Kleefstra syndrome, caused by haploinsufficiency of euchromatin histone methyltransferase 1 (EHMT1), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic ...facial dysmorphisms, and other variable clinical features. In addition to EHMT1 mutations, de novo variants were reported in four additional genes (MBD5, SMARCB1, NR1I3, and KMT2C), in single individuals with clinical characteristics overlapping Kleefstra syndrome. Here, we present a novel cohort of five patients with de novo loss of function mutations affecting the histone methyltransferase KMT2C. Our clinical data delineates the KMT2C phenotypic spectrum and reinforces the phenotypic overlap with Kleefstra syndrome and other related ID disorders. To elucidate the common molecular basis of the neuropathology associated with mutations in KMT2C and EHMT1, we characterized the role of the Drosophila KMT2C ortholog, trithorax related (trr), in the nervous system. Similar to the Drosophila EHMT1 ortholog, G9a, trr is required in the mushroom body for short term memory. Trr ChIP-seq identified 3371 binding sites, mainly in the promoter of genes involved in neuronal processes. Transcriptional profiling of pan-neuronal trr knockdown and G9a null mutant fly heads identified 613 and 1123 misregulated genes, respectively. These gene sets show a significant overlap and are associated with nearly identical gene ontology enrichments. The majority of the observed biological convergence is derived from predicted indirect target genes. However, trr and G9a also have common direct targets, including the Drosophila ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of ID/ASD-related disorders.
Range expansions by generalists can alter communities and introduce competitive pressures on native species. In the Great Basin Desert, USA, coyotes (Canis latrans Say, 1823) have colonized and are ...now sympatric with native kit foxes (Vulpes macrotis Merriam, 1888). Since both species have similar diets, dietary partitioning may facilitate coexistence. We analyzed coyote and kit fox diets, then compared our results to an earlier study. Because populations are dynamic, we expected that decreases in prey or increases in predator abundance could alter dietary patterns. We found no significant changes in population-level prey diversity for kit foxes or coyotes, but found high levels of dietary overlap between species. We did detect a significant decrease in the relative importance of leporids (family Leporidae) in the diets of both canids, but they remained important for coyotes. The relative importance of small mammals was greater for kit foxes than coyotes, but their importance had not changed significantly over time. We detected significant declines in prey diversity per sample (scat-level dietary diversity) for both canids, suggesting that during a foraging event, individuals may encounter less diverse prey now than historically. These findings suggested that kit foxes and coyotes were not limited by prey, despite high dietary overlap.
To examine the effect of first- vs. second-generation antipsychotics on electronically monitored adherence in outpatients with schizophrenia or schizoaffective disorder.
The sample consisted of 61 ...outpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who took either a first-generation (
N
=
25) or second-generation (
N
=
36) oral antipsychotic during study participation. Treatment group designation (first-vs. second-generation antipsychotic) was based on the particular antipsychotic medication the patient was receiving as part of routine care at study entry (i.e., non-random assignment). Adherence to prescribed antipsychotic medication was assessed monthly over a 6-month study period using electronic monitoring (EM) of medication bottle opening. Various participant characteristics were collected at baseline to test for group differences and for potential associations with prospectively measured adherence. The primary data analysis was a mixed-model analysis of repeated measures.
The analysis of EM adherence revealed no significant difference between those taking first-generation (6-month adjusted mean adherence
=
64.35%) and second-generation antipsychotics (6-month adjusted mean adherence
=
69.17%; Group effect,
p
=
.29) and no significant Group X Period interaction (
p
=
.13).
There was no statistical difference in EM adherence, over a 6-month period, between patients taking first- and second-generation antipsychotics. However, since the patients were not randomized, conclusions must be interpreted within the context of the quasi-experimental design used in the current study.
We examined the reliability and construct validity of the 5-Item Arizona Sexual Experience Scale (ASEX) in patients with schizophrenia or schizoaffective disorder. In addition, we assessed the ...performance of two 1-item screening questions to detect sexual dysfunction as defined by a cut-off scoring criteria of sexual dysfunction for the ASEX. One question was a general question about any side effects. The second question asked specifically about sexual dysfunction. Altogether 247 participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder provided data at a single interview. Results indicated that the ASEX has good internal consistency and construct validity for the patients with schizophrenia and schizoaffective disorder. The point-biserial correlations and logistic regression found a high degree of agreement between the one-item specific screening question for sexual dysfunction and the ASEX. Overall, sensitivity (85%), specificity (63.7%), and positive (83%) and negative (67.1%) predictive values for the specific one-item screening question were satisfactory. The single general side effect question performed poorly (sensitivity
=
11.3%; specificity
=
92.5%; positive predictive value
=
76%; negative predictive value
=
33%).
The current findings demonstrate the highly acceptable psychometric properties of the ASEX in patients with schizophrenia or schizoaffective disorder. In addition, a specific one-item screening question is of clinical utility in patients with schizophrenia or schizoaffective disorder.
Summary
Opioids have long held a prominent role in the management of perioperative pain in adults and children. Published reports concerning the appropriate, and inappropriate, use of these ...medications in pediatric patients have appeared in various publications over the last 50 years. For this document, the Society for Pediatric Anesthesia appointed a taskforce to evaluate the available literature and formulate recommendations with respect to the most salient aspects of perioperative opioid administration in children. The recommendations are graded based on the strength of the available evidence, with consensus of the experts applied for those issues where evidence is not available. The goal of the recommendations was to address the most important issues concerning opioid administration to children after surgery, including appropriate assessment of pain, monitoring of patients on opioid therapy, opioid dosing considerations, side effects of opioid treatment, strategies for opioid delivery, and assessment of analgesic efficacy. Regular updates are planned with a re‐release of guidelines every 2 years.
