Dietary nitrate biochemistry and physiology. An update on clinical benefits and mechanisms of action.

It is now more than 35 years since endothelium derived relaxing factor was identified as nitric oxide (NO). The last few decades have seen an explosion around nitric oxide biochemistry, physiology and clinical translation. The science reveals that all chronic disease is associated with decreased blood flow to the affected organ which results in increased inflammation, oxidative stress and immune dysfunction. This is true for cardiovascular disease, neurological disease, kidney, lung, liver disorders and every other major disorder. Since nitric oxide controls and regulates blood flow, oxygen and nutrient delivery to every cell, tissue and organ in the body and also mitigates inflammation, oxidative stress and immune dysfunction, a focus on restoring nitric oxide production is an obvious therapeutic strategy for a number of poorly managed chronic diseases. Since dietary nitrate is a major contributor to endogenous nitric oxide production, it should be considered as a means of therapy and restoration of nitric oxide. This review will update on the current state of the science and effects of inorganic nitrate administered through the diet on several chronic conditions and reveal how much is needed. It is clear now that antiseptic mouthwash and use of antacids disrupt nitrate metabolism to nitric oxide leading to clinical symptoms of nitric oxide deficiency. Based on the science, nitrate should be considered an indispensable nutrient that should be accounted for in dietary guidelines.

Enantioselective Cyclopropanation Catalyzed by Gold(I)-Carbene Complexes.

The formation of polysubstituted cyclopropane derivatives in the gold(I)-catalyzed reaction of olefins and propargylic esters is a potentially useful transformation to generate diversity, therefore any method in which its stereoselectivity could be controlled is of significant interest. We prepared and tested a series of chiral gold(I)-carbene complexes as a catalyst in this transformation. With a systematic optimization of the reaction conditions, we were able to achieve high enantioselectivity in the test reaction while the cis:trans selectivity of the transformation was independent of the catalyst. Using the optimized conditions, we reacted a series of various olefins and acetylene derivatives to find that, although the reactions proceeded smoothly and the products were usually isolated in good yield and with good to exclusive cis selectivity, the observed enantioselectivity varied greatly and was sometimes moderate at best. We were unable to establish any structure-property relationship, which suggests that for any given reagent combination, one has to identify individually the best catalyst.

Comparative analysis of gene expression platforms for cell-of-origin classification of diffuse large B-cell lymphoma shows high concordance.

Cell-of-origin subclassification of diffuse large B cell lymphoma (DLBCL) into activated B cell-like (ABC), germinal centre B cell-like (GCB) and unclassified (UNC) or type III by gene expression profiling is recommended in the latest update of the World Health Organization's classification of lymphoid neoplasms. There is, however, no accepted gold standard method or dataset for this classification. Here, we compare classification results using gene expression data for 68 formalin-fixed paraffin-embedded DLBCL samples measured on four different gene expression platforms (Illumina wG-DASLTM arrays, Affymetrix PrimeView arrays, Illumina TrueSeq RNA sequencing and the HTG EdgeSeq DLBCL Cell of Origin Assay EU using an established platform agnostic classification algorithm (DAC) and the classifier native to the HTG platform, which is CE marked for in vitro diagnostic use (CE-IVD). Classification methods and platforms show a high level of concordance, with agreement in at least 80% of cases and rising to much higher levels for classifications of high confidence. Our results demonstrate that cell-of-origin classification by gene expression profiling on different platforms is robust, and that the use of the confidence value alongside the classification result is important in clinical applications.

Zinc Nitrate Hexahydrate Pseudobinary Eutectics for Near-Room-Temperature Thermal Energy Storage.

