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The present study examined both mothers' reports and adolescents' perceptions of parents' educational involvement and their effects on the adolescents' functioning in school. The sample was drawn from 5 urban schools in Israel. Participants were 449 eighth grade students/adolescents (Female = 47%) and 126 mothers. Adolescents and their mothers completed parallel parents' educational involvement questionnaires, and adolescents completed questionnaires on learning strategies and self-evaluation. Multiple-group confirmatory factor analyses, based on the mothers' reports and adolescents' perceptions of parents' educational involvement revealed three factors: home-based, school-based, and communication-based knowledge of adolescents' activities in school. The analysis showed no relation between mothers' reports and adolescents' perceptions. However, adolescents' perceptions of their parents' educational involvement were significant predictors of the adolescents' learning strategies, self-evaluation, and academic achievement. Findings underline the congruence and incongruence between mothers and their adolescents, and the significant role parents play in their adolescents' schooling according to the adolescents' perceptions.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Abstract The low resolution of spatial transcriptomics data necessitates additional information for optimal use. We developed scDOT, which combines spatial transcriptomics and single cell RNA sequencing to improve the ability to reconstruct single cell resolved spatial maps and identify senescent cells. scDOT integrates optimal transport and expression deconvolution to learn non-linear couplings between cells and spots and to infer cell placements. Application of scDOT to lung spatial transcriptomics data improves on prior methods and allows the identification of the spatial organization of senescent cells, their neighboring cells and novel genes involved in cell-cell interactions that may be driving senescence.

In 2021, the Israel Ministry of Health began a national hepatitis C elimination program. Implementing a World Health Organization goal, Israel’s program involved targeted screening, barrier minimization, workup simplification, awareness campaigns, and a patient registry. We evaluated program costs for testing and treatment. By May 15, 2023, the program had identified 865,382 at-risk persons, of whom 555,083 (64.3%) were serologically screened for hepatitis C virus (HCV), which was detected in 24,361 (4.4%). Among 20,928 serologically positive patients, viremia was detected in 13,379 (63.9%), of whom 10,711 (80%) were treated, and 4,618 (96.5%) of 4,786 persons receiving posttreatment HCV RNA testing had sustained virologic response. We estimated costs of ₪14,426 (new Israel shekel; ≈$3,606 USD) per person whose HCV infection was diagnosed and successfully treated. The program yielded screening and treatment in almost two thirds of the identified at-risk population. Although not eliminated, HCV prevalence will likely decrease substantially by the 2030 target.

Given its known prognostic role, we aimed to investigate the role of neutrophil–lymphocyte ratio (NLR) as a biomarker in metastatic castration-resistant prostate cancer (mCRPC) patients receiving ADT, either as monotherapy or in conjunction with abiraterone acetate (AA) and prednisone. This retrospective cohort study analyzed the LATITUDE study of men with high-risk mCSPC. Patients were assigned to receive either AA, prednisone, and androgen deprivation therapy (ADT) or placebo plus ADT. Using a previously established NLR threshold of 2.5, we evaluated if this could predict clinical response to abiraterone. At baseline, there were no significant differences in NLR values between the treatment groups. Of the known baseline prognostic factors, NLR was associated with albumin levels and Eastern Cooperative Oncology Group performance scores. Moreover, the number of bone metastases was higher in patients with NLR ≥ 2.5. On multivariable analysis, baseline NLR ≥ 2.5 did not predict overall survival, PSA progression-free, or metastasis-free survival. However, changes in PSA and NLR at six months indicated distinct survival patterns between the placebo and AA groups, suggesting the potential for their combined assessment as a prognostic tool. Baseline NLR was not an independent predictor factor for response to AA in the LATITUDE study, though NLR changes at 6 months may predict better survival beyond PSA values alone. Further research is required to better understand in which patients with advanced prostate cancer NLR changes may be a useful prognostic tool.