The National Institute of Mental Health initiated the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program to evaluate the effectiveness of antipsychotic drugs in typical ...settings and populations so that the study results will be maximally useful in routine clinical situations. The CATIE schizophrenia trial blends features of efficacy studies and large, simple trials to create a pragmatic trial that will provide extensive information about antipsychotic drug effectiveness over at least 18 months. The protocol allows for subjects who receive a study drug that is not effective to receive subsequent treatments within the context of the study. Medication dosages are adjusted within a defined range according to clinical judgment. The primary outcome is all-cause treatment discontinuation because it represents an important clinical endpoint that reflects both clinician and patient judgments about efficacy and tolerability. Secondary outcomes include symptoms, side effects, neurocognitive functioning, and cost-effectiveness. Approximately 50 clinical sites across the United States are seeking to enroll a total of 1,500 persons with schizophrenia. Phase 1 is a double-blinded randomized clinical trial comparing treatment with the second generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone to perphenazine, a midpotency first generation antipsychotic. If the initially assigned medication is not effective, subjects may choose one of the following phase 2 trials: (1) randomization to open-label clozapine or a double-blinded second generation drug that was available but not assigned in phase 1; or (2) double-blinded randomization to ziprasidone or another second generation drug that was available but not assigned in phase 1. If the phase 2 study drug is discontinued, subjects may enter phase 3, in which clinicians help subjects select an open-label treatment based on individuals' experiences in phases 1 and 2.
The apicomplexan parasite
is a leading global cause of diarrheal disease, and the infection poses a particularly grave threat to young children and those with weakened immune function. Infection ...occurs by ingestion of meiotic spores called oocysts, and transmission relies on fecal shedding of new oocysts. The entire life cycle thus occurs in a single host and features asexual as well as sexual forms of replication. Here, we identify and locus tag two Apetala 2-type (AP2) transcription factors and demonstrate that they are exclusively expressed in male and female gametes, respectively. To enable functional studies of essential genes in Cryptosporidium parvum, we develop and validate a small-molecule-inducible gene excision system, which we apply to the female factor AP2-F to achieve conditional gene knockout. Analyzing this mutant, we find the factor to be dispensable for asexual growth and early female fate determination
but to be required for oocyst shedding in infected animals
. Transcriptional analyses conducted in the presence or absence of AP2-F revealed that the factor controls the transcription of genes encoding crystalloid body proteins, which are exclusively expressed in female gametes. In C. parvum, the organelle is restricted to sporozoites, and its loss in other apicomplexan parasites leads to blocked transmission. Overall, our development of conditional gene ablation in C. parvum provides a robust method for genetic analysis in this parasite that enabled us to identify AP2-F as an essential regulator of transcription required for oocyst shedding and transmission.
The parasite
infects millions of people worldwide each year, leading to life-threatening diarrheal disease in young children and immunosuppressed individuals. There is no vaccine and only limited treatment. Transmission occurs via the fecal-oral route by an environmentally resilient spore-like oocyst. Infection takes place in the intestinal epithelium, where parasites initially propagate asexually before transitioning to male and female gametes, with sex leading to the formation of new oocysts. The essential role of sexual development for continuous infection and transmission makes it an attractive target for therapy and prevention. To study essential genes and potential drug targets across the life cycle, we established inducible gene excision for C. parvum. We determined that the female-specific transcription factor AP2-F is not required for asexual growth and early female development
but is necessary for oocyst shedding
. This work enhances the genetic tools available to study
gene function.
Studies in the
KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory ...hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS.
EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s.
Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits.
This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from
KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.
Museum genomics provide an opportunity to investigate population demographics of extinct species, especially valuable when research prior to extinction was minimal. The Bachman’s warbler (Vermivora ...bachmanii) is hypothesized to have gone extinct due to loss of its specialized habitat. However, little is known about other potential contributing factors such as natural rarity or changes to connectivity following habitat fragmentation. We examined mitochondrial DNA (mtDNA) and genome-wide SNPs using specimens collected from breeding and migration sites across the range of the Bachman’s warbler. We found no signals of strong population structuring across the breeding range of Bachman’s warblers in both mtDNA and genome-wide SNPs. Thus, long-term population isolation did not appear to be a significant contributor to the extinction of the Bachman’s warbler. Instead, our findings support the theory that Bachman’s warblers underwent a rapid decline likely driven by habitat destruction, which may have been exacerbated by the natural rarity, habitat specificity and low genetic diversity of the species.
•Summary of the state-of-the-art soft magnetic materials and applications in power electronics.•Characteristics of oxide-based, metal-insulator, and insulator-insulator type composites.•Overview on ...thermodynamics and kinetics of self-assembled nanocomposites.•Microstructure engineering of soft magnetic composites based on traditional and advanced powder processing techniques.
Oxide-based nanocomposites have potential to offer much higher switching frequencies compared with state-of-the-art soft magnetic materials for applications in power electronics. However, scalable techniques for synthesizing high performance bulk oxide-based nanostructured and nanocomposite systems with superior performance compared to traditional materials are limited. This review aims at identifying existing and potential opportunities for the development of high performance nanocomposite systems through microstructure engineering specific to soft magnetic property optimization by traditional processing routes. The review begins with general introduction about soft magnetic properties of different classes of materials, followed by a detailed description of crystal structures and the underlying physics responsible for their magnetic performance. These include; soft ferrites, bulk crystalline alloys, metal-amorphous nanocomposites, and metal-oxide nanocomposites of various nature such as metal-insulator and insulator-insulator type composites. An overview on powder metallurgy techniques is provided and aspects relevant to optimizing the balance between competing requirements of high effective electrical resistivity to mitigate eddy current losses and high saturation magnetization are highlighted.
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