Robust perceptual-load-dependent audiovisual integration in adult ADHD.

We perceive our daily-life surrounded by different senses (e.g., visual, and auditory). For a coherent percept, our brain binds those multiple streams of sensory stimulations, i.e., multisensory integration (MI). Dependent on stimulus complexity, early MI is triggered by bottom-up or late via top-down attentional deployment. Adult attention-deficit/hyperactivity disorder (ADHD) is associated with successful bottom-up MI and deficient top-down MI. In the current study, we investigated the robustness of the bottom-up MI by adding additional task demand varying the perceptual load. We hypothesized diminished bottom-up MI for high perceptual load for patients with ADHD. 18 adult patients with ADHD and 18 age- and gender-matched healthy controls participated in this study. In the visual search paradigm, a target letter was surrounded by uniform distractors (low load) or by different letters (high load). Additionally, either unimodal (visual flash, auditory beep) or multimodal (audiovisual) flanked the visual search. Linear-mixed modeling was used to investigate the influence of load on reaction times. Further, the race model inequality was calculated. Patients with ADHD showed a similar degree of MI performance like healthy controls, irrespective of perceptual load manipulation. ADHD patients violated the race model for the low load but not for the high-load condition. There seems to be robust bottom-up MI independent of perceptual load in ADHD patients. However, the sensory accumulation might be altered when attentional demands are high.

Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs.

Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.

Financing Preventive Medicine Graduate Medical Education.

Financing US preventive medicine residency programs has been a persistently difficult issue. The unique nature of preventive medicine renders training more burdensome and costly than other specialties. This article describes the numerous and varied federal sources of Graduate Medical Education funding to outline available residency financing options for the specialty of preventive medicine. This information could be utilized by various preventive medicine organizations in their efforts to strengthen the specialty.

Preventive medicine's equivalence problem.

The structure of preventive medicine residency training in the U.S. warrants serious examination. U.S. public health and general preventive medicine residencies have suffered a 17% decline in the number of residency programs since 2000, and current residency programs are, on average, half-empty. The required clinical year is not unique to preventive medicine, a basic, undifferentiated MPH for preventive medicine doesn't distinguish the preventive medicine specialist, and practicum year requirements are overly broad and not necessarily specific to the specialty, leaving the specialty vulnerable to equivalence by most other specialties. Strategies including creation of an additional preventive medicine-specific clinical year, developing a new public health degree for the specialty, and more specific practicum rotations, as well as potentially changing the specialty's name and altering the annual structure of training, are proposed along with an equivalence test.

Integration of the preventive medicine specialty in the rural and Tribal public health workforce.

The majority of the U.S. American Indian and Alaska Native (AI/AN) population live in rural areas, and are thus disproportionately affected by rural health issues. In addition, the AI/AN population has unique health characteristics resulting from a distinct cultural and sociopolitical history. A public health approach to both rural and Tribal health should include the medical specialty of preventive medicine, a unique physician specialty that combines both direct patient care and public health skills. To best prepare preventive medicine physicians for rural and Tribal practice, medical schools could recruit students from rural and Tribal areas and encourage them to pursue the specialty of preventive medicine. Additionally, preventive medicine residency training programs could establish clinical and public health practicum rotations in rural and Tribal areas, and develop curricula that address rural and Tribal health issues. Currently very few preventive medicine residency programs expressly state a mission to train physicians in rural or Tribal settings.

Credentialing and privileging the preventive medicine physician.

The practice of preventive medicine remains ill-defined, and the specialty is threatened by a void in the definition of the specialty's practice. The authors propose a cohesive, active identification of skills provided by trained preventive medicine physicians through the credentialing and privileging process. The privileging process should incorporate clinical skills specific to the provider and non-clinical skills based on preventive medicine residency training competency requirements, preventive medicine board certification examination requirements, and the ten essential public health services. The specialty may benefit from development of clinical training based on public health clinical services as well as privileging of physicians in health organization leadership positions.

Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts.

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague-Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

Do preventive medicine physicians practice medicine?

As some preventive medicine physicians have been denied medical licenses for not engaging in direct patient care, this paper attempts to answer the question, "Do preventive medicine physicians practice medicine?" by exploring the requirements of licensure, the definition of "practice" in the context of modern medicine, and by comparing the specialty of preventive medicine to other specialties which should invite similar scrutiny. The authors could find no explicit licensure requirement for either a certain amount of time in patient care or a number of patients seen. No physicians board certified in Public Health and General Preventive Medicine sit on any state medical boards. The authors propose that state medical boards accept a broad standard of medical practice, which includes the practice of preventive medicine specialists, for licensing purposes.

Changes in gut microbiota during development of compulsive checking and locomotor sensitization induced by chronic treatment with the dopamine agonist quinpirole.

Long-term treatment of rats with the D2/D3 dopamine agonist quinpirole induces compulsive checking (proposed as animal model of obsessive-compulsive disorder) and locomotor sensitization. The mechanisms by which long-term use of quinpirole produces those behavioral transformations are not known. Here we examined whether changes in gut microbiota play a role in these behavioral phenomena, by monitoring the development of compulsive checking and locomotor sensitization at the same time as measuring the response of gut microbiota to chronic quinpirole injections. Two groups of rats received nine injections of saline (n=16) or quinpirole (n=15; 0.25 mg/kg), at weekly intervals for the first 5 weeks and then two injections per week until the end of treatment. After each injection, rats were placed on a large open field for 55 min, and their behavior was video recorded for subsequent analysis. Fecal matter was collected after each trial and frozen for bacterial community profiling of the 16S rRNA gene, using paired-end reads of the V3 region. The results indicated that the induction of locomotor sensitization and compulsive checking was accompanied by changes in several communities of bacteria belonging to the order Clostridiales (class Clostridia, phylum Firmicutes), and predominantly in Lachnospiraceae and Ruminococcaceae families of bacteria. It is suggested that changes in these microbes may serve to support the energy use requirements of compulsive checking and obsessive-compulsive disorder.

Saccharomyces cerevisiae Forms D-2-Hydroxyglutarate and Couples Its Degradation to D-Lactate Formation via a Cytosolic Transhydrogenase.

The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3Δ knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2Δ knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to α-ketoglutarate. Depletion of D-lactate levels in the dld3Δ, but not in the dld2Δ mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to α-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3-phosphoglycerate in the main serine biosynthesis pathway, in addition reduce α-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1.

Road traffic injuries in Peace Corps Volunteers, 1996-2014.

INTRODUCTION: Road traffic injuries are a leading cause of mortality and morbidity worldwide. Travellers are at risk given unfamiliarity with local road conditions and traffic rules. Peace Corps Volunteers are a unique population of long-term travellers who live and work in-country, often in remote settings, over a period of 27 months and use a range of transportation modes. METHODS: Data from Peace Corps' Epidemiologic Surveillance System (ESS) and Death In-Service (DIS) database were analysed in 2015 for non-fatal and fatal road traffic injuries among in-service Volunteers from 1996 to 2014. Volunteer-months were used to calculate incidence rates, and rates were compared among countries and regions. RESULTS: A total of 5047 non-fatal and 15 fatal road crash injuries were reported during 1 616 252 Volunteer-months for an overall rate of 3.12 non-fatal injuries and 0.01 fatalities per 1000 Volunteer-months. The total combined rate of nonfatal road traffic injuries among Volunteers generally declined from 4.01 per 1000 Volunteer-months in 1996 to 2.84 in 2014. Pedestrian and bicycle injuries emerged as the most frequent mechanisms of injury during this timeframe. Differences in rates of observed road traffic-related fatalities among Volunteers compared with expected age-matched cohort rates in the US were not statistically significant. CONCLUSIONS: Peace Corps transportation policies and training, and changes to road environments worldwide, may have led to a decrease in the rate of road traffic injuries among Peace Corps Volunteers. Pedestrians and bicyclists remain at risk of road traffic injuries.

Population genomics reveals chromosome-scale heterogeneous evolution in a protoploid yeast.

Yeast species represent an ideal model system for population genomic studies but large-scale polymorphism surveys have only been reported for species of the Saccharomyces genus so far. Hence, little is known about intraspecific diversity and evolution in yeast. To obtain a new insight into the evolutionary forces shaping natural populations, we sequenced the genomes of an expansive worldwide collection of isolates from a species distantly related to Saccharomyces cerevisiae: Lachancea kluyveri (formerly S. kluyveri). We identified 6.5 million single nucleotide polymorphisms and showed that a large introgression event of 1 Mb of GC-rich sequence in the chromosomal arm probably occurred in the last common ancestor of all L. kluyveri strains. Our population genomic data clearly revealed that this 1-Mb region underwent a molecular evolution pattern very different from the rest of the genome. It is characterized by a higher recombination rate, with a dramatically elevated A:T → G:C substitution rate, which is the signature of an increased GC-biased gene conversion. In addition, the predicted base composition at equilibrium demonstrates that the chromosome-scale compositional heterogeneity will persist after the genome has reached mutational equilibrium. Altogether, the data presented herein clearly show that distinct recombination and substitution regimes can coexist and lead to different evolutionary patterns within a single genome.

Dissection of quantitative traits by bulk segregant mapping in a protoploid yeast species.

Since more than a decade ago, Saccharomyces cerevisiae has been used as a model to dissect complex traits, revealing the genetic basis of a large number of traits in fine detail. However, to have a more global view of the genetic architecture of traits across species, the examination of the molecular basis of phenotypes within non-conventional species would undoubtedly be valuable. In this respect, the Saccharomycotina yeasts represent ideal and potential non-model organisms. Here we sought to assess the feasibility of genetic mapping by bulk segregant analysis in the protoploid Lachancea kluyveri (formerly S. kluyveri) yeast species, a distantly related species to S. cerevisiae For this purpose, we designed a fluorescent mating-type marker, compatible with any mating-competent strains representative of this species, to rapidly create a large population of haploid segregants (>10(5) cells). Quantitative trait loci can be mapped by selecting and sequencing an enriched pool of progeny with extreme phenotypic values. As a test bed, we applied this strategy and mapped the causal loci underlying halotolerance phenotypes in L. kluyveri Overall, this study demonstrates that bulk segregant mapping is a powerful way for investigating the genetic basis of natural variations in non-model yeast organisms and more precisely in L. kluyveri.

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

Influence of Preventive Medicine Residency Programs and Combined Master of Public Health Programs on Specialty Selection.

INTRODUCTION: To determine medical school characteristics that may result in graduates entering the specialty of public health and general preventive medicine (PH&GPM), the authors conducted an analysis comparing the presence of affiliated preventive medicine residency programs and combined Master of Public Health degree programs with the likelihood of graduates entering the specialty of PH&GPM. METHODS: Using data from the American Board of Preventive Medicine and publicly available information on medical schools and residencies, in spring 2022, the authors compared medical schools that produced PH&GPM physicians with the presence of a PH&GPM residency program, the presence of any preventive medicine residency (public health and general preventive medicine or occupational medicine or aerospace medicine), and the presence of a combined Doctor of Medicine‒Master of Public Health or Doctor of Osteopathic Medicine‒Master of Public Health program. RESULTS: Between 2017 and 2021, there were 385 physicians newly board certified in PH&GPM, 210 medical schools, and 75 preventive medicine residencies. The 385 physicians graduated from 110 of the 210 medical schools. Analyses showed statistically significant associations between medical schools that graduated PH&GPM physicians and the presence of PH&GPM residencies (OR=3.74; 95% CI=1.61, 8.69), all preventive medicine residencies (OR=2.75; 95% CI=1.37, 5.51), and combined degree programs (OR=4.37; 95% CI=2.45, 7.79). CONCLUSIONS: Because PH&GPM residency programs affiliated with medical schools are a significant factor associated with PH&GPM physicians obtaining board certification, such analyses may provide critical guidance in the utilization of resources intended to produce more physicians certified in this specialty.

CRISPR Activation/Interference Screen to Identify Genetic Networks in HDAC-Inhibitor-Resistant Cells.

Epigenetic alterations have been identified in various tumor types. In part, these alterations are mediated via increased histone deacetylase activity. Although preclinical results of monotherapies with histone deacetylase inhibitors (HDACi) are promising, success in clinical trials is limited. Reasons for these limitations may be de novo or acquired resistance to HDAC inhibitors that could be overcome with rational combination therapies. This requires knowledge of resistance mechanism along with the involved genetic networks. One way to identify such genetic networks is the implementation of a CRISPR-based technology allowing transcriptional repression (CRISPRi) and activation (CRISPRa) at a genome-wide scale. We describe a simple approach to amplify and validate sgRNA libraries, generate a myeloid progenitor cell line expressing catalytically dead Cas9 (dCas9) fusion proteins with transcriptional effectors to repress or activate genetic regions of interest and demonstrate a complementary genome-wide HDACi resistance screening approach. Furthermore, we present bioinformatics tools for quality control and analysis of the sequencing data.

Global phylogeographical distribution of Gloeoporus dichrous.

Phylogeographic analyses are efficient in ecological and evolutionary studies to discover the origin of a lineage, its dispersal routes, and the divergence of ancestral traits. Studies on widespread wood-decay fungi have revealed the phylogenetic division of several polypores based on geographical distribution. In this study, specimens of Gloeoporus dichrous, a cosmopolitan polypore species, were collected globally and analyzed for their geographic distribution. Multi-marker Bayesian molecular clock and haplotype analyses revealed a clear division of G. dichrous populations by continent. The species diverged from its neighboring clades 10.3 (16.0-5.6) million years ago, with Asian and North American populations at the center of divergence. Possible dispersal mechanisms and pathways are predicted and discussed based on the evaluated transfer routes. The biogeography of G. dichrous analyzed in this study represents a fraction of the polypore evolution and may advance the understanding of the overall evolution of wood-decay fungi.