Abstract Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

IntroductionSince the onset of the COVID-19 pandemic in 2020, a significant body of research has explored the impact of the virus and its preventative measures on mental health among individuals with OCD. However, to our knowledge, no study has been conducted to test whether the very behaviors considered symptomatic of OCD inadvertently offer a protective shield against COVID-19 infection.MethodsThis retrospective cohort study utilized the electronic health record database of Israel’s largest healthcare provider, Clalit Health Services (CHS), to compare patients with and without recorded OCD diagnoses in terms of the number of COVID-19 tests taken, hospitalizations, vaccination rates, and infection rates during and after different pandemic waves.ResultsThe OCD group had a slightly higher rate of positive COVID-19 tests compared to the control group (p

Orthostatic intolerance (and its subtype postural orthostatic tachycardia syndrome [POTS]) is an increasingly common complaint among adolescents associated with significant decrease in quality of life and frequent visits to primary care offices. As orthostatic intolerance becomes increasingly discussed online and through social media, we have observed that family angst and anxiety only heighten, often leading to requests for specialist referral to manage the symptoms. This often leads to delay in diagnosis, which further exacerbates the situation. In truth, however, a pragmatic approach applied by the primary care provider, including a ready explanation for the experienced symptoms, not only provides the bedrock for patient improvement, but also eases the anxiety of having a seemingly nebulous diagnosis. As physicians caring for these patients, we have seen success with treatment and seek to share this blueprint. Key points that will be covered include how to make an accurate diagnosis (using the “dizziness rule”), how to counsel about treatment, and clinic pitfalls to avoid. The description of care that follows is not based on systematic review and instead is exactly what is used in our office and what we hope will be successful in yours as well.

Abstract Crohn disease (CD) burden has increased with globalization/urbanization, and the rapid rise is attributed to environmental changes rather than genetic drift. The Study Of Urban and Rural CD Evolution (SOURCE, n = 380) has considered diet-omics domains simultaneously to detect complex interactions and identify potential beneficial and pathogenic factors linked with rural-urban transition and CD. We characterize exposures, diet, ileal transcriptomics, metabolomics, and microbiome in newly diagnosed CD patients and controls in rural and urban China and Israel. We show that time spent by rural residents in urban environments is linked with changes in gut microbial composition and metabolomics, which mirror those seen in CD. Ileal transcriptomics highlights personal metabolic and immune gene expression modules, that are directly linked to potential protective dietary exposures (coffee, manganese, vitamin D), fecal metabolites, and the microbiome. Bacteria-associated metabolites are primarily linked with host immune modules, whereas diet-linked metabolites are associated with host epithelial metabolic functions.

This work focuses on the parameter development and microstructural characterization of Nb-based alloy C103 for thin wall structures produced via laser powder – directed energy deposition (LP – DED). Laser power and scanning speeds were varied as part of a design of experiments to identify adequate print parameters. Combinations were evaluated for relative density, porosity, and geometrical accuracy. A combination of a laser power of 1420 W and scanning speed of 14 mm/s resulted in a relative density >99%, exhibited a consistent weld bead profile and was used for further microstructural evaluation. A mix of optical and scanning electron microscopy (SEM) revealed small, slightly elongated grains along the edges and large epitaxial grains in the central region along the Build – Transverse view. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analysis revealed Hf rich columnar cells in the center that transition into an evenly spaced cellular structure towards the edges of the built sample. Electron backscatter diffraction (EBSD) scans show a sharp [001] texture when looking at the cross section of the sample along the build direction. The Build – Scan view revealed a zig – zag pattern that follows the back – and – forth deposition strategy that was used. Finally, microhardness measurements were taken in the as – built (AB) and stress relieved (SR) conditions to baseline preliminary mechanical properties. The AB condition exhibited a large amount of scatter in the data and averages up to 11% larger than the SR condition. The reduction in scatter upon applying the SR cycle are indicative of a large concertation of dislocations present in the AB condition.

