Miracle-dz/UniFAR-FTUs huggingface dataset:
Vitamin D receptor absence does not enhance intestinal tumorigenesis in ApcPirc/+rats

ABSTRACT Epidemiological observations have prompted some to posit that elevated circulating vitamin D is responsible for reduced colon cancer in individuals residing near the equator. We have previously demonstrated that vitamin D has no effect on colon cancer in two rodent models of intestinal tumorigenesis. We have now extended this line of inquiry to ask whether ablation of vitamin D receptor (VDR) affects tumorigenesis. A VDR null rat was developed using Cas9-CRISPR technology, which allowed us to investigate whether 1,25(OH)D3 signaling through its receptor plays a role in intestinal tumorigenesis. Loss of VDR expression alone did not induce tumorigenesis, even in animals exposed to the inflammatory agent dextran sodium sulfate. These VDR−/− rats were then crossed with ApcPirc/+ rats, which are predisposed to the development of intestinal neoplasms. In combination with the Pirc/+ mutation, VDR loss did not enhance tumor multiplicity, growth, or progression in the colon or small intestine. This study demonstrates that the vitamin D receptor does not impact tumor development, and strongly supports previous findings that vitamin D itself does not play a role in colon cancer development or progression. Alternative explanations are needed for the original latitude hypothesis, as well as observational data in humans. This article has an associated First Person interview with the first author of the paper.
PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.

BACKGROUND Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. METHODS We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
Insights into the genetic basis of predator-induced response in Daphnia - a comparative transcriptomic approach

Phenotypic plastic responses allow organisms to rapidly adjust to environmental challenges. Although phenotypic plastic responses to predation risk have been reported for the ecological and genomic model organism Daphnia, their genetic basis is not well understood. Here, we characterized the transcriptional profile of Daphnia galeata when exposed to fish kairomones. First, we investigated the differential gene expression, identifying candidate transcripts being involved in shifts of life history traits. A total of 125 differentially expressed transcripts (40 up- and 85 downregulated) were identified. Second, we applied a gene coexpression network analysis to find clusters of tightly linked transcripts and reveal the genetic pathways underlying predator-induced responses. Our results showed that transcripts involved in remodeling of the cuticle, growth and digestion correlated with life history shifts in D. galeata . Furthermore, we compared our results with previous studies on other Daphnia species. This was achieved using an orthology approach on D. magna predator-induced response on the one hand, and reproduction associated genes in D. pulex on the other hand. The unique combination of methods including the comparative approach allowed for the identification of candidate transcripts, their functions and orthologs associated with predator-induced responses in Daphnia .
Impact of methionine restriction on muscle aerobic metabolism and hypertrophy in young and old mice on an obesogenic diet

Abstract Methionine restriction (MR) reduces inflammation and increases longevity. We studied the effects of MR (0.17% kCal methionine, 10% kCal fat) and MR + high-fat diet (HFD) (0.17% methionine, 45% kCal fat) and overload-induced hypertrophy on inflammation, angiogenesis and mitochondrial activity in the hind-limb muscle in 10- and 26-month-old male C57BL/6J mice. Plasma IL-6 concentrations were higher in old compared to young mice. M. plantaris hypertrophy was accompanied by increased p-Akt, without a significant change in Akt and VEGF levels. In young mice on a HFD or MR + HFD diet the SDH activity was higher than in those from mice on other diets, irrespective of overload. There were no significant differences in total NAD concentration in the m. gastrocnemius. MR enhanced the skeletal muscle hypertrophic response in old age that was accompanied with an increase in p-Akt without significant changes in muscle oxidative capacity, low-grade systemic inflammation, NAD, VEGF or Akt levels.
Teclistamab in Relapsed or Refractory Multiple Myeloma.

BACKGROUND Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS Among 165 patients who received teclistamab, 77.8% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).
Limosilactobacillus reuteri SLZX19-12 Protects the Colon from Infection by Enhancing Stability of the Gut Microbiota and Barrier Integrity and Reducing Inflammation

The use of antibiotics to treat bacterial infections leads to a series of side effects. As an alternative method, the biocontrol strategy, which uses probiotics to suppress pathogens, is considered a potential way to deal with bacterial infections in gut. ABSTRACT Limosilactobacillus reuteri plays an important role in regulating intestinal functions and maintaining barrier integrity in animals. In this study, Limosilactobacillus reuteri strain SLZX19-12 was isolated from the fecal microbiota of Tibetan pigs, and it was found that this strain is sensitive to common antibiotics and has strong resistance to stress. Upon being administered by gavage at different doses, including low, medium, and high doses, for 14 days, Limosilactobacillus reuteri SLZX19-12 may enhance the intestinal barrier. After administration of a high dose of SLZX19-12, mice were challenged with Salmonella enterica serovar Typhimurium SL1344. Infection with Salmonella Typhimurium SL1344 led to disordered colonic microbiotas, colonic inflammation through the S100A8/S100A9–NF-κB pathway and potential apoptosis, and translocation of pathogens to parenteral visceral organs in mice. However, the mice pretreated with Limosilactobacillus reuteri SLZX19-12 showed lower loads of Salmonella in visceral organs, less colonic inflammation, and higher barrier integrity. More importantly, the administration of strain SLZX19-12 resulted in a more stable microbiota structure of the colon, in which the abundance of Alloprevotella was greatly enhanced. Therefore, this study suggests that Limosilactobacillus reuteri SLZX19-12 can protect the colon from infection by enhancing the stability of gut microbiota and barrier integrity and reducing inflammation. IMPORTANCE The use of antibiotics to treat bacterial infections leads to a series of side effects. As an alternative method, the biocontrol strategy, which uses probiotics to suppress pathogens, is considered a potential way to deal with bacterial infections in gut. However, there are few probiotics that are currently safe and can protect against infection. In this study, Limosilactobacillus reuteri strain SLZX19-12 was obtained from Tibetan pigs, which have higher resistance to infection. This strain is sensitive to conventional antibiotics, secretes a wide spectrum of enzymes, and also promotes the intestinal barrier function in mice. In addition, Limosilactobacillus reuteri SLZX19-12 can promote the stability of the gut microbiota to avoid or alleviate the occurrence or development of foodborne infections.
Neural Correlates of Variation in Personal Space and Social Functioning in Schizophrenia and Healthy Individuals

Abstract Background Changes in the regulation of interpersonal distance, or “personal space” (PS), have been repeatedly observed in schizophrenia and, in some studies, linked to negative symptoms. However, the neurobiological basis of these impairments is poorly understood. Methods Personal space measurements, functional connectivity of a brain network sensitive to intrusions into PS, and symptoms of social withdrawal and anhedonia were assessed, and associations among these outcomes measured, in 33 individuals with a psychotic disorder (primarily schizophrenia [SCZ]) and 36 control subjects (CON). Results Personal space size was significantly higher (P = .002) and PS permeability (reflecting the capacity to tolerate intrusions into PS) was significantly lower (P = .021) in the SCZ relative to the CON group, and both measures were significantly correlated with social anhedonia and withdrawal in the full sample (all P < .007). Moreover, functional connectivity between the PS and default mode (DM) networks was significantly correlated with the permeability, but not the size, of PS in the full sample and in the SCZ and CON groups separately, and with social withdrawal in the SCZ group. Lastly, the association between PS-DM network connectivity and social withdrawal in the SCZ group was fully mediated by PS permeability. Discussion Neural and behavioral aspects of PS regulation are linked to social motivation in both healthy individuals and those with psychotic disorders, suggesting that measurements of PS could serve as transdiagnostic markers of social functioning.
On a conjecture of Beltrametti and Sommese

Let X be a projective manifold of dimension n. Beltrametti and Sommese conjectured that if A is an ample divisor such that K_X+(n-1)A is nef, then K_X+(n-1)A has non-zero global sections. We prove a weak version of this conjecture in arbitrary dimension. In dimension three, we prove the stronger non-vanishing conjecture of Ambro, Ionescu and Kawamata and give an application to Seshadri constants.
Distinct but overlapping roles of LRRTM1 and LRRTM2 in developing and mature hippocampal circuits

LRRTMs are postsynaptic cell adhesion proteins that have region-restricted expression in the brain. To determine their role in the molecular organization of synapses in vivo, we studied synapse development and plasticity in hippocampal neuronal circuits in mice lacking both Lrrtm1 and Lrrtm2. We found that LRRTM1 and LRRTM2 regulate the density and morphological integrity of excitatory synapses on CA1 pyramidal neurons in the developing brain but are not essential for these roles in the mature circuit. Further, they are required for long-term-potentiation in the CA3-CA1 pathway and the dentate gyrus, and for enduring fear memory in both the developing and mature brain. Our data show that LRRTM1 and LRRTM2 regulate synapse development and function in a cell-type and developmental-stage-specific manner, and thereby contribute to the fine-tuning of hippocampal circuit connectivity and plasticity.
What is the clinical impact of occult HBV infections and anti‐HBc positivity in patients with chronic hepatitis C?

Occult hepatitis B infection (OBI) is defined by the persistence of the hepatitis B virus (HBV) genome in the liver of individuals testing negative for hepatitis B surface antigen (HBsAg). Hepatitis B core antibody (anti‐HBc) is the serological marker that indicates HBV exposure. The impact of anti‐HBc and OBI on patients with chronic hepatitis C remains unclear. The aim of the present study was to determine the prevalence of anti‐HBc and OBI and to evaluate their impact on the clinical and pathological outcomes of patients with chronic hepatitis C. The study included 59 HBsAg‐negative chronic hepatitis C patients who underwent a liver parenchymal biopsy. The presence of HBV DNA was investigated using an in‐house nested PCR method. OBI was detected in 16 (27.1%) of the 59 cases and also in 10 (62.5%) of 22 (37.3%) anti‐HBc‐positive patients. None of the patients had positive serum HBV DNA. OBI was associated with the presence of anti‐HBV antibodies (P < 0.05). There was also an association between anti‐HBc positivity and the activity grades and fibrosis stages of the liver and also a prevalence of liver steatosis (P < 0.05). Positive anti‐HBc results may predict OBI and may also be associated with the progression of liver injury in HBsAg‐negative patients with chronic hepatitis C. Therefore, it is suggested that patients with chronic hepatitis C should be screened for anti‐HBc positivity, and anti‐HBc‐positive patients should be carefully evaluated for disease progression.
Effects of Mass Shootings on Mental Illness Stigma in the United States

Although the vast majority of people with mental illness (PWMI) are not violent, Americans tend to think they are more dangerous than the general population. Because negative media portrayals may contribute to stigma, we used time-series analyses to examine changes in the public’s perceived dangerousness of PWMI around six mass shootings whose perpetrators were reported to have a mental illness. From 2011 to 2019, 38,094 U.S. participants completed an online study assessing implicit and explicit perceived dangerousness of PWMI. There were large, upward spikes in perceived dangerousness the week of the Sandy Hook mass shooting that were relatively short-lived. However, there was not a consistent pattern of effects for other events analyzed, and any other spikes observed were smaller. Effects tended to be larger for explicit versus implicit perceived dangerousness. Sandy Hook seemed to temporarily worsen perceived dangerousness of PWMI, but this pattern was not observed for other mass shootings.
Validity of clinical psoriatic arthritis diagnoses made by rheumatologists in the Swedish National Patient Register

Objectives : Knowledge of the correspondence between clinical ICD diagnoses and classification criteria fulfilment is crucial to interpret studies identifying cases via ICD codes. We assessed the degree to which patients registered with ICD-10 diagnoses of psoriatic arthritis (PsA) in the Swedish National Patient Register (NPR) fulfil established PsA classification criteria. Method Four hundred patients with at least one outpatient visit to one of five rheumatology or internal medicine departments (three university/two county departments across Sweden) in 2013–2015, with a main ICD-10 diagnosis of PsA (L40.5, M07.0–M07.3), were randomly selected (80 cases/site). Through a structured medical record review, positive predictive values (PPVs) for fulfilment of the following classification criteria were assessed: CASPAR, Moll and Wright, Vasey and Espinoza, and modified ESSG criteria for PsA. A subset analysis regarding CASPAR fulfilment was also performed among cases with available rheumatoid factor and peripheral X-ray status (central CASPAR items; n = 227). Results Of the 400 patients with a main ICD-10 diagnosis of PsA, 343 (86%) fulfilled at least one of the four PsA classification criteria. PPVs for the different criteria were: CASPAR 69% (82% in the subset analysis), Moll and Wright 51%, Vasey and Espinoza 76%, and modified ESSG 64%. Overall, only 6.5% of the 400 PsA diagnoses were judged as clearly incorrect by the medical record reviewers. Conclusion The validity of rheumatologist-made, clinical ICD-10 diagnoses for PsA in the Swedish NPR is good, with PPVs of 69–82% for CASPAR fulfilment and 86% for meeting any established PsA classification criteria.
The 3-Meter Backward Walk Test (3MBWT): Reliability and validity in individuals with subacute and chronic stroke

ABSTRACT Introduction Backward walking (BW) is an important gait adaptation and BW speed may be an important indicator of walking function and fall risk. However, the measurement characteristics of a standardized assessment of BW post-stroke have not been fully established. Objectives To determine intra- and interrater reliability, concurrent validity and minimal detectable change (MDC) scores for the 3-Meter Backward Walk Test (3MBWT) post-stroke. Methods Thirty-four individuals with subacute and 29 individuals with chronic stroke participated. Two trials of comfortable BW was measured over a total distance of 5-meters, while speed was calculated during the middle 3-meters of the walking distance. Intra and interrater reliability were determined by comparing the two trials from one rater and simultaneous assessment of two raters, respectively. Two additional trials were performed and BW speed was calculated using 3MBWT and an instrumented walkway to determine concurrent validity. Intraclass correlation coefficients (ICC) estimated reliability and validity. The MDC was calculated from the standard error of measurement. Results Excellent ICC values were obtained for the 3MBWT in the subacute (interrater: ICC2,1 = 0.99; intrarater: ICC2,1 = 0.96; validity: ICC2,1 = 0.96) and chronic (interrater: ICC2,1 = 0.99; intrarater: ICC2,1 = 0.94; validity: ICC2,1 = 0.97) groups. The MDC was 0.07 m/s (subacute) and 0.11 m/s (chronic). Conclusions Establishment of the 3MBWT as a reliable and valid measure in assessing BW speed is an important addition to the assessment toolbox for rehabilitation post-stroke.
Substrate speciﬁcity of human ceramide kinase

Previous studies in our laboratory have established ceramide kinase (CERK) as a critical mediator of eico-sanoid synthesis. To date, CERK has not been well charac-terized in vitro. In this study, we investigated the substrate speciﬁcity of CERK using baculovirus-expressed human CERK (6 (cid:1) His) and a newly designed assay based on mixed micelles of Triton X-100. The results indicate that the ability of CERK to recognize ceramide as a substrate is stereospeciﬁc. A minimum of a 12 carbon acyl chain was required for nor-mal CERK activity, and the 4-5 trans double bond was important for substrate recognition. A signiﬁcant discrimination by CERK was not observed between ceramides with long saturated and long unsaturated fatty acyl chains. Methylation of the primary hydroxyl group resulted in a loss of activity, conﬁrming that CERK produces ceramide-1-phosphate versus ceramide-3-phosphate. In addition, methylation of the secondary hydroxyl group drastically decreased the phosphorylation by CERK. These results also indicated that the free hydrogen of the secondary amide group is critical for substrate recognition. Lastly, the sphingoid chain was also required for substrate recognition by CERK. Together, these results indicate a very high
Neural mechanisms of intergroup exclusion and retaliatory aggression

ABSTRACT Aggression occurs frequently and severely between rival groups. Although there has been much study into the psychological and socio-ecological determinants of intergroup aggression, the neuroscience of this phenomenon remains incomplete. To examine the neural correlates of aggression directed at outgroup (versus ingroup) targets, we recruited 35 healthy young male participants who were current or former students of the same university. While undergoing functional MRI, participants completed an aggression task against both an ingroup and an outgroup opponent in which their opponents repeatedly provoked them at varying levels and then participants could retaliate. Participants were then socially included and then excluded by two outgroup members and then completed the same aggression task against the same two opponents. Both before and after outgroup exclusion, aggression toward outgroup members was positively associated with activity in the ventral striatum during decisions about how aggressive to be toward their outgroup opponent. Aggression toward outgroup members was also linked to greater post-exclusion activity in the rostral and dorsal medial prefrontal cortex during provocation from their outgroup opponent. These altered patterns of brain activity suggest that frontostriatal mechanisms may play a significant role in motivating aggression toward outgroup members.