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Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

As an important biological element, nitrogen is causally linked with organic matter accumulation, but a systematic and regular understanding has not been developed. This paper discusses this issue by taking the widely developed Permian-Paleogene terrestrial (lacustrine) hydrocarbon source rocks in China as an example. The results show that the terrestrial source rocks in China can be classified into three groups according to the nitrogen isotope (δ15N) compositions and combined with the salinity and evaporative alkali mineral characteristics: the circum-neutral group 1 (average δ15N=4.0‰±1.5‰), the circum-neutral group 2 (average δ15N=7.1‰±1.6‰), and the alkaline group (average δ15N=18.4‰±3.3‰). In the circum-neutral group with δ15N < 10‰, the δ15N of the source rocks is positively correlated with organic matter abundance, type, hydrocarbon generating capacity and shale oil potential due to the fact that higher δ15N characterizes changes in the composition of the hydrocarbon generating bio-precursors. In the alkaline group with δ15N>10‰, the organic matter types are good and shale oil potentials are higher, but the response relationship between δ15N of source rocks and organic matter accumulation is not as good as that of the circum-neutral group, reflecting that the organic matter accumulation in alkaline group is influenced by other comprehensive factors other than δ15N. Accordingly, the organic matter accumulation models of three types of lacustrine source rocks (< 5‰, 5‰-10‰, and >10‰) classified on the basis of δ15N were established. The δ15N has the potential to trace organic matter accumulation and quality of source rocks. For example, low δ15N type (δ15N < 5‰) is of poor quality and medium-high δ15N type (δ15N>5‰) is of good qualityin lacustrine source rocks. This paper enriches the biogeochemical and hydrocarbon source rock geochemical studies of nitrogen by exploring organic matter accumulation in source rocks from the new perspective of nitrogen isotope composition and nitrogen cycling.

Introduction: Genetic factors impact alcohol consumption and use disorder (AUD), with large-scale genome-wide association studies (GWAS) identifying numerous associated variants. Aggregate genetic methods in combination with important environmental factors (e.g., interpersonal trauma [IPT]) can be applied to expand our understanding of the ways by which genetic and environmental variables work together to influence alcohol consumption and disordered use. The present study aimed to detail the relationships between genome-wide polygenic scores (PGS) for alcohol phenotypes (i.e., alcohol consumption and AUD status) and IPT exposure as well as the interaction between them across ancestry.Methods: Data were drawn from the Spit for Science (S4S) study, a US college student population, where participants reported on IPT exposure prior to college and alcohol consumption and problems during college (N = 9,006; ancestry: 21.3% African [AFR], 12.5% Admixed Americas [AMR], 9.6% East Asian [EAS], 48.1% European [EUR], 8.6% South Asian [SAS]). Two trans-ancestry PGS were constructed, one for alcohol consumption and another for AUD, using large-scale GWAS summary statistics from multiple ancestries weighted using PRS-CSx. Regression models were applied to test for the presence of associations between alcohol-PGS and IPT main and interaction effects.Results: In the meta-analysis across ancestry groups, IPT exposure and PGS were significantly associated with alcohol consumption (βIPT = 0.31, PIPT = 0.0002; βPGS = 0.09, PPGS = 0.004) and AUD (ORIPT = 1.12, PIPT = 3.5 × 10−8; ORPGS = 1.02, PPGS = 0.002). No statistically significant interactions were detected between IPT and sex nor between IPT and PGS. When inspecting ancestry specific results, the alcohol consumption-PGS and AUD-PGS were only statistically significant in the EUR ancestry group (βPGS = 0.09, PPGS = 0.04; ORPGS = 1.02, PPGS = 0.022, respectively).Discussion: IPT exposure prior to college was strongly associated with alcohol outcomes in this college-age sample, which could be used as a preventative measure to identify students at high risk for problematic alcohol use. Additionally, results add to developing evidence of polygenic score association in meta-analyzed samples, highlighting the importance of continued efforts to increase ancestral representation in genetic studies and inclusive analytic approaches to increase the generalizability of results from genetic association studies.