Abstract Background High prostate eicosapentaenoic fatty acid (EPA) levels were associated with a significant reduction of upgrading to grade group (GG) ≥ 2 prostate cancer in men under active surveillance. We aimed to evaluate the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation. Methods A phase II double-blind randomized placebo-controlled trial was conducted in 130 men diagnosed with GG ≥ 2 prostate cancer and undergoing radical prostatectomy between 2015–2017 (Clinicaltrials.gov: NCT02333435). Participants were randomized to receive 3 g daily of either MAG-EPA (n = 65) or placebo (n = 65) for 7 weeks (range 4–10) prior to radical prostatectomy. The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. Additional planned outcomes at surgery are reported including plasma levels of 27 inflammatory cytokines and fatty acid profiles in circulating red blood cells membranes and prostate tissue. Results Cancer proliferation index measured by Ki-67 expression was not statistically different between the intervention (3.10%) and placebo (2.85%) groups (p = 0.64). In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. Secondary outcome was the changes in plasma levels of 27 cytokines, of which only IL-7 was higher in MAG-EPA group compared to placebo (p = 0.026). Men randomized to MAG-EPA prior to surgery had four-fold higher EPA levels in prostate tissue compared to those on placebo. Conclusions This MAG-EPA intervention did not affect the primary outcome of prostate cancer proliferation according to nuclear Ki-67 expression. More studies are needed to decipher the effects of long-chain omega-3 fatty acid dietary supplementation in men with prostate cancer.

ABSTRACTSpinal cord injury (SCI) is a devastating event that significantly changes daily function and quality of life and is linked to bowel and bladder dysfunction and frequent antibiotic treatment. We aimed to study the composition of the gut microbiome in individuals with SCI during the initial sub-acute rehabilitation process and during the chronic phase of the injury. This study included 100 fecal samples from 63 participants (Median age 40 years, 94% males): 13 cases with SCI in the sub-acute phase with 50 longitudinal samples, 18 cases with chronic SCI, and 32 age and gender-matched controls. We show, using complementary methods, that the time from the injury was a dominant factor linked with gut microbiome composition. Surprisingly, we demonstrated a lack of gut microbial recovery during rehabilitation during the sub-acute phase, with further deviation from the non-SCI control group in the chronic ambulatory SCI group. To generalize the results, we were able to show significant similarity of the signal when comparing to a previous cohort with SCI, to subjects from the American Gut Project who reported low physical activity, and to subjects from another population-based cohort who reported less normal stool consistency. Restoration of the microbiome composition may be another desirable measure for SCI recovery in the future, but further research is needed to test whether such restoration is associated with improved neurological outcomes and quality of life.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.

Abstract In this brief report, we provide an analysis of the influence of a novel CYP2C haplotype (CYP2C:TG) on proton pump inhibitor (PPI) pharmacokinetics (PK) in children. The CYP2C:TG haplotype has been proposed to be associated with increased CYP2C19 activity. We sought to determine if this CYP2C:TG haplotype resulted in similar alterations in metabolism for proton pump inhibitors, which are primarily metabolized by CYP2C19. In a cohort of 41 children aged 6–21 participating in a PPI pharmacokinetic study, effects of the CYP2C:TG allele were assessed by fitting two linear regression models for each of the six PK outcomes assessed, the second of which accounted for the presence of the CYP2C:TG allele. The difference in R2 values between the two models was computed to quantify the variability in the outcome that could be accounted for by the CYP2C:TG allele after adjustment for the CYP2C19 genotype. We found the CYP2C:TG haplotype to have no measurable additive impact on CYP2C19‐mediated metabolism of PPIs in vivo in older children and adolescents. The findings of this study do not support the clinical utility of routine testing for the CYP2C:TG haplotype to guide PPI dose adjustments in children.

