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Abstract Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present. We then tested the hypothesis that individuals with ASD harbor a microbiota that might differentially influence GI health by performing microbiota transplantation studies into male germfree animals, followed by induction of colitis. Animals that harbor a microbiota from ASD individuals have worsened gut phenotypes when compared to animals colonized with microbiotas from familial neurotypical (NT) controls. We identify the enrichment of Blautia species in all familial NT controls and observe an association between elevated abundance of Bacteroides uniformis and reductions in intestinal injury. Oral treatment with either of these microbes reduces colon injury in mice. Finally, provision of a Blautia isolate from a NT control ameliorates gut injury-associated active social engagement in mice. Collectively, our data demonstrate that past intestinal distress is associated with changes in active social behavior in mice that can be ameliorated by supplementation of members of the human microbiota.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Abstract Climate change causes extreme conditions like prolonged drought, which results in yield reductions due to its effects on nutrient balances such as nitrogen uptake and utilization by plants. Nitrogen (N) is a crucial nutrient element for plant growth and productivity. Understanding the mechanistic basis of nitrogen use efficiency (NUE) under drought conditions is essential to improve wheat (Triticum aestivum L.) yield. Here, we evaluated the genetic variation of NUE‐related traits and photosynthesis response in a diversity panel of 200 wheat genotypes under drought and nitrogen stress conditions to uncover the inherent genetic variation and identify quantitative trait loci (QTLs) underlying these traits. The results revealed significant genetic variations among the genotypes in response to drought stress and nitrogen deprivation. Drought impacted plant performance more than N deprivation due to its effect on water and nutrient uptake. GWAS identified a total of 27 QTLs with a significant main effect on the drought‐related traits, while 10 QTLs were strongly associated with the NUE traits. Haplotype analysis revealed two different haplotype blocks within the associated region on chromosomes 1B and 5A. The two haplotypes showed contrasting effects on N uptake and use efficiency traits. The in silico and transcript analyses implicated candidate gene coding for cold shock protein. This gene was the most highly expressed gene under several stress conditions, including drought stress. Upon validation, these QTLs on 1B and 5A could be used as a diagnostic marker for NUE and drought tolerance screening in wheat.

Iron deficiency is the number one nutritional problem worldwide. Iron uptake is regulated at the intestine and is highly influenced by the gut microbiome. Blood from the intestines drains directly into the liver, informing iron status and gut microbiota status. Changes in either iron or the microbiome are tightly correlated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD). To investigate the underlying mechanisms of the development of MASLD that connect altered iron metabolism and gut microbiota, we compared specific pathogen free (SPF) or germ-free (GF) mice, fed a normal or low-iron diet. SPF mice on a low-iron diet showed reduced serum triglycerides and MASLD. In contrast, GF low-iron diet-fed mice showed increased serum triglycerides and did not develop hepatic steatosis. SPF mice showed significant changes in liver lipid metabolism and increased insulin resistance that was dependent upon the presence of the gut microbiota. We report that total body loss of mitochondrial iron importer Mitoferrin2 (Mfrn2−/−) exacerbated the development of MASLD on a low-iron diet with significant lipid metabolism alterations. Our study demonstrates a clear contribution of the gut microbiome, dietary iron, and Mfrn2 in the development of MASLD and metabolic syndrome.

Polarization transfer to a bound proton in polarized electron knock-out reactions, A(e→,e′p→), is a powerful tool to look for an in-medium modification of the bound proton. It requires comparison to calculations that consider the many-body effects accompanying the quasi-free process. We report here measured components Px′, Pz′, and their ratio Px′/Pz′, of polarization transfer to protons bound in Ca40, which is described well by the shell model and for which reliable calculations are available. While the calculations capture the essence of the data, our statistical precision allows us to observe deviations that cannot be explained by simple scaling, including by varying the proton electromagnetic form factor ratio GE/GM. We further explore the deviations of the ratio of the polarization transfer components from that of a free proton, (Px′/Pz′)A/(Px′/Pz′)H, and its dependence on the bound-proton virtuality.

The microbiota influences obesity, yet organisms that protect from disease remain unknown. During studies interrogating host-microbiota interactions, we observed the development of age-associated metabolic syndrome (MetS). Expansion of Desulfovibrio and loss of Clostridia were key features associated with obesity in this model and are present in humans with MetS. T cell-dependent events were required to prevent disease, and replacement of Clostridia rescued obesity. Inappropriate immunoglobulin A targeting of Clostridia and increased Desulfovibrio antagonized the colonization of beneficial Clostridia. Transcriptional and metabolic analysis revealed enhanced lipid absorption in the obese host. Colonization of germ-free mice with Clostridia, but not Desulfovibrio, down-regulated genes that control lipid absorption and reduced adiposity. Thus, immune control of the microbiota maintains beneficial microbial populations that constrain lipid metabolism to prevent MetS.

Background: Providing medical and dental care for adults with developmental disabilities requires specialised care that includes caregiver's perceptions of processes of care as integral to informing care delivery. Method: We examined the reach and efficacy of a medical-dental clinic serving adults with developmental disabilities as part of a program evaluation in the community setting. Using the RE-AIM framework, we analysed caregivers' perceptions of the processes of care and associations with sociodemographic factors and stress and depression levels. Results: Perceptions of the processes of care were correlated with caregiver stress levels. Low satisfaction with receipt of general and specific information suggests that care coordination should be prioritised. Conclusions: The ecosystem of care needs to be targeted in addition to services directed at the individual. Shared evaluation frameworks between service deliveries modalities would allow comparison of family-centred care delivery systems.

Abstract Background Ionized calcium (iCa) is the biologically active fraction of total calcium (tCa) with clinical relevance to evaluate calcium homeostasis, but not all primary veterinarians have access to serum iCa. Formulas that adjust tCa to correct for variability in serum protein concentrations were not designed to predict iCa and are considered unreliable surrogates for iCa. Objectives To determine whether adjusted calcium concentration (aCa) can predict ionized hypocalcemia in hypoalbuminemic dogs without hyperphosphatemia. Animals A total of 262 hypoalbuminemic dogs without hyperphosphatemia. Methods Retrospective review of paired tCa and iCa. Patients were included if serum albumin concentration was ≤2.5 g/L and serum phosphorus concentration was ≤5 mg/dL. The aCa was calculated using tCa (mg/dL) − serum albumin concentration (g/dL) + 3.5 (g/dL). Sensitivity, specificity, positive (PPVs) and negative (NPVs) predictive values, and accuracy were determined for tCa and aCa at predicting any (

Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.

BackgroundThe presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample.ResultsA fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy.ConclusionsThe identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Abstract We report on the measurements of the spectra of gamma radiation generated by 855 MeV electrons in bent silicon and germanium crystals at MAMI (MAinzer MIkrotron). The crystals were 15 $$\upmu \text {m}$$ μ m thick along the beam direction to ensure high deflection efficiency. Their (111) crystalline planes were bent by means of a piezo-actuated mechanical holder, which allowed to remotely change the crystal curvature. In such a way it was possible to investigate the radiation emitted under planar channeling and volume reflection as a function of the curvature of the crystalline planes. We showed that, using volume reflection, intense gamma radiation can be produced – with intensity comparable to that obtained in channeling but with higher angular acceptance. We studied the trade-off between radiation intensity and angular acceptance at different values of the crystal curvature. The measurements of radiation spectra have been carried out for the first time in bent germanium crystals. In particular, the intensity of radiation in the germanium crystal is higher than in the silicon one due to the higher atomic number, which is important for the development of the X-ray and gamma radiation sources based on higher-Z deformed crystals, such as crystalline undulators.

Background/Aims The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their entire life, and the quality of life (QUOL) interacts with disease activity, improving QUOL should be one of the main goals of therapy. This study aims to identify factors contributing to good or impaired QUOL. Methods Questionnaires addressing health-related QUOL and other psychological and social features were positioned on our institutions’ webpage and on the webpage of the largest self-help group for IBD in Germany. Patients were subdivided according to their QUOL score with a cutoff of

Abstract Background Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. Methods We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). Results We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. Conclusions Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.

Abstract We observed reduction of multiple Coulomb scattering of 855 MeV electrons within a Si crystalline plate w.r.t. an amorphous plate with the same mass thickness. The reduction owed to complete or partial suppression of the coherent part of multiple scattering in a crystal vs crystal orientation with the beam. Experimental data were collected at Mainz Mikrotron and critically compared to theoretical predictions and Monte Carlo simulations. Our results highlighted maximal 7% reduction of the r.m.s. scattering angle at certain beam alignment with the [100] crystal axes. However, partial reduction was recorded over a wide range of alignment of the electron beam with the crystal up to 15$$^{\circ }$$ ∘ . This evidence may be relevant to refine the modelling of multiple scattering in crystals for currently used software, which is interesting for detectors in nuclear, medical, high energy physics.

ObjectivesThe primary objective of this study was to report the prevalence and magnitude of elevated liver enzyme activity in feline hyperthyroidism using a large cohort of cats presenting for iodine-131 treatment. The secondary objective was to determine if elevated liver enzyme activity was a reversible process following successful iodine-131 treatment.MethodsCases that presented for a single iodine-131 treatment were retrospectively reviewed. Short-term and long-term follow-up clinicopathologic data was then reviewed for the secondary objective.ResultsTwo hundred seventeen hyperthyroid cats met the inclusion criteria for the primary objective. In total, 123/217 (56.7%) of the cats had at least one liver enzyme elevation on their chemistry panel, with alanine transaminase activity being the most common. All cats who were successfully treated with iodine-131 had liver enzyme activity within the reference range at short-term follow-up and long-term follow-up points.Conclusion and RelevanceOur study demonstrates that elevated liver values are common in cats presenting for iodine-131 treatment. Additionally, our study demonstrates that even when liver values are markedly elevated prior to treatment, the liver enzyme activity will return to normal after successful resolution of hyperthyroidism using iodine-131 treatment. Investigation into hepatobiliary disease and liver function tests for cats with a diagnosis of hyperthyroidism may be unnecessary as the liver values will likely return to normal with successful iodine-131 treatment.

We present measurements of the electron helicity asymmetry in quasi-elastic proton knockout from 2H and 12C nuclei by polarized electrons. This asymmetry depends on the fifth structure function, is antisymmetric with respect to the scattering plane, and vanishes in the absence of final-state interactions, and thus it provides a sensitive tool for their study. Our kinematics cover the full range in off-coplanarity angle ϕpq, with a polar angle θpq coverage up to about 8°. The missing energy resolution enabled us to determine the asymmetries for knock-out resulting in different states of the residual 11B system. We find that the helicity asymmetry for p-shell knockout from 12C depends on the final state of the residual system and is relatively large (up to ≈0.16), especially at low missing momentum. It is considerably smaller (up to ≈0.01) for s-shell knockout from both 12C and 2H. The data for 2H are in very good agreement with theoretical calculations, while the predictions for 12C exhibit differences with respect to the data.

Compared to conventional photovoltaic (PV), there are more influencing factors in bifacial photovoltaics to be considered to calculate incoming irradiance and energy yield. Accurate models to investigate the influences of the elevation, the albedo of the ground, the shading conditions between the PV rows and many other rear-side related factors are required. This paper combines the ray tracing (RT) and view factor (VF) models to calculate the irradiance with a subsequent electrical yield calculation using the one-diode model. To verify the results of the developed open-source simulation program BifacialSimu, accurate data from a plant in Golden, USA (single-axis tracked) and a commercially operated plant in Germany (fixed-tilt) are used. Through comparisons to the actual data, it can be concluded that a combination of RT and VF models seems to be valid for longer simulation periods with several months since the relative errors balance out. The RT-only simulation accurately reproduces the precise hourly radiation and electrical yield pattern. Still, a continuous positive deviation was found, which does not even out over long periods and is thus less accurate than the VF/RT combination. A simulation for a single month with RT can take several hours. Thus, the best simulation mode results according to user requirements.

The subject of the article is the satirical portrayal of Joyce scholarship in Evelyn Conlon’s short story “Two Gallants”, offered for the tribute volume of Dubliners 100, a writerly joint venture edited by Thomas Morris in 2014. The analysis acknowledges the intertextual richness of Conlon’s creation, as she engages not only with the master text, but with other writers’ responses to Joyce’s work. Questions related to repetition, referencing and repurposing of the words of others prove central to the story’s plot, in which a female scholar has to guard her research against an ungallant tandem of plagiarist colleagues. The motif of feminist revenge looms large in the narrative which ties the fate of a cheated servant maid with that of her modern granddaughter, lashing out against unfair academic practice.

Summary: In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shifted – platelets are now seen as alert “sentinels” of the immune compartment, rather than passive bystanders. Herein, we review well-established and newly discovered features of platelets that define their natural role in maintaining blood haemostasis, but also their functional relationship with other cells of the immune system. We focus on recent studies underlining functional involvement of platelets in chronic liver diseases and cancer, as well as the effects of anti-platelet therapy in these contexts. Finally, we illustrate the potential of platelets as possible diagnostic and therapeutic tools in liver disease based on recently developed methodologies. Keywords: Platelets, cirrhosis, HCC, cancer, immune system, immunology, NASH, NAFLD

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.