Abstract Background Segmentation of the Gross Tumor Volume (GTV) is a crucial step in the brachytherapy (BT) treatment planning workflow. Currently, radiation oncologists segment the GTV manually, which is time-consuming. The time pressure is particularly critical for BT because during the segmentation process the patient waits immobilized in bed with the applicator in place. Automatic segmentation algorithms can potentially reduce both the clinical workload and the patient burden. Although deep learning based automatic segmentation algorithms have been extensively developed for organs at risk, automatic segmentation of the targets is less common. The aim of this study was to automatically segment the cervical cancer GTV on BT MRI images using a state-of-the-art automatic segmentation framework and assess its performance. Methods A cohort of 195 cervical cancer patients treated between August 2012 and December 2021 was retrospectively collected. A total of 524 separate BT fractions were included and the axial T2-weighted (T2w) MRI sequence was used for this project. The 3D nnU-Net was used as the automatic segmentation framework. The automatic segmentations were compared with the manual segmentations used for clinical practice with Sørensen–Dice coefficient (Dice), 95th Hausdorff distance (95th HD) and mean surface distance (MSD). The dosimetric impact was defined as the difference in D98 (ΔD98) and D90 (ΔD90) between the manual segmentations and the automatic segmentations, evaluated using the clinical dose distribution. The performance of the network was also compared separately depending on FIGO stage and on GTV volume. Results The network achieved a median Dice of 0.73 (interquartile range (IQR) = 0.50–0.80), median 95th HD of 6.8 mm (IQR = 4.2–12.5 mm) and median MSD of 1.4 mm (IQR = 0.90–2.8 mm). The median ΔD90 and ΔD98 were 0.18 Gy (IQR = -1.38–1.19 Gy) and 0.20 Gy (IQR =-1.10–0.95 Gy) respectively. No significant differences in geometric or dosimetric performance were observed between tumors with different FIGO stages, however significantly improved Dice and dosimetric performance was found for larger tumors. Conclusions The nnU-Net framework achieved state-of-the-art performance in the segmentation of the cervical cancer GTV on BT MRI images. Reasonable median performance was achieved geometrically and dosimetrically but with high variability among patients.

In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients’ burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition.Clinical trial registrationhttps://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205.

We previously identified Keratinocyte-associated protein 3, Krtcap3, as a novel adiposity gene, but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between Krtcap3, adiposity, and stress, we exposed wild-type (WT) and Krtcap3 knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited metabolic and behavioral responses to chronic stress exposure. Specifically, stress-exposed KO rats gained more weight, consumed more food when socially isolated, and displayed more anxiety-like behaviors relative to control KO rats. Meanwhile, there were minimal differences between control and stressed WT rats. At study conclusion stress-exposed KO rats had increased corticosterone (CORT) relative to control KO rats with no differences between WT rats. In addition, KO rats, independent of prior stress exposure, had an increased CORT response to removal of their cage-mate (psychosocial stress), which was only seen in WT rats when exposed to chronic stress. Finally, we found differences in expression of the glucocorticoid receptor, Nr3c1, in the pituitary and colon between control and stress-exposed KO rats that were not present in WT rats. These data support that Krtcap3 expression affects stress response, potentially via interactions with Nr3c1, with downstream effects on adiposity and behavior. Future work is necessary to more thoroughly understand the role of Krtcap3 in the stress response.