Abstract Background Intervertebral disc degeneration (IDD) is a leading contributor to low back pain (LBP). Autophagy, strongly activated by hypoxia and nutrient starvation, is a vital intracellular quality control process that removes damaged proteins and organelles to recycle them for cellular biosynthesis and energy production. While well‐established as a major driver of many age‐related diseases, autophagy dysregulation or deficiency has yet been confirmed to cause IDD. Methods In vitro, rat nucleus pulposus (NP) cells treated with bafilomycin A1 to inhibit autophagy were assessed for glycosaminoglycan (GAG) content, proteoglycan synthesis, and cell viability. In vivo, a transgenic strain (Col2a1‐Cre; Atg7fl/fl) mice were successfully generated to inhibit autophagy primarily in NP tissues. Col2a1‐Cre; Atg7fl/fl mouse intervertebral discs (IVDs) were evaluated for biomarkers for apoptosis and cellular senescence, aggrecan content, and histological changes up to 12 months of age. Results Here, we demonstrated inhibition of autophagy by bafilomycin produced IDD features in the rat NP cells, including increased apoptosis and cellular senescence (p21CIP1) and decreased expression of disc matrix genes Col2a1 and Acan. H&E histologic staining showed significant but modest degenerative changes in NP tissue of Col2a1‐Cre; Atg7fl/fl mice compared to controls at 6 and 12 months of age. Intriguingly, 12‐month‐old Col2a1‐Cre; Atg7fl/fl mice did not display increased loss of NP proteoglycan. Moreover, markers of apoptosis (cleaved caspase‐3, TUNEL), and cellular senescence (p53, p16INK4a, IL‐1β, TNF‐α) were not affected in 12‐month‐old Col2a1‐Cre; Atg7fl/fl mice compared to controls. However, p21CIP1and Mmp13 gene expression were upregulated in NP tissue of 12‐month‐old Col2a1‐Cre; Atg7fl/fl mice compared to controls, suggesting p21CIP1‐mediated cellular senescence resulted from NP‐targeted Atg7 knockout might contribute to the observed histological changes. Conclusion The absence of overt IDD features from disrupting Atg7‐mediated macroautophagy in NP tissue implicates other compensatory mechanisms, highlighting additional research needed to elucidate the complex biology of autophagy in regulating age‐dependent IDD.

Abstract Background In the general population, a higher omega‐3 polyunsaturated fatty acids intake is associated with lower levels of several psychological symptoms, especially depression. However, the existing evidence in cancer is equivocal. Methods This phase IIB double‐blind, placebo‐controlled trial was aimed at comparing the effects of eicosapentaenoic acid monoacylglyceride (MAG‐EPA) supplementation and high oleic acid sunflower oil (HOSO; placebo) on depression levels (primary outcome) and other symptoms (anxiety, fear of cancer recurrence, fatigue, insomnia, perceived cognitive impairments; secondary outcomes). Participants, recruited in a prostate cancer clinic, were randomized to MAG‐EPA (3.75 g daily; n = 65) or HOSO (3.75 g daily; n = 65) for 1 year post‐radical prostatectomy (RP), starting 4–10 weeks before surgery. Patients completed self‐report scales at baseline (before RP) and 3, 6, 9, and 12 months after: Hospital Anxiety and Depression Scale (HADS), Fear of Cancer Recurrence Inventory (FCRI), Insomnia Severity Index (ISI), Fatigue Symptom Inventory (FSI), and Functional Assessment of Cancer Therapy—Cognitive Function (FACT‐Cog). Results Analyses showed significant reductions in HADS‐depression, HADS‐anxiety, FCRI, ISI, FSI‐number of days, and FACT‐Cog‐impact scores over time. A significant group‐by‐time interaction was obtained on FACT‐Cog‐Impact scores only; yet, the temporal change was significant in HOSO patients only. Conclusions Several symptoms significantly decreased over time, mainly within the first months of the study. However, MAG‐EPA did not produce greater reductions than HOSO. Omega‐3 supplementation does not seem to improve psychological symptoms of men treated with RP.

Little is known about co-occurring tuberculosis (TB) and COVID-19 in low TB incidence settings. We obtained a cross-section of 333 persons in the United States co-diagnosed with TB and COVID-19 within 180 days and compared them to 4,433 persons with TB only in 2020 and 18,898 persons with TB during 2017‒2019. Across both comparison groups, a higher proportion of persons with TB–COVID-19 were Hispanic, were long-term care facility residents, and had diabetes. When adjusted for age, underlying conditions, and TB severity, COVID-19 co-infection was not statistically associated with death compared with TB infection only in 2020 (adjusted prevalence ratio 1.0 [95% CI 0.8‒1.4]). Among TB–COVID-19 patients, death was associated with a shorter interval between TB and COVID-19 diagnoses, older age, and being immunocompromised (non-HIV). TB–COVID-19 deaths in the United States appear to be concentrated in subgroups sharing characteristics known to increase risk for death from either disease alone.

