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Summary: Preeclampsia is a major hypertensive pregnancy disorder with a 50% heritability. The first identified gene involved in the disease is STOX1, a transcription factor, whose variant Y153H predisposes to the disease. Two rare mutations were also identified in Colombian women affected by the hemolysis, elevated liver enzyme, low platelet syndrome, a complication of preeclampsia (T188N and R364X). Here, we explore the effects of these variants in trophoblast cell models (BeWo) where STOX1 was previously invalidated. We firstly showed that STOX1 knockout alters response to oxidative stress, cell proliferation, and fusion capacity. Then, we showed that mutant versions of STOX1 trigger alterations in gene profiles, growth, fusion, and oxidative stress management. The results also reveal alterations of the STOX interaction with DNA when the mutations affected the DNA-binding domain of STOX1 (Y153H and T188N). We also reveal here that a major contributor of these effects appears to be the E2F3 transcription factor.

The process of sharing of data has become easier than ever with the advancement of cloud computing and software tools. However, big challenges remain such as efficient handling of big geospatial data, supporting and sharing of crowd sourced/citizen science data, integration with semantic heterogeneity, and inclusion of agile processes for continuous improvement of geospatial technology. This paper discusses the new frontiers regarding these challenges and the related work performed by the Open Geospatial Consortium, the world leading organization focused on developing open geospatial standards that “geo-enable” the Web, wireless, and location-based services and mainstream IT.

We report 1 case of lobomycosis caused by Lacazia loboi in a fisherman and 1 case of lobomycosis-like disease in a bottlenose dolphin (Tursiops truncatus) along the coast of Venezuela. These findings suggest that the marine environment is a likely habitat for L. loboi and a reservoir for infection.

Abstract By analyzing a mouse Interspecific Recombinant Congenic Strain (IRCS), we previously identified a quantitative trait locus (QTL), called Mafq1 on mouse chromosome 1, that is associated with male hypofertility and ultrastructural sperm abnormalities. Within this locus, we identified a new candidate gene that could be implicated in a reproductive phenotype: Tex44 (Testis-expressed protein 44). We thus performed a CRISPR/Cas9-mediated complete deletion of this gene in mice in order to study its function. Tex44-KO males were severely hypofertile in vivo and in vitro due to a drastic reduction of sperm motility which itself resulted from important morphological sperm abnormalities. Namely, Tex44-KO sperm showed a disorganized junction between the midpiece and the principal piece of the flagellum, leading to a 180° flagellar bending in this region. In addition, the loss of some axonemal microtubule doublets and outer dense fibers in the flagellum’s principal piece has been observed. Our results suggest that, in mice, TEX44 is implicated in the correct set-up of the sperm flagellum during spermiogenesis and its absence leads to flagellar abnormalities and consequently to severe male hypofertility. Graphical Abstract

Abstract Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation or silencing of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. In the present study, a systematic evaluation of DNA repair addiction at the pan-cancer level was performed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). From 241 DDR genes, 59 were identified as commonly essential in cancer cell lines. However, large differences were observed in terms of dependency scores in 423 cell lines and transcriptomic alterations across 18 cancer types. Among these 59 commonly essential genes, 14 genes were exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes like UBE2T, RFC4, POLQ, BRIP1, and H2AFX showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival. The present study supports the existence and importance of non-oncogenic addiction to DNA repair in cancer and may facilitate the identification of prognostic biomarkers and therapeutic opportunities.

Abstract Mutations in DNA repair enzymes can cause two neurological clinical manifestations: a developmental impairment and a degenerative disease. Polynucleotide kinase 3′-phosphatase (PNKP) is an enzyme that is actively involved in DNA repair in both single and double strand break repair systems. Mutations in this protein or others in the same pathway are responsible for a complex group of diseases with a broad clinical spectrum. Besides, mitochondrial dysfunction also has been consolidated as a hallmark of brain degeneration. Here we provide evidence that supports a shared role between mitochondrial dysfunction and DNA repair defects in the pathogenesis of the nervous system. As models, we analyze PNKP-related disorders, focusing on Charcot-Marie-Tooth disease and ataxia. A better understanding of the molecular dynamics of this relationship could provide improved diagnosis and treatment for neurological diseases.

Five decades ago, Franz Halberg conceived the idea of ​​a circadian-based therapy for cancer, given the differential tolerance to treatment derived from the intrinsic host rhythms. Nowadays, different experimental models have demonstrated that both the toxicity and efficacy of several anticancer drugs vary by more than 50% as a function of dosing time. Accordingly, it has been shown that chemotherapeutic regimens optimally timed with the circadian cycle have jointly improved patient outcomes both at the preclinical and clinical levels. Along with chemotherapy, radiation therapy is widely used for cancer treatment, but its effectiveness relies mainly on its ability to damage DNA. Notably, the DNA damage response including DNA repair, DNA damage checkpoints, and apoptosis is gated by the circadian clock. Thus, the therapeutic potential of circadian-based radiotherapy against cancer is mainly dependent upon the control that the molecular clock exerts on DNA repair enzymes across the cell cycle. Unfortunately, the time of treatment administration is not usually considered in clinical practice as it varies along the daytime working hours. Currently, only a few studies have evaluated whether the timing of radiotherapy affects the treatment outcome. Several of these studies show that it is possible to reduce the toxicity of the treatment if it is applied at a specific time range, although with some inconsistencies. In this Perspective, we review the main advances in the field of chronoradiotherapy, the possible causes of the inconsistencies observed in the studies so far and provide some recommendations for future trials.

La epibiosis es una estrategia común en muchos organismos acuáticos, y puede constituir una herramienta de estudio muy valiosa en ecología y conservación. Las ballenas barbadas conforman un taxón muy vulnerable a las pesquerías, lo que exige grandes esfuerzos para su preservación. El varamiento de un ejemplar macho de Balaenoptera physalus en aguas del nororiente venezolano permitió evaluar puntualmente el fenómeno epibiótico. El tegumento del cetáceo fue evaluado in situ, trasladándose algunas barbas al laboratorio para su estudio pormenorizado. El único epibionte observado, aunque en número muy abundante, fue el copépodo harpacticoide Balaenophilus unisetus. Se describen los diferentes estadios de desarrollo detectados: adulto, copepoditos (cinco) y nauplios (tres), acompañándose de ilustraciones y las mediciones pertinentes. Se presentan y discuten aspectos morfológicos, biogeográficos y de hospedero. Resalta de este estudio: la expansión del ámbito geográfico del copépodo, siendo el primer registro en aguas del Atlántico Occidental, caribeñas y venezolanas; la observación de algunos pocos caracteres morfológicos discrepantes a los previamente descritos, los cuales pudieran referir a distintos morfotipos del epibionte; y la primera detección de un tercer estadio naupliar para B. unisetus.

The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term "Wald's domain" for future studies analyzing the possible survivorship bias in multidomain proteins.

Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family. Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients.

AIM:This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. PATIENTS & METHODS:A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. RESULTS:The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p

En este estudio se evaluó la fluctuación en la población de Haematobia irritans de febrero 2004 a febrero 2005, en Martínez de la Torre, Veracruz, México. Se utilizaron 15 vaquillas F1 (Holstein por Brahman) de 11 Ó 2 meses de edad y 170 Ó 19 kg de peso, infestadas en forma natural por la H. irritans. La población de moscas se correlacionó con cinco variables climáticas y se evaluó por medio de conteos semanales con observaciones directas a los bovinos a potrero. La mosca H. irritans estuvo presente todo el año (35,1 Ó 35,2 moscas/animal); sin embargo, las mayores infestaciones con esta plaga se registraron en los meses de septiembre y octubre. El pico poblacional de H. irritans fue de 121 moscas/ animal. El grado de infestación estuvo asociado principalmente con la precipitación acumulada (r = 0,70, P menor 0,05). Otros factores como la temperatura y humedad relativa, también fueron importantes en determinar la incidencia y nivel de infestación de ataque de este ecto-parásito. Se concluye que en esta región, el control de la H. irritans debe realizarse hacia el final de la época de lluvias y principios de la época de tormentas invernales.

The diagnosis and management of vulnerable plaques are topics of high interest in the cardiovascular field. Although imaging techniques like computed tomography angiography (MCTA) and ultrasonography (USG) can structurally evaluate atherosclerotic plaques, they are limited in examining internal cellular processes. Positron emission tomography (PET) molecular imaging, on the other hand, can highlight these cellular processes, including inflammation, angiogenesis, and lipid oxidation. Magnetic resonance imaging (MRI) is also a valuable non-invasive imaging technique that can provide detailed anatomical and functional information on the cardiovascular system. In this review, we compare the advantages and drawbacks of MCTA, USG and MRI imaging techniques with PET molecular imaging in evaluating vulnerable plaques. PET imaging allows physicians to measure different pathophysiological events within the plaque using intravenous radiotracers, of which 18F-fluorodeoxyglucose (18F-FDG) is the most validated one. By using 18F-FDG, physicians can understand the formation of the plaque, assess the accumulation of macrophages, and predict major cardiovascular events. However, some limitations exist in using 18F-FDG, including myocardial uptake and low sensitivity in imaging coronary arteries. We also mention other radiotracers that can help in evaluating vulnerable plaques, including 18F-NaF. Although PET imaging is still challenging, it has shown promise in evaluating vulnerable plaques and could be used to intervene in high-risk patients before major cardiovascular events occur.

Subcapsular renal hematomas may appear spontaneously in patients in chronic hemodialysis, though other causes as neoplasms, vasculitis, and infections should be excluded. Patients may present with abdominal pain and hemorrhagic shock; hence, early diagnosis is vital. Nephrectomy or renal artery embolization are suitable treatment options.

Ischemia-reperfusion injury is a common problem in the age of interventional cardiology; it is primarily mediated by oxidative stress and reactive agents. Melatonin has antioxidative properties that make its use promising for treating ischemia-reperfusion injury. Multiple experimental studies in murine and porcine models have been performed with good results. Clinical trials have also been conducted but given their heterogeneity, no conclusive results can be made. Melatonin pharmacokinetic properties are not ideal; therefore, many analogs have been proposed with improved characteristics, and some studies have evaluated their efficacy in animal models, but clinical trials are needed to recommend their use. In this review, we expose the results of the most impactful studies regarding melatonin use in ischemia-reperfusion injury.