Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection

<p>Abstract</p> <p>Background</p> <p>West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.</p> <p>Results</p> <p>Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19⁺B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4⁺and CD8⁺T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8⁺T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.</p> <p>Conclusions</p> <p>Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.</p

Embryonic Lethality in Mice Homozygous for a Targeted Disruption of the N-myc Gene

The N-myc gene encodes a putative transcription factor that is thought to function in the regulation of gene expression during cell differentiation and/or growth. To examine the role of N-myc during development, we have used targeted mutagenesis in embryonic stem cells to produce a mouse line that carries an N-myc null allele. Mice homozygous for the mutation died between 10.5 and 12.5 days of gestation. Histological analysis of mutant embryos revealed that organs and tissues expected at these stages of development were present. However, multiple defects were observed, primarily in tissues and organs that normally express N-myc. In particular, mutant hearts were underdeveloped, often retaining the S-shape more typical of 9-day-old embryos. In addition, cranial and spinal ganglia were reduced in size and/or cellularity. Most of the noted defects were more consistent with a role of N-myc in proliferation of precursor populations than with a block in differentiation per se, at least at these early stages. These results demonstrate that N-myc plays an essential role during development and clearly confirm that N-myc has a physiological function that is distinct from that of the other myc-family genes

Judge-Jury Agreement in Criminal Cases: A Partial Replication of Kalven and Zeisel\u27s The American Jury

This study uses a new criminal case data set to partially replicate Kalven and Zeisel\u27s classic study of judge-jury agreement. The data show essentially the same rate of judge-jury agreement as did Kalven and Zeisel for cases tried almost 50 years ago. This study also explores judge-jury agreement as a function of evidentiary strength (as reported by both judges and juries), evidentiary complexity (as reported by both judges and juries), legal complexity (as reported by judges), and locale. Regardless of which adjudicator\u27s view of evidentiary strength is used, judges tend to convict more than juries in cases of middle evidentiary strength. Judges tend to acquit more than juries in cases in which judges regard the evidence favoring the prosecution as weak. Judges tend to convict more than juries in cases in which judges regard the evidence favoring the prosecution as strong. Rates of adjudicator agreement are thus partly a function of which adjudicator\u27s view of evidentiary strength is used, a result not available to Kalven and Zeisel, who were limited to judges\u27 views of the evidence. We find little evidence that evidentiary complexity or legal complexity help explain rates of judge-jury disagreement. Rather, the data support the view that judges have a lower conviction threshold than juries. Local variation exists among the sites studied. The influences of juror race, sex, and education are also considered

Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review

Objective To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items. Study Design and Setting Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items. Results After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1–6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7–9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11–14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15–16); and informing trial participants about using surrogate end points (item 17). Conclusion The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials–SURROGATE and Consolidated Standards of Reporting Trials–SURROGATE extensions

Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesised that a previously reported dark skin mouse mutant (Dsk7), which has a germline hypermorphic Gα11 mutation, Ile62Val, may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain-offunction. Treatment with NPS-2143, a calcilytic compound, normalised these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2; and demonstrated calcilytics as a potential targeted therapy

Effects of nordic walking exercise on gait, motor/non-motor symptoms, and serum brain-derived neurotrophic factor in individuals with Parkinson's disease

ObjectiveThe primary purpose of this study was to investigate the immediate and long-term effects of Nordic Walking (NW) exercise on walking function, motor/non-motor Parkinson's Disease (PD) symptoms, and serum brain-derived neurotrophic factor (BDNF) in persons with idiopathic PD.MethodsTwelve community-dwelling participants with mild to moderate idiopathic PD and varied degrees of gait dysfunction were recruited for this prospective, repeated measures design that examined clinical measures and BDNF levels at baseline (T0), post-intervention (T1) and 3-month follow-up (T2). Participants engaged in 6 weeks of supervised NW exercise training with individualized instruction, followed by 14 weeks of independent NW exercise with remote coaching. Outcome measurements included daily step counts, 6-Minute Walk Test (6-MinWT), 10-Meter Walk Test (10MWT), spatiotemporalparameters, Timed Up and Go Test (TUG), dual-task TUG, Revised-Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Revised-Freezing of Gait Questionnaire, MDS-Nonmotor Symptom scale (NMS), Parkinson's Fatigue Scale, and serum BDNF levels. The Friedman test with post hoc Wilcoxon sign-ranked pairwise comparisons were used to compare baseline to T1, baseline to T2, and T1 to T2 timepoints with a Benjamini-Hockberg correction applied.ResultsStatistically significant improvements found post-training and retained at 3-month follow-up included 6-MinWT, daily step count, 10mWT, MDS-UPDRS, and TUG with effect sizes of 0.57 to 1.03. Serum BDNF at T2 was significantly greater than T0 and T1. Although no statistically significant improvements were observed in the MDS-NMS, 9 of 12 participants had improved non-motor symptoms. There was good adherence, sustained independent exercise engagement, and no adverse events over the 5-month study duration.ConclusionsThis study demonstrated that NW exercise was a safe, feasible, and sustainable mode of aerobic exercise for this sample of participants with varied Parkinson's disease duration and severity. Following an individualized and progressive NW training intervention, significant improvements in walking function, daily activity level, and motor function were observed. Following the supervised NW training phase, independent three-month engagement in NW exercise was sustained with long-term retention of these clinical improvements and an increase in serum BDNF levels over this five-month NW exercise trial.ImpactNordic walking exercise may be a safe, feasible and sustainable mode of independent exercise for improving daily ambulatory activity, gait and motor function, and serum BDNF in individuals with mild to moderate PD with varied gait abilities.Clinical Trials Registry ID20-101-

A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination.

Psychosocial predictors of weight regain in the weight loss maintenance trial

This study's purpose was to identify psychosocial predictors of weight loss maintenance in a multi-site clinical trial, following a group-based weight loss program. Participants (N = 1025) were predominately women (63 %) and 38 % were Black (mean age = 55.6 years; SD = 8.7). At 12 months, higher SF-36 mental health composite scores were associated with less weight regain (p < .01). For Black participants, an interaction existed between race and friends' encouragement for exercise, where higher exercise encouragement was related to more weight regain (p < .05). At 30 months, friends' encouragement for healthy eating was associated with more weight regain (p < .05), whereas higher SF-36 mental health composite scores were related to less weight regain (p < .0001). Perceived stress and select health-related quality of life indices were associated with weight regain; this relationship varied across gender, race, and treatment conditions. Temporal changes in these variables should be investigated for their impact on weight maintenance

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function