Background: Girls with a mild intellectual disability generally receive less sexuality education than their non-disabled peers, while their needs for sexual knowledge are possibly greater. This study aimed to evaluate the effect and process of a new sexuality education programme (Girls' Talk+), focused on sexual health among girls with a mild intellectual disability in the Netherlands. Methods: A mixed methods approach was applied, using participant questionnaires (n = 249), logs written by trainers (n = 17) and interviews with trainers (n = 10). Descriptive statistics and linear regression models were used to analyse the quantitative data. Several coding phases were used to analyse the interviews. Results and conclusions: This study provides some indication that Girls' Talk+ has positive results on improving knowledge, attitude, and self-efficacy in relation to sexual health as well as trainer and participant satisfaction with the programme.

Abstract Background Sexual dysfunction is a common side effect of Serotonergic antidepressants (SA) treatment, and persists in some patients despite drug discontinuation, a condition termed post-SSRI sexual dysfunction (PSSD). The risk for PSSD is unknown but is thought to be rare and difficult to assess. This study aims to estimate the risk of erectile dysfunction (ED) and PSSD in males treated with SAs. Methods A 19-year retrospective cohort analysis was conducted using a computerized database of the largest HMO in Israel. ED was defined by phosphodiesterase-5 inhibitors prescriptions. 12,302 males aged 21–49 met the following criteria: non-smokers, no medical or psychiatric comorbidities or medications associated with ED, no alcohol or substance use. Logistic regression was used for estimation of ED risk in SA-treated subjects compared to non-SA-treated controls, assessed with and without the effects of age, body mass index (BMI), socioeconomic status (SES), depression and anxiety, yielding crude and adjusted odds ratios (cOR and aOR, respectively). Results SAs were associated with an increased risk for ED (cOR = 3.6, p

Objective: Transcriptional complex activity drives the development and function of pancreatic islet cells to allow for proper glucose regulation. Prior studies from our lab and others highlighted that the LIM-homeodomain transcription factor (TF), Islet-1 (Isl1), and its interacting co-regulator, Ldb1, are vital effectors of developing and adult β-cells. We further found that a member of the Single Stranded DNA-Binding Protein (SSBP) co-regulator family, SSBP3, interacts with Isl1 and Ldb1 in β-cells and primary islets (mouse and human) to impact β-cell target genes MafA and Glp1R in vitro. Members of the SSBP family stabilize TF complexes by binding directly to Ldb1 and protecting the complex from ubiquitin-mediated turnover. In this study, we hypothesized that SSBP3 has critical roles in pancreatic islet cell function in vivo, similar to the Isl1::Ldb1 complex. Methods: We first developed a novel SSBP3 LoxP allele mouse line, where Cre-mediated recombination imparts a predicted early protein termination. We bred this mouse with constitutive Cre lines (Pdx1- and Pax6-driven) to recombine SSBP3 in the developing pancreas and islet (SSBP3ΔPanc and SSBP3ΔIslet), respectively. We assessed glucose tolerance and used immunofluorescence to detect changes in islet cell abundance and markers of β-cell identity and function. Using an inducible Cre system, we also deleted SSBP3 in the adult β-cell, a model termed SSBP3Δβ-cell. We measured glucose tolerance as well as glucose-stimulated insulin secretion (GSIS), both in vivo and in isolated islets in vitro. Using islets from control and SSBP3Δβ-cell we conducted RNA-Seq and compared our results to published datasets for similar β-cell specific Ldb1 and Isl1 knockouts to identify commonly regulated target genes. Results: SSBP3ΔPanc and SSBP3ΔIslet neonates present with hyperglycemia. SSBP3ΔIslet mice are glucose intolerant by P21 and exhibit a reduction of β-cell maturity markers MafA, Pdx1, and UCN3. We observe disruptions in islet cell architecture with an increase in glucagon+ α-cells and ghrelin+ ε-cells at P10. Inducible loss of β-cell SSBP3 in SSBP3Δβ-cell causes hyperglycemia, glucose intolerance, and reduced GSIS. Transcriptomic analysis of 14-week-old SSBP3Δβ-cell islets revealed a decrease in β-cell function gene expression (Ins, MafA, Ucn3), increased stress and dedifferentiation markers (Neurogenin-3, Aldh1a3, Gastrin), and shared differentially expressed genes between SSBP3, Ldb1, and Isl1 in adult β-cells. Conclusions: SSBP3 drives proper islet identity and function, where its loss causes altered islet-cell abundance and glucose homeostasis. β-Cell SSBP3 is required for GSIS and glucose homeostasis, at least partially through shared regulation of Ldb1 and Isl1 target genes.