Introducción: El aumento en la producción de sustancias para mejorar la calidad de vida, la biodiversidad de los diferentes ecosistemas en México, así como las características propias de los pacientes pediátricos, contribuyen a la intoxicación dentro de esta población. Método: Estudio retrospectivo analítico de los ingresos por envenenamiento en niños menores de 16 años en urgencias pediátricas (2016 a 2020). Se analizaron la edad, el sexo, el tipo de xenobiótico, las características de exposición y la estación del año. Se obtuvieron frecuencias, porcentajes, rango, promedio y desviación estándar. En el análisis bivariado se utilizó la prueba chi al cuadrado, considerando estadísticamente significativo un valor p < 0.05. Resultados: En el periodo de 5 años se atendieron 459 casos, con una prevalencia del 3.16%. No se observó predominio de sexo. La intoxicación más frecuente fue por animales venenosos (28.5%), seguida de la ingesta de medicamentos (27.6%). El 95% de los casos fueron accidentales y el 5% por intento de suicidio. En los menores de 5 años, lo más frecuente fue la ingesta de medicamentos, hidrocarburos o productos de uso doméstico (p = 0.03, p = 0.0001), mientras que en los mayores de 6 años fue por contacto con animales venenosos e ingesta de drogas estimulantes (alcohol, anfetaminas, cannabis, cocaína) (p = 0.0001, p = 0.006). El 100% de los intoxicados por herbicida cuaternario de amonio fallecieron. Conclusiones: Los menores de 5 años son más propensos a la intoxicación con productos que se utilizan en sus propios domicilios. En los mayores de 6 años es más frecuente la combinación de drogas estimulantes.

Vaginal infections are a public health problem associated with serious health complications due to the exacerbated inflammation they generate. Vaginal inflammation may also occur in some noninfectious processes, such as noninfectious vaginitis and cytolytic vaginosis. Immune system cells respond to infections through various mechanisms, such as the formation of extracellular traps (ETs), which are DNA networks associated with effector proteins. Many pathogens induce ETs formation in vitro, as occurs in some natural infections. A recent report indicates that human vaginal infections in vivo generate ETs. Therefore, in this study, we aimed to identify ETs in samples from 40 donors who were diagnosed with infectious (i.e., bacterial vaginosis, candidiasis and trichomoniasis) and noninfectious (i.e., noninfectious vaginitis and cytolytic vaginosis) vaginal inflammation. We were able to observe ETs by identifying the LL-37 peptide, which is associated with DNA networks. In seven vaginal swabs from the control group (formed by 19 donors without vaginal infection symptoms), we detected at least one pathogen per sample and observed ETs; thus, these donors were considered asymptomatic. The remaining 12 donors were confirmed to be healthy, as their exudates did not present any tested pathogens, sign of inflammation or ETs. ETs in vaginal inflammatory processes can worsen inflammation but may also help control infection.

Genetically diverse inbred strains are frequently used in quantitative trait mapping to identify sequence variants underlying trait variation. Poor locus resolution and high genetic complexity impede variant discovery. As a solution, we explore reduced complexity crosses (RCCs) between phenotypically divergent, yet genetically similar, rodent substrains. RCCs accelerate functional variant discovery via decreasing the number of segregating variants by orders of magnitude. The simplified genetic architecture of RCCs often permit immediate identification of causal variants or rapid fine-mapping of broad loci to smaller intervals. Whole-genome sequences of substrains make RCCs possible by supporting the development of array- and targeted sequencing-based genotyping platforms, coupled with rapid genome editing for variant validation. In summary, RCCs enhance discovery-based genetics of complex traits.

Based on geochemical and paleontological data, this study shows that habitable open-oceans extended to mid-latitude coastal oceans during the waning stage of the Marinoan snowball Earth, offering refugia for benthic photosynthetic eukaryotes

Background: Accurate identification of men who harbor nodal metastases is necessary to select patients who most likely benefit from whole pelvis radiotherapy (WPRT). Limited sensitivity of diagnostic imaging approaches for the detection of nodal micrometastases has led to the exploration of the sentinel lymph node biopsy (SLNB). Objective: To evaluate whether SLNB can be used as a tool to select pathologically node-positive patients who likely benefit from WPRT. Design, setting, and participants: We included 528 clinically node-negative primary prostate cancer (PCa) patients with an estimated nodal risk of >5% treated between 2007 and 2018. Intervention: A total of 267 patients were directly treated with prostate-only radiotherapy (PORT; non-SLNB group), while 261 patients underwent SLNB to remove lymph nodes directly draining from the primary tumor prior to radiotherapy (SLNB group); pN0 patients were treated with PORT, while pN1 patients were offered WPRT. Outcome measurements and statistical analysis: Biochemical recurrence–free survival (BCRFS) and radiological recurrence-free survival (RRFS) were compared using propensity score weighted (PSW) Cox proportional hazard models. Results and limitations: The median follow-up was 71 mo. Occult nodal metastases were found in 97 (37%) SLNB patients (median metastasis size: 2 mm). Adjusted 7-yr BCRFS rates were 81% (95% confidence interval [CI] 77–86%) in the SLNB group and 49% (95% CI 43–56%) in the non-SLNB group. The corresponding adjusted 7-yr RRFS rates were 83% (95% CI 78–87%) and 52% (95% CI 46–59%), respectively. In the PSW multivariable Cox regression analysis, SLNB was associated with improved BCRFS (hazard ratio [HR] 0.38, 95% CI 0.25–0.59, p < 0.001) and RRFS (HR 0.44, 95% CI 0.28–0.69, p < 0.001). Limitations include the bias inherent to the study’s retrospective nature. Conclusions: SLNB-based selection of pN1 PCa patients for WPRT was associated with significantly improved BCRFS and RRFS compared with (conventional) imaging-based PORT. Patient summary: Sentinel node biopsy can be used to select patients who will benefit from the addition of pelvis radiotherapy. This strategy results in a longer duration of prostate-specific antigen control and a lower risk of radiological recurrence.

Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm–trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a cis DNAm–GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm–trait associations generated by EWAS.

On September 7th, 2021, the project “Lives in Chemistry” (LiC) became visible through the virtual global launch event l-i-c.org/launch.html.

Background and purpose: Existing methods for quality assurance of the radiotherapy auto-segmentations focus on the correlation between the average model entropy and the Dice Similarity Coefficient (DSC) only. We identified a metric directly derived from the output of the network and correlated it with clinically relevant metrics for contour accuracy. Materials and Methods: Magnetic Resonance Imaging auto-segmentations were available for the gross tumor volume for cervical cancer brachytherapy (106 segmentations) and for the clinical target volume for rectal cancer external-beam radiotherapy (77 segmentations). The nnU-Net’s output before binarization was taken as a score map. We defined a metric as the mean of the voxels in the score map above a threshold (λ). Comparisons were made with the mean and standard deviation over the score map and with the mean over the entropy map. The DSC, the 95th Hausdorff distance, the mean surface distance (MSD) and the surface DSC were computed for segmentation quality. Correlations between the studied metrics and model quality were assessed with the Pearson correlation coefficient (r). The area under the curve (AUC) was determined for detecting segmentations that require reviewing. Results: For both tasks, our metric (λ = 0.30) correlated more strongly with the segmentation quality than the mean over the entropy map (for surface DSC, r > 0.65 vs. r

The Archean Eon was a time of predominantly anoxic Earth surface conditions, where anaerobic processes controlled bioessential element cycles. In contrast to "oxygen oases" well documented for the Neoarchean [2.8 to 2.5 billion years ago (Ga)], the magnitude, spatial extent, and underlying causes of possible Mesoarchean (3.2 to 2.8 Ga) surface-ocean oxygenation remain controversial. Here, we report δ15N and δ13C values coupled with local seawater redox data for Mesoarchean shales of the Mozaan Group (Pongola Supergroup, South Africa) that were deposited during an episode of enhanced Mn (oxyhydr)oxide precipitation between ∼2.95 and 2.85 Ga. Iron and Mn redox systematics are consistent with an oxygen oasis in the Mesoarchean anoxic ocean, but δ15N data indicate a Mo-based diazotrophic biosphere with no compelling evidence for a significant aerobic nitrogen cycle. We propose that in contrast to the Neoarchean, dissolved O2 levels were either too low or too limited in extent to develop a large and stable nitrate reservoir in the Mesoarchean ocean. Since biological N2 fixation was evidently active in this environment, the growth and proliferation of O2-producing organisms were likely suppressed by nutrients other than nitrogen (e.g., phosphorus), which would have limited the expansion of oxygenated conditions during the Mesoarchean.