Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate the failure to ensure COs in juvenile ...male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and alternative complexes, which can act upon precursors to generate noncrossovers (NCOs) at the expense of COs. We propose that some designated CO sites fail to mature efficiently in juveniles owing to inappropriate activity of these alternative repair pathways, leading to chromosome mis-segregation. We also find lower MutLγ focus density in juvenile human spermatocytes, suggesting that weaker CO maturation efficiency may explain why younger men have a higher risk of fathering children with Down syndrome.
Display omitted
•Juvenile mouse spermatocytes have fewer crossovers and more achiasmate chromosomes•Greater use of alternative DNA repair pathways in juvenile mouse spermatocytes•Lower MutLγ focus density in juvenile human spermatocytes•Juvenile spermatocytes likely suffer from crossover maturation inefficiency
A lower incidence of efficient meiotic crossover recombination in young males is attributed to the preferred utilization of pathways involving structure-selective nucleases and alternative complexes that generate noncrossovers at the expense of crossovers.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical outcomes vary among youths at clinical high risk for psychosis (CHR-P), with approximately 20% progressing to full-blown psychosis over 2 to 3 years and 30% achieving remission. Recent ...research efforts have focused on identifying biomarkers that precede psychosis onset and enhance the accuracy of clinical outcome prediction in CHR-P individuals, with the ultimate goal of developing staged treatment approaches based on the individual’s level of risk. Identifying such biomarkers may also facilitate progress toward understanding pathogenic mechanisms underlying psychosis onset, which may support the development of mechanistically informed early interventions for psychosis. In recent years, electroencephalography-based event-related potential measures with established sensitivity to schizophrenia have gained traction in the study of CHR-P and its clinical outcomes. In this review, we describe the evidence for event-related potential abnormalities in CHR-P and discuss how they inform our understanding of information processing deficits as vulnerability markers for emerging psychosis and as indicators of future outcomes. Among the measures studied, P300 and mismatch negativity are notable because deficits predict conversion to psychosis and/or CHR-P remission. However, the accuracy with which these and other measures predict outcomes in CHR-P has been obscured in the prior literature by the tendency to only report group-level differences, underscoring the need for inclusion of individual predictive accuracy metrics in future studies. Nevertheless, both P300 and mismatch negativity show promise as electrophysiological markers of risk for psychosis, as target engagement measures for clinical trials, and as potential translational bridges between human studies and animal models focused on novel drug development for early psychosis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible ...to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective:Although patients with schizophrenia exhibit impaired suppression of the P50 event-related brain potential in response to the second of two identical auditory stimuli during a ...paired-stimulus paradigm, uncertainty remains over whether this deficit in inhibitory gating of auditory sensory processes has relevance for patients’ clinical symptoms or cognitive performance. The authors examined associations between P50 suppression deficits and several core features of schizophrenia to address this gap.Method:P50 was recorded from 52 patients with schizophrenia and 41 healthy comparison subjects during a standard auditory paired-stimulus task. Clinical symptoms were assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. The MATRICS Consensus Cognitive Battery was utilized to measure cognitive performance in a subsample of 39 patients. Correlation and regression analyses were conducted to examine P50 suppression in relation to clinical symptom and cognitive performance measures.Results:Schizophrenia patients demonstrated a deficit in P50 suppression when compared with healthy subjects, replicating prior research. Within the patient sample, impaired P50 suppression covaried reliably with greater difficulties in attention, poorer working memory, and reduced processing speed.Conclusions:Impaired suppression of auditory stimuli was associated with core pathological features of schizophrenia, increasing confidence that P50 inhibitory processing can inform the development of interventions that target cognitive impairments in this chronic and debilitating mental illness.
We investigated the effects of intranasal oxytocin (OXT) on trust and cooperation in borderline personality disorder (BPD), a disorder marked by interpersonal instability and difficulties with ...cooperation. Although studies in healthy adults show that intranasal OXT increases trust, individuals with BPD may show an altered response to exogenous OXT because the effects of OXT on trust and pro-social behavior may vary depending on the relationship representations and expectations people possess and/or altered OXT system functioning in BPD. BPD and control participants received intranasal OXT and played a social dilemma game with a partner. Results showed that OXT produced divergent effects in BPD participants, decreasing trust and the likelihood of cooperative responses. Additional analyses focusing on individual differences in attachment anxiety and avoidance across BPD and control participants indicate that these divergent effects were driven by the anxiously attached, rejection-sensitive participants. These data suggest that OXT does not uniformly facilitate trust and pro-social behavior in humans; indeed, OXT may impede trust and pro-social behavior depending on chronic interpersonal insecurities, and/or possible neurochemical differences in the OXT system. Although popularly dubbed the 'hormone of love', these data suggest a more circumspect answer to the question of who will benefit from OXT.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
P300 in schizophrenia: Then and now Hamilton, Holly K.; Mathalon, Daniel H.; Ford, Judith M.