ABSTRACT: A vascular graft or endograft infection (VGEI) is a severe complication that can occur after vascular graft or endograft surgery and is associated with high morbidity and mortality rates. A multidisciplinary approach, consisting of a team of vascular surgeons, infectious diseases specialists, medical microbiologists, radiologists, nuclear medicine specialists, and hospital pharmacists, is needed to adequately diagnose and treat VGEI. A structured diagnostic, antibiotic, and surgical treatment algorithm helps clinical decision making and ultimately aims to improve the clinical outcome of patients with a VGEI.

Background: Men are three to four times more likely to be diagnosed with bladder cancer (BCa) than women, who often have more aggressive tumors. Intravesical bacillus Calmette-Guerin (BCG) for non–muscle-invasive bladder cancer (NMIBC) is one of the first immunotherapies, with use of immune checkpoint inhibitors for BCa immunotherapy expanding. Sex hormones, and notably androgens, might impact the outcome of these therapies. Objective: To understand immunological sex differences in BCa and investigate androgen receptor (AR) inhibition as a novel strategy to improve the response to BCa immunotherapy. Design, setting, and participants: Human NMIBC tumors were freshly collected following transurethral resection. In vivo studies used the subcutaneous MBT-2 BCa model in male and female C3H mice. The AR antagonist enzalutamide was given alone or in combination with anti–programmed cell death protein-1 (anti–PD-1) or intratumoral BCG + poly(I:C) treatments. Outcome measurements and statistical analysis: Tumor growth and survival were evaluated in vivo. Flow cytometry and RNA sequencing characterized the immune cells present in murine and human tumors. Descriptive comparisons were performed for MBT-2 tumors between sexes and with human NMIBC tumors. Results and limitations: The MBT-2 model shows multiple similarities to the immune composition of human NMIBC tumors and recapitulates previously observed human tumor immune cell sex differences. Enzalutamide in combination with either anti–PD-1 or BCG + poly(I:C) treatment in male mice synergized to improve response rates. Notably, the proportion of complete responses in male mice treated with the combination treatment resembles that observed in female mice with either immunotherapy alone. Limitations include the sample size for murine experiments. Conclusions: Our results suggest that combining AR antagonism with immunotherapy in male BCa patients may potentiate the antitumor immune response and increase response rates. The MBT-2 model appears relevant to investigate immunological BCa sex differences. Patient summary: Our studies suggest that combining antiandrogen treatments with BCa immunotherapy may improve response rates in men. We also demonstrate the utility of the MBT-2 mouse model to study sex differences in BCa.

Summary: MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/− mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.

Oil-type transformers (OTT) are used more than dry-type transformers, based on cost in the transmission and distribution of electrical energy. Therefore, this usage density increases the importance of cost in OTT. Weight is important in transformer cost. The weight of the transformers depends on the variable parameters of the weights of the core and windings, C (iron cross section conformity factor) and s (current density), respectively. In this study, unlike the previous heuristic optimization studies, an innovative and complementary optimum weight was obtained by using the Gray Wolf - Whale Optimization hybrid algorithm for both distribution type and power transformer type OTT. A weight reduction of 44% and approximately 14% in power transformers was achieved. It was determined that this decrease in weights provided the same reduction in OTT costs. The comparison test of the study was performed both with the values of other algorithms and statistically.

IntroductionProstate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.MethodsInfiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.ResultsPositive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.ConclusionA higher level of infiltration of CD209+ immature DC and CD163+ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes.