS osteosarcoma cell line with HTTr. Assay reproducibility was assessed using three reference chemicals that were screened on every assay plate. The resulting transcriptomics data were analyzed by aggregating signal from genes into signature scores using gene set enrichment analysis, followed by concentration-response modeling of signatures scores. Signature scores were used to predict putative mechanisms of action, and to identify biological pathway altering concentrations (BPACs). BPACs were consistent across replicates for each reference chemical, with replicate BPAC standard deviations as low as 5.6 × 10-3 µM, demonstrating the internal reproducibility of HTTr-derived potency estimates. BPACs of test chemicals showed modest agreement (R2 = 0.55) with existing phenotype altering concentrations from high throughput phenotypic profiling using Cell Painting of the same chemicals in the same cell line. Altogether, this HTTr based chemical screen contributes to an accumulating pool of publicly available transcriptomic data relevant for chemical hazard evaluation and reinforces the utility of cell based molecular profiling methods in estimating chemical potency and predicting mechanism of action across a diverse set of chemicals.

Molecular mimicry in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Appropriate care in chronic limb threatening ischemia: A review of current evidence and outcomes.

Chronic limb threatening ischemia (CLTI) poses a significant treatment challenge for vascular surgeons, interventionalists, podiatrists, and associated medical specialists. The evidence for what constitutes appropriate care is rapidly evolving and new treatment options are in constant development. This review examines the current guidelines for CLTI care, as well as reported outcomes for multiple care strategies in this patient population, including revascularization and medical optimization. We performed a literature review of the PubMed database, reviewing articles that reported outcomes for CLTI care between 2000 and 2023, and described these outcomes as they relate to the current state of CLTI treatment. Significant data are still forthcoming regarding CLTI care, but widespread adoption of appropriate CLTI care is essential for the treatment of this vulnerable population.

Surgically Correctable Central Cyanosis: Congenital Extrahepatic Portosystemic Shunt in a Child.

Congenital extrahepatic portosystemic shunts (CEPS) are rare anomalies connecting the portal system to the inferior vena cava. This report discusses a 10-year-old boy with Type II c CEPS, presenting cyanosis and dyspnea. Surgical ligation resulted in significant improvement in symptoms. Early identification and intervention are crucial, necessitating a protocolized approach.

Parametrically guided design of beta barrels and transmembrane nanopores using deep learning.

Francis Crick's global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations required from ideal beta barrel geometry to maintain extensive inter-strand hydrogen bonding without introducing considerable backbone strain. Instead, beta barrels and other protein folds have been designed guided by 2D structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires considerable expert knowledge and provides only indirect control over the global barrel shape. Here we show that the simplicity and control over shape and structure provided by global parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence-structure relationships implicit in RoseTTAFold based inpainting and diffusion design methods. Starting from parametrically generated idealized barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate the backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of global beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a novel beta barrel topology, and de novo designed 12, 14, and 16 stranded transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.

Position paper on advancing sickle cell disease management in France by bridging the clinical practices and guidelines through expert insights.

In France, sickle cell disease (SCD) is the most common rare disease and represents the most prevalent genetic disorder, with 19,800 to 32,400 patients diagnosed in 2016 and 1:714 newborns affected in 2019. SCD is caused by a single mutation in the ß-globin gene, resulting in the production of abnormal hemoglobin (called HbS), chronic hemolytic anemia, and impaired red blood cell rheology. SCD patients face several severe acute and chronic complications, including stroke, acute chest syndrome (ACS), painful vaso-occlusive crisis (VOC), organ failure, and a high risk of infections. As patients' care pathway remains unclear in France, a roundtable advisory board meeting was organized in the country to provide insights into the management of SCD in alignment with clinical guidelines. The meeting brought together a panel of esteemed key opinion leaders (KOLs) in SCD management, encompassing both clinical practice and research. During the meeting, the KOLs discussed clinical practices and their alignment with French guidelines, identifying areas of concordance and discrepancy. They also addressed disparities in SCD clinical practices across regions and medical centers. The KOLs discussed the prophylactic and therapeutic options currently available for SCD patients in France, with a focus on transfusion therapies, especially automated red blood cell exchange (aRBCX). The results of this advisory board meeting provide a valuable platform for gathering expert perspectives on SCD management, clinical practices, guideline alignment, and the potential for contributions to guideline updates.

Climate, demography, immunology, and virology combine to drive two decades of dengue virus dynamics in Cambodia.

The incidence of dengue virus disease has increased globally across the past half-century, with highest number of cases ever reported in 2019 and again in 2023. We analyzed climatological, epidemiological, and phylogenomic data to investigate drivers of two decades of dengue in Cambodia, an understudied endemic setting. Using epidemiological models fit to a 19-y dataset, we first demonstrate that climate-driven transmission alone is insufficient to explain three epidemics across the time series. We then use wavelet decomposition to highlight enhanced annual and multiannual synchronicity in dengue cycles between provinces in epidemic years, suggesting a role for climate in homogenizing dynamics across space and time. Assuming reported cases correspond to symptomatic secondary infections, we next use an age-structured catalytic model to estimate a declining force of infection for dengue through time, which elevates the mean age of reported cases in Cambodia. Reported cases in >70-y-old individuals in the 2019 epidemic are best explained when also allowing for waning multitypic immunity and repeat symptomatic infections in older patients. We support this work with phylogenetic analysis of 192 dengue virus (DENV) genomes that we sequenced between 2019 and 2022, which document emergence of DENV-2 Cosmopolitan Genotype-II into Cambodia. This lineage demonstrates phylogenetic homogeneity across wide geographic areas, consistent with invasion behavior and in contrast to high phylogenetic diversity exhibited by endemic DENV-1. Finally, we simulate an age-structured, mechanistic model of dengue dynamics to demonstrate how expansion of an antigenically distinct lineage that evades preexisting multitypic immunity effectively reproduces the older-age infections witnessed in our data.

Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in a South African population.

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations' unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed and has one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts (N=308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGAex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and âˆ¼ 221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51 %; Bantu and San); European (26 %; Northern/Western); South Asian (18 %); and East Asian (5 %; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6 %), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with higher FASD risk, and maternal and child ancestry-by-prenatal alcohol exposure interaction effects were seen on child cognition. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.

Societal Costs of Dementia: 204 Countries, 2000-2019.

Background: Dementia prevalence is expected to increase as populations grow and age. Therefore, additional resources will be needed to meet the global demand for care for Alzheimer's disease and related dementias (ADRD). Objective: Estimate global and country-level health care spending attributable to ADRD and the cost of informal care for people living with ADRD. Methods: We gathered data from three systematic literature reviews and the Global Burden of Disease 2019 study. We used spatiotemporal Gaussian process regression to impute estimates for the many countries without underlying data. We projected future costs to 2050 based on past trends in costs, diagnosis rates, and institutionalization rate. Results: We estimated that in 2019, the direct health care spending attributable to ADRD across 204 countries reached $260.6 billion (95% uncertainty interval [UI] 131.6-420.4) and the cost of informal ADRD care was $354.1 billion (95% UI 190.0-544.1). On average, informal care represents 57% (95% UI 38-75%) of the total cost of care. We estimated that direct health care spending attributable to ADRD will reach $1.6 trillion (95% UI 0.6-3.3) in 2050, or 9.4% (95% UI 3.9-19.6%) of projected health spending worldwide. We estimated the cost of informal care will reach $0.9 trillion (95% UI 0.3-1.7) in 2050. Conclusions: These cost estimates underscore the magnitude of resources needed to ensure sufficient resources for people living with ADRD and highlight the role that informal care plays in provision of their care. Incorporating informal care cost estimates is critical to capture the social cost of ADRD.

Financing health in sub-Saharan Africa 1990-2050: Donor dependence and expected domestic health spending.

In 2021, global life expectancy at birth was 74 years whereas in sub-Saharan Africa it was 66 years. Yet in that same year, $92 per person was spent on health in sub- Saharan Africa, which is roughly one fifth of what the next lowest geographic region-North Africa and Middle East-spent ($379). The challenges to healthy lives in sub-Saharan Africa are many while health spending remains low. This study uses gross domestic product, government, and health spending data to give a more complete picture of the patterns of future health spending in sub-Saharan Africa. We analyzed trends in growth in gross domestic product, government health spending, development assistance for health and the prioritization of health in national spending to compare countries within sub-Saharan Africa and globally.We found that while gross domestic product was projected to increase through 2050 in sub-Saharan Africa, the share of gross domestic product that goes to health spending is only expected to increase moderately. Our exploration shows that this tepid growth is expected because the percent of overall government spending that is dedicated to health 7·2% (6·3-8·3) compared to average of 12·4% (11·7-13·2) in other regions) is expected to stay low. Even if the amount, of resources provided from donors climbs some, it is not expected to keep pace with growing economies in sub-Saharan Africa and may transition towards other global public health goods. Critically, development assistance for health provided to sub-Saharan Africa is expected to decrease in some countries, and the expected growth in government health spending might not be enough to cover this expected decline. Increases in spending with a concordant prioritization of health and the appropriate health system governance and structural reforms are critical to ensure that people who live in sub-Saharan Africa are not left behind.

Tensile properties of glaucomatous human sclera, optic nerve, and optic nerve sheath.

We characterized the tensile behavior of sclera, optic nerve (ON), and ON sheath in eyes from donors with glaucoma, for comparison with published data without glaucoma. Twelve freshly harvested eyes were obtained from donors with history of glaucoma, of average age 86 ± 7 (standard deviation) years. Rectangular samples were taken from anterior, equatorial, posterior, and peripapillary sclera, and ON sheath, while ON was in native form and measured using calipers. Under physiological temperature and humidity, tissues were preconditioned at 5% strain before loading at 0.1 mm/s. Force-displacement data were converted into engineering stress-strain curves fit by reduced polynomial hyperelastic models and analyzed by tangent moduli at 3% and 7% strain. Data were compared with an age-matched sample of 7 published control eyes. Optic atrophy was supported by significant reduction in ON cross section to 73% of normal in glaucomatous eyes. Glaucomatous was significantly stiffer than control in equatorial and peripapillary regions (P < 0.001). However, glaucomatous ON and sheath were significantly less stiff than control, particularly at low strain (P < 0.001). Hyperelastic models were well fit to stress-strain data (R2 > 0.997). Tangent moduli had variability similar to control in most regions, but was abnormally large in peripapillary sclera. Tensile properties were varied independently among various regions of the same eyes. Glaucomatous sclera is abnormally stiff, but the ON and sheath are abnormally compliant. These abnormalities correspond to properties predicted by finite element analysis to transfer potentially pathologic stress to the vulnerable disk and lamina cribrosa region during adduction eye movement.

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimposed by the breakage of natural protective barriers (e.g., mucosal damage, chronic indwelling catheters, and alterations of anatomical structures), increases the risk of various infections. These and other conditions that mimic sepsis pose substantial diagnostic and therapeutic challenges. Factors that elevate the risk of progression to septic shock in these patients include advanced age, pre-existing comorbidities, frailty, type of cancer, the severity of immunosuppression, hypoalbuminemia, hypophosphatemia, Gram-negative bacteremia, and type and timing of responses to initial treatment. The management of vulnerable cancer patients with sepsis or septic shock varies due to biased clinical practices that may result in delayed access to intensive care and worse outcomes. While septic shock is typically associated with poor outcomes in patients with malignancies, survival has significantly improved over time. Therefore, understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system (e.g., wireless technologies, medical informatics, precision medicine), targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with prompt admission to high-level care facilities that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates.

Molecular Manipulation of the miR160/AUXIN RESPONSE FACTOR Expression Module Impacts Root Development in Arabidopsis thaliana.

In Arabidopsis thaliana (Arabidopsis), microRNA160 (miR160) regulates the expression of AUXIN RESPONSE FACTOR10 (ARF10), ARF16 and ARF17 throughout development, including the development of the root system. We have previously shown that in addition to DOUBLE-STRANDED RNA BINDING1 (DRB1), DRB2 is also involved in controlling the rate of production of specific miRNA cohorts in the tissues where DRB2 is expressed in wild-type Arabidopsis plants. In this study, a miR160 overexpression transgene (MIR160B) and miR160-resistant transgene versions of ARF10 and ARF16 (mARF10 and mARF16) were introduced into wild-type Arabidopsis plants and the drb1 and drb2 single mutants to determine the degree of requirement of DRB2 to regulate the miR160 expression module as part of root development. Via this molecular modification approach, we show that in addition to DRB1, DRB2 is required to regulate the level of miR160 production from its precursor transcripts in Arabidopsis roots. Furthermore, we go on to correlate the altered abundance of miR160 or its ARF10, ARF16 and ARF17 target genes in the generated series of transformant lines with the enhanced development of the root system displayed by these plant lines. More specifically, promotion of primary root elongation likely stemmed from enhancement of miR160-directed ARF17 expression repression, while the promotion of lateral and adventitious root formation was the result of an elevated degree of miR160-directed regulation of ARF17 expression, and to a lesser degree, ARF10 and ARF16 expression. Taken together, the results presented in this study identify the requirement of the functional interplay between DRB1 and DRB2 to tightly control the rate of miR160 production, to in turn ensure the appropriate degree of miR160-directed ARF10, ARF16 and ARF17 gene expression regulation as part of normal root system development in Arabidopsis.

Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons drives sex-specific behavioral impairments linked to autism.

There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in TSC1 result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of Tsc1 selectively in cerebellar Purkinje neurons, referred to here as Tsc1 mut/mut , have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male Tsc1 mut/mut animals. Here, we used cohorts of male and female Tsc1 mut/mut animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. W e determined balance and motor coordination deficits are similar in male and female Tsc1 mut/mut mice, and that deficits in the firing of Tsc1 mut/mut Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in Tsc1 mut/mut males compared to females. These results indicate the selective deletion of Tsc1 in Purkinje neurons differentially impairs cerebellar circuits based on sex.