Biological psychology,
March 2024, 2024-Mar, 2024-03-00, 20240301, Volume:
187
Journal Article
Peer reviewed
The 1965 discovery of the P300 component of the electroencephalography (EEG)-based event-related potential (ERP), along with the subsequent identification of its alteration in people with ...schizophrenia, initiated over 50 years of P300 research in schizophrenia. Here, we review what we now know about P300 in schizophrenia after nearly six decades of research. We describe recent efforts to expand our understanding of P300 beyond its sensitivity to schizophrenia itself to its potential role as a biomarker of risk for psychosis or a heritable endophenotype that bridges genetic risk and psychosis phenomenology. We also highlight efforts to move beyond a syndrome-based approach to understand P300 within the context of the clinical, cognitive, and presumed pathophysiological heterogeneity among people diagnosed with schizophrenia. Finally, we describe several recent approaches that extend beyond measuring the traditional P300 ERP component in people with schizophrenia, including time-frequency analyses and pharmacological challenge studies, that may help to clarify specific cognitive mechanisms that are disrupted in schizophrenia. Moreover, we discuss several promising areas for future research, including studies of animal models that can be used for treatment development.
•The 1965 discovery of P300 led to nearly six decades of P300 studies in schizophrenia.•P300 deficits show trait-like stability but fluctuate with clinical severity.•Deficits precede the illness and occur in relatives, but the genetic basis is unclear.•The relationship between P300 deficits and clinical symptoms remains elusive.•Promising new approaches include time-frequency analysis and animal model studies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For future climate projections to be useful they must be actionable at the local level. In this study, we develop daily temperature and precipitation climate scenarios suitable for use in projections ...of drought, energy use, water use, and crop production. We investigate the magnitude of future changes to air temperature and precipitation in the Midwest United States in response to three future climate change scenarios. Results are used to assess changes to incidence of precipitation extremes and human comfort (using heat index) associated with the anticipated climate changes in the region. We use self‐organizing maps and random forest based techniques to generate daily realizations of temperature and precipitation for 279 weather stations in a region centred on Illinois. We determine that the random forest model performs best for maximum and minimum temperatures, while the self‐organizing map performs best for precipitation. Using nine models from the Coupled Model Inter‐Comparison Project Phase 5, downscaled daily temperature and precipitation values are generated for low, moderate, and high greenhouse gas emissions scenarios for historical and future periods. Based on recent trends, we focus our results on the high emissions scenario, and show an average increase of 4.3°C in maximum daily air temperature across the region for the 2071–2100 period. Precipitation decreases by up to 15% in the southern half of the study region, with a similar percentage increase in the northern half of the region. The regional environmental changes result in an increase of 5.8° in average summer heat index, and increase of 48% in the number of days likely to produce extreme heat, and a decrease in the average value of the standardized precipitation and evapotranspiration index of 1.9 (indicating increased drought) across the region by 2100.
Climate change will lead to significant impacts in the Midwest US, including significant shifts in the patterns of precipitation. Statistical downscaling provides an effective method for translating between the large scale of global models, and the local scale on which many impacts occur. Shown is the percentage change in average precipitation between 1976‐2005 and 20721‐2100 under the RCP 8.5 scenario, using these downscaling methods
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Gonococci undergo frequent and efficient natural transformation. Transformation occurs so often that the population structure is panmictic, with only one long‐lived clone having been ...identified. This high degree of genetic exchange is likely necessary to generate antigenic diversity and allow the persistence of gonococcal infection within the human population. In addition to spreading different alleles of genes for surface markers and allowing avoidance of the immune response, transformation facilitates the spread of antibiotic resistance markers, a continuing problem for treatment of gonococcal infections. Transforming DNA is donated by neighbouring gonococci by two different mechanisms: autolysis or type IV secretion. All types of DNA are bound non‐specifically to the cell surface. However, for DNA uptake, Neisseria gonorrhoeae recognizes only DNA containing a 10‐base sequence (GCCGTCTGAA) present frequently in the chromosome of neisserial species. Type IV pilus components and several pilus‐associated proteins are necessary for gonococcal DNA uptake. Incoming DNA is subject to restriction, making establishment of replicating plasmids difficult but not greatly affecting chromosomal transformation. Processing and integration of transforming DNA into the chromosome involves enzymes required for homologous recombination. Recent research on DNA donation mechanisms and extensive work on type IV pilus biogenesis and recombination proteins have greatly improved our understanding of natural transformation in N. gonorrhoeae. The completion of the gonococcal genome sequence has facilitated the identification of additional transformation genes and provides insight into previous investigations of gonococcal transformation. Here we review these recent developments and address the implications of natural transformation in the evolution and pathogenesis N. gonorrhoeae.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