Stoichiometric salt hydrates can be inexpensive and provide higher volumetric energy density relative to other near-room-temperature phase change materials (PCMs), but few salt hydrates exhibit congruent melting behavior between 0 and 30 °C. Eutectic salt hydrates offer a strategy to design bespoke PCMs with tailored application-specific eutectic melting temperatures. However, the general solidification behavior and stability of eutectic salt hydrate systems remain unclear, as metastable solidification in eutectic salt hydrates may introduce opportunities for phase segregation. Here, we present a new family of low-cost zinc-nitrate-hexahydrate-based eutectics: Zn(NO3)2·6(H2O)-NaNO3 (Teu = 32.7 ± 0.3 °C; ΔHeu = 151 ± 6 J·g-1), Zn(NO3)2·6(H2O)-KNO3 (Teu = 22.1 ± 0.3 °C; ΔHeu = 140 ± 6 J·g-1), Zn(NO3)2·6(H2O)-NH4NO3 (Teu = 11.2 ± 0.3 °C; ΔHeu = 137 ± 5 J·g-1). While the tendency to undercool varies greatly between different eutectics in the family, the geologic mineral talc has been identified as an active and stable phase that dramatically reduces undercooling in Zn(NO3)2·6(H2O) and all related eutectics. Zn(NO3)2·6(H2O) and its related eutectics have shown stability for over a hundred thermal cycles in mL scale volumes, suggesting that they are capable of serving as robust and stable media for near-room-temperature thermal energy storage applications in buildings.

Two decades of influenza and pneumonia mortality trends: Demographics, regional shifts and disparities in the United States: 1999 to 2020.

BACKGROUND: In the 20th century, influenza and pneumonia constituted the largest proportion of infectious disease deaths in the United States. Despite progress in management, US mortality trends for these diseases have not been thoroughly investigated. OBJECTIVES: We aim to examine the patterns of influenza and pneumonia-related deaths among US residents. METHODS: Crude death rates and age-adjusted mortality rates (AAMRs) per 100,000 individuals were calculated using influenza and pneumonia mortality data (International Classification of Diseases, 10th revision codes: J09-J18) from the CDC WONDER database. Annual percentage changes with a 95% confidence interval were determined using joinpoint regression analysis. Average annual percentage changes were computed as the weighted average of annual percentage changes. RESULTS: From 1999 to 2020, US influenza and pneumonia deaths totaled 1,257,088 (AAMR: 17.09), with a significantly decreasing AAMR (-2.94). Males had a higher AAMR (20.13) than females (15.02). Non-Hispanic American Indians had the highest AAMR (20.44), while Hispanics had the lowest AAMR (13.91). The Northeast had the highest AAMR (18.02). All other regions had similar AAMRs. Rural regions had a consistently higher AAMR (19.80) than urban regions (AAMR: 16.51). CONCLUSION: Tailoring interventions toward high-risk groups can enhance the effectiveness of preventive measures, vaccination, and health care access.

Disparities in mortality trends of adults with HIV in the USA: A comprehensive examination across 2 decades.

Approximately 38 million people worldwide are affected by human immunodeficiency virus (HIV), with 4000 new infections daily. While literature explores HIV mortality among the elderly in the US, there is an underrepresentation of mortality data for adults. By scrutinizing mortality trends based on demographic factors such as gender, race or ethnicity, age groups, and geographic location, the study seeks to uncover patterns that may facilitate a longitudinal perspective for tailoring interventions and allocating resources effectively. Crude death rates and age-adjusted mortality rates (AAMR) per 100,000 individuals were calculated using HIV mortality data (ICD-10 Codes B20-24) from CDC WONDER database. Permutation test was used to calculate annual percentage changes in AAMR with 95% confidence interval. Average annual percentage changes were computed as weighted average of annual percentage changes. Between 1999 to 2020, US adult HIV deaths totaled 225,396 (AAMR: 5.03), with a significantly decreasing average annual percentage changes (-5.94). Males exhibited a 3-fold higher AAMR (7.50) than females (2.67). Non-Hispanic Blacks had the highest AAMR (21.82), while Non-Hispanic Asians had the lowest (0.67). The South and Northeast regions had the highest AAMRs (6.91 and 6.33, respectively). Notably, the District of Columbia had an alarmingly high mortality rate of 39.9, while North Dakota had the lowest (0.7). Urban regions (5.47) had double the mortality rates of rural regions (2.70). Mortality rate peaked in age groups 45 to 54 (8.65) and 35 to 44 (7.42). While overall HIV mortality is declining, disparities persist among demographics. Targeted interventions are crucial to improve preventive measures and healthcare access for disproportionately affected groups.

Temporal and regional trends in adults with diabetics kidney disease in the US from 1999 to 2020.

AIMS: We aim to analyze trends in mortality rates among adults with diabetic kidney disease (DKD) in the US from 1999 to 2020. METHODS: We queried the Centers for Disease Control Wide-Ranging Online Data for Epidemiologic Research database for mortality statistics from 1999 to 2020 associated with DKD in adults aged ≥25 years. Age-adjusted mortality rates (AAMRs) were calculated and trends were analyzed using the Joinpoint Regression Program. RESULTS: From 1999 to 2020, a total of 528,430 deaths were reported among adults with DKD. The mortality rates increased over time with males consistently exhibiting higher AAMR than females. NH American Indian or Alaska Native individuals had the highest AAMR, followed by NH Blacks, Hispanics, NH Whites, and NH Asians. The West region had the highest AAMR, followed by the Midwest, South, and Northeast. Rural regions had higher AAMR than urban areas, and mortality rates increased with age. CONCLUSIONS: This study reveals notable disparities in DKD mortality rates across demographic groups and geographic regions. NH American Indians or Alaska Natives, males, elderly individuals, rural residents, and those in the West region were disproportionately affected. Understanding these trends is crucial for developing targeted interventions to reduce DKD-related mortality and address healthcare disparities.

Mortality patterns in older adults with infective endocarditis in the US: A retrospective analysis.

BACKGROUND: Infective Endocarditis (IE) has become a significant cause of morbidity and mortality over the last two decades. Despite management advancements, mortality trends in the USA's geriatric population are unexplored. The aim of this study was to assess the trends and regional differences in IE related mortality among geriatric patients in the USA. METHODS: We analyzed death certificates sourced from the CDC WONDER database spanning 1999 to 2020. The research targeted individuals aged 65 and older. Age-adjusted mortality rates (AAMRs) per 100,000 and annual percent change (APC), along with 95% CI, were calculated through joinpoint regression analysis. RESULTS: From 1999 to 2020, infective endocarditis caused 222,573 deaths, showing a declining trend (APC: -0.8361). Males had higher AAMR (26.8) than females (22.2). NH White had the highest AAMR (25.8), followed by NH American Indians or Alaska Natives (19.6). Geographically, the Midwest had the highest AAMR (27.4), followed by the Northeast (25.8). Rural areas consistently had higher AAMRs (26.6) than urban areas (23.6), while 80.16% of deaths occurring in urban settings. North Dakota, Nebraska, and Montana had the highest state AAMRs, approximately double than the states with the lowest mortality rates: Mississippi, Hawaii, California, and Massachusetts. Those aged 85 and above accounted for 42.9% of deaths. CONCLUSION: IE mortality exhibited a clear pattern: rising till 2004, declining from 2004 to 2018, and increasing again till 2020. Key risk factors were male gender, Midwest residence, NH White ethnicity, and age ≥85.Targeted interventions are essential to reduce IE mortality, especially among vulnerable older populations.

Tuning Fluorescence and Singlet Oxygen Quantum Yields of Subporphyrazines by Axial Functionalization.

The axial functionalization of Subporphyrazines (SubPzs) with unreported alkoxy groups, carboxy and carboperoxy rests, as well as sulfanyl, aryl and amino groups, forming B-O, B-S, B-C, and B-N bonds, respectively, has been investigated. The studied oxygen nucleophiles include aromatic and sterically demanding aliphatic alcohols, along with carboxylic acids and peracids. In general, direct substitution of the chloro-SubPz by oxygen nucleophiles of diverse nature proceeds smoothly, with yields of the isolated alkoxy and carboxy-substituted SubPzs ranging from 49 to 100 %. Conversely, direct substitution with sulphur, carbon and nitrogen nucleophiles do not afford the corresponding substituted SubPzs. In these cases, a stepwise procedure involving an axial triflate-SubPz intermediate was employed, affording only the phenyl-SubPz in 8 % yield. The major compound under these conditions was the unreported SubPz µ-oxo dimer, presumably arising from substitution of the triflate-SubPz by the in situ generated hydroxy-SubPz. This result indicates a quite low reactivity of the TfO-SubPz intermediate with carbon, sulphur and nitrogen nucleophiles. All SubPzs prepared in this work exhibited fluorescence at 510-515 nm with quantum yields ranging from 0.1 to 0.24. Additionally, all SubPzs generated singlet oxygen, with ΦΔ values ranging from 0.15 to 0.57, which show no apparent correlation with the axial substituents.

Insurance Status and Access to Otolaryngology Care: National Mystery Caller Study in the United States.

OBJECTIVE: To investigate potential differences in new patient appointment wait times for otolaryngology care based on insurance types and explore factors influencing these wait times. STUDY DESIGN: A cross-sectional audit study, using a "mystery caller" approach, analyzed with a linear mixed Poisson model to adjust for confounding factors. SETTING: A total of 612 physicians across 49 states and the District of Columbia, representing 6 otolaryngology subspecialties, were included. METHODS: Otolaryngology physicians were contacted by mystery callers via telephone with scripted clinical vignettes as patients with either Medicaid or Blue Cross/Blue Shield (BCBS) insurance. Callers requested next available appointment. Wait times for new patient appointments were recorded and analyzed in R using a generalized linear mixed Poisson model. RESULTS: A total of 1183 of 1224 calls reached a representative. Medicaid patients waited 5.73% longer (P < .001) compared to BCBS patients (IRR: 1.06; confidence interval [CI]: 1.03-1.09; P < .001), with respective mean wait times of 36.8 days (SE ± 1.6) and 32.4 days (SE ± 1.6). Longer waiting times were also associated with physicians affiliated with universities (P = .001) and certain subspecialties, such as pediatric otolaryngology (P < .001) and neurotology (P = .008). Regional differences were also observed, with specific AAO-HNS regions showing shorter wait times. The model achieved a conditional R-squared value of 0.947. CONCLUSION: This study reveals disparities in wait times for otolaryngology care based on insurance type, with extended wait times for Medicaid beneficiaries. The findings highlight a potential access to care disparity, which begets the need for strategies that ensure equitable access to otolaryngology care and further research to understand the underlying reasons for these potential disparities.

Ecological and evolutionary genomics of marine photosynthetic organisms.

Environmental (ecological) genomics aims to understand the genetic basis of relationships between organisms and their abiotic and biotic environments. It is a rapidly progressing field of research largely due to recent advances in the speed and volume of genomic data being produced by next generation sequencing (NGS) technologies. Building on information generated by NGS-based approaches, functional genomic methodologies are being applied to identify and characterize genes and gene systems of both environmental and evolutionary relevance. Marine photosynthetic organisms (MPOs) were poorly represented amongst the early genomic models, but this situation is changing rapidly. Here we provide an overview of the recent advances in the application of ecological genomic approaches to both prokaryotic and eukaryotic MPOs. We describe how these approaches are being used to explore the biology and ecology of marine cyanobacteria and algae, particularly with regard to their functions in a broad range of marine ecosystems. Specifically, we review the ecological and evolutionary insights gained from whole genome and transcriptome sequencing projects applied to MPOs and illustrate how their genomes are yielding information on the specific features of these organisms.

Emerging virulence arising from hybridisation facilitated by multiple introductions of the sunflower downy mildew pathogen Plasmopara halstedii.

The sunflower downy mildew pathogen Plasmopara halstedii is an invasive plant pathogen in Europe of American origin. Despite efforts to produce resistant host varieties, nationwide monitoring in France has revealed the rapid emergence of new virulent races increasing the number from one founder identified in 1966 to as many as 14 today. We have genotyped 146 samples (including all 14 races) using 13 nuclear and one mtDNA marker. Samples of the same race were found to share alleles/mtDNA haplotype and the two most common races had individuals with multiple matching genotypes. Cluster analyses confirmed that the samples form three groups to which races strongly adhere. Clusters were highly differentiated (F(ST) 0.65) and characterised by high inbreeding coefficients. Despite this, samples of recently emergent races, including six that are unique to France had mixed ancestry between the groups suggesting they have arisen in situ due to hybridisation. Five such samples also had conflicting mtDNA and nuclear DNA profiles. This demonstrates that multiple introductions have aided the establishment of this pathogen in France, and suggests recombination facilitated by these introductions is driving the emergence of new and endemic races in response to host resistance.

Wind-borne insects mediate directional pollen transfer between desert fig trees 160 kilometers apart.

The question of how far pollen can move between plants has implications for topics as diverse as habitat fragmentation, conservation management, and the containment of genetically modified crops. The monoecious African fig tree Ficus sycomorus L. relies on the small, short-lived, night-flying, host-specific fig wasp Ceratosolen arabicus Mayr for pollination. We used microsatellite markers to characterize a geographically isolated riparian population of F. sycomorus growing along the Ugab River in the Namib Desert, Namibia, together with paternity analysis of seedlings from known mothers, to map pollen movement within this population. In this way we tracked insect movements between individually recognizable trees by means of their pollen cargo and documented the movement of C. arabicus between known trees separated by more than 160 km, with a mean distance for confirmed successful pollination events of 88.6 km. The predominant observed movement of pollinators was in a westerly direction, toward the sea, reflecting seasonal nighttime wind direction and the wind-borne dispersal of fig wasps. Our results suggest the existence of an extensive panmictic population of trees that are well suited to overcome the effects of geographical isolation.

Encapsulation of hygroscopic liquids via polymer precipitation in non-aqueous emulsions.

HYPOTHESIS: Encapsulation of ionic liquids (ILs) and phase change materials (PCMs) can overcome limitations associated with bulk materials, e.g., slow mass transfer rates, high viscosities, or susceptibility to external environment. Single step soft-templated encapsulation methods commonly use interfacial polymerization for shell formation, with a multifunctional monomer in the continuous phase and another in the discontinuous phase, and thus do not give pristine core material. We posit that polymer precipitation onto emulsion droplets in non-aqueous emulsions could produce a robust shell without contamination of the core, ideal for the encapsulation of water-sensitive or water-miscible materials. EXPERIMENTS: Solutions of commodity polymers were added to the continuous phase of non-aqueous Pickering emulsions stabilized by alkylated graphene oxide (GO) nanosheets such that the change in solubility of the polymer led to formation of robust shells and the production of capsules that could be isolated. FINDINGS: We demonstrate that a polymer precipitation approach can produce capsules with pristine core of the IL 1-ethyl-3-methylimidazolium hexafluorophosphate [Emim][PF6] or the salt hydrate PCM magnesium nitrate hexahydrate (MNH) and shell of nanosheets and polystyrene, poly(methyl methacrylate), or polyethylene. The capsules are approximately 80 wt% [Emim][PF6] or >90 wt% MNH, and the core can undergo multiple cycles of solidification and melting without leakage or destruction. This novel, single-step methodology provides a distinct advantage to access capsules with pristine core composition and is amenable to different core and shell, paving the way for tailoring capsule composition for desired applications.

Endosomal cargo recycling mediated by Gpa1 and phosphatidylinositol 3-kinase is inhibited by glucose starvation.

Cell surface protein trafficking is regulated in response to nutrient availability, with multiple pathways directing surface membrane proteins to the lysosome for degradation in response to suboptimal extracellular nutrients. Internalized protein and lipid cargoes recycle back to the surface efficiently in glucose-replete conditions, but this trafficking is attenuated following glucose starvation. We find that cells with either reduced or hyperactive phosphatidylinositol 3-kinase (PI3K) activity are defective for endosome to surface recycling. Furthermore, we find that the yeast Gα subunit Gpa1, an endosomal PI3K effector, is required for surface recycling of cargoes. Following glucose starvation, mRNA and protein levels of a distinct Gα subunit Gpa2 are elevated following nuclear translocation of Mig1, which inhibits recycling of various cargoes. As Gpa1 and Gpa2 interact at the surface where Gpa2 concentrates during glucose starvation, we propose that this disrupts PI3K activity required for recycling, potentially diverting Gpa1 to the surface and interfering with its endosomal role in recycling. In support of this model, glucose starvation and overexpression of Gpa2 alter PI3K endosomal phosphoinositide production. Glucose deprivation therefore triggers a survival mechanism to increase retention of surface cargoes in endosomes and promote their lysosomal degradation.

A Pilot Study to Assess Urban, Fire-Based Paramedic Accuracy in Identification of Anatomical Landmarks Necessary for Cricothyrotomy and Needle Chest Decompression Using Live Patient Models.

BACKGROUND: Cricothyrotomy and chest needle decompression (NDC) have a high failure and complication rate. This article sought to determine whether paramedics can correctly identify the anatomical landmarks for cricothyrotomy and chest NDC. METHODS: A prospective study using human models was performed. Paramedics were partnered and requested to identify the location for cricothyrotomy and chest NDC (both mid-clavicular and anterior axillary sites) on each other. A board-certified or board-eligible emergency medicine physician timed the process and confirmed location accuracy. All data were collected de-identified. Descriptive analysis was performed on continuous data; chi-square was used for categorical data. RESULTS: A total of 69 participants were recruited, with one excluded for incomplete data. The paramedics had a range of six to 38 (median 14) years of experience. There were 28 medical training officers (MTOs) and 41 field paramedics. Cricothyroidotomy location was correctly identified in 56 of 68 participants with a time to identification range of 2.0 to 38.2 (median 8.6) seconds. Chest NDC (mid-clavicular) location was correctly identified in 54 of 68 participants with a time to identification range of 3.4 to 25.0 (median 9.5) seconds. Chest NDC (anterior axillary) location was correctly identified in 43 of 68 participants with a time to identification range of 1.9 to 37.9 (median 9.6) seconds. Chi-square (2-tail) showed no difference between MTO and field paramedic in cricothyroidotomy site (P = .62), mid-clavicular chest NDC site (P = .21), or anterior axillary chest NDC site (P = .11). There was no difference in time to identification for any procedure between MTO and field paramedic. CONCLUSION: Both MTOs and field paramedics were quick in identifying correct placement of cricothyroidotomy and chest NDC location sites. While time to identification was clinically acceptable, there was also a significant proportion that did not identify the correct landmarks.

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.

Diabetic Muscle Infarction.

A 58-year-old male with past medical history of diabetes mellitus presented with pain to the bilateral groin for six weeks. Magnetic resonance imaging of the patient's lower extremities revealed acute myoedema, and he was diagnosed with myositis secondary to diabetic muscle infarction.

Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.

PURPOSE: Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. PATIENTS AND METHODS: We defined a molecular high-grade (MHG) group by applying a gene expression-based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. RESULTS: The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. CONCLUSION: MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.

Genetic Diversity in the UV Sex Chromosomes of the Brown Alga Ectocarpus.

Three types of sex chromosome system exist in nature: diploid XY and ZW systems and haploid UV systems. For many years, research has focused exclusively on XY and ZW systems, leaving UV chromosomes and haploid sex determination largely neglected. Here, we perform a detailed analysis of DNA sequence neutral diversity levels across the U and V sex chromosomes of the model brown alga Ectocarpus using a large population dataset. We show that the U and V non-recombining regions of the sex chromosomes (SDR) exhibit about half as much neutral diversity as the autosomes. This difference is consistent with the reduced effective population size of these regions compared with the rest of the genome, suggesting that the influence of additional factors such as background selection or selective sweeps is minimal. The pseudoautosomal region (PAR) of this UV system, in contrast, exhibited surprisingly high neutral diversity and there were several indications that genes in this region may be under balancing selection. The PAR of Ectocarpus is known to exhibit unusual genomic features and our results lay the foundation for further work aimed at understanding whether, and to what extent, these structural features underlie the high level of genetic diversity. Overall, this study fills a gap between available information on genetic diversity in XY/ZW systems and UV systems and significantly contributes to advancing our knowledge of the evolution of UV sex chromosomes.