Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation.

BACKGROUND: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. OBJECTIVES: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. METHODS: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). RESULTS: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). CONCLUSIONS: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.

Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes.

Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKß-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.

Hepatic Venous Pressure Gradient: Measurement and Pitfalls.

Measurement of hepatic venous pressure gradient (HVPG) effectively mirrors the severity of portal hypertension (PH) and offers valuable insights into prognosis of liver disease, including the risk of decompensation and mortality. Additionally, HVPG offers crucial information about treatment response to nonselective beta-blockers and other medications, with its utility demonstrated in clinical trials in patients with PH. Despite the widespread dissemination and validation of noninvasive tests, HVPG still holds a significant role in hepatology. Physicians treating patients with liver diseases should comprehend the HVPG measurement procedure, its applications, and how to interpret the results and potential pitfalls.

Museomics help resolving the phylogeny of snowfinches (Aves, Passeridae, Montifringilla and allies).

Historical specimens from museum collections provide a valuable source of material also from remote areas or regions of conflict that are not easily accessible to scientists today. With this study, we are providing a taxon-complete phylogeny of snowfinches using historical DNA from whole skins of an endemic species from Afghanistan, the Afghan snowfinch, Pyrgilauda theresae. To resolve the strong conflict between previous phylogenetic hypotheses, we generated novel mitogenome sequences for selected taxa and genome-wide SNP data using ddRAD sequencing for all extant snowfinch species endemic to the Qinghai-Tibet Plateau (QTP) and for an extended intraspecific sampling of the sole Central and Western Palearctic snowfinch species (Montifringilla nivalis). Our phylogenetic reconstructions unanimously refuted the previously suggested paraphyly of genus Pyrgilauda. Misplacement of one species-level taxon (Onychostruthus tazcanowskii) in previous snowfinch phylogenies was undoubtedly inferred from chimeric mitogenomes that included heterospecific sequence information. Furthermore, comparison of novel and previously generated sequence data showed that the presumed sister-group relationship between M. nivalis and the QTP endemic M. henrici was suggested based on flawed taxonomy. Our phylogenetic reconstructions based on genome-wide SNP data and on mitogenomes were largely congruent and supported reciprocal monophyly of genera Montifringilla and Pyrgilauda with monotypic Onychostruthus being sister to the latter. The Afghan endemic P. theresae likely originated from a rather ancient Pliocene out-of-Tibet dispersal probably from a common ancestor with P. ruficollis. Our extended trans-Palearctic sampling for the white-winged snowfinch, M. nivalis, confirmed strong lineage divergence between an Asian and a European clade dated to 1.5 - 2.7 million years ago (mya). Genome-wide SNP data suggested subtle divergence among European samples from the Alps and from the Cantabrian mountains.

Species interactions affect dispersal: a meta-analysis.

Context-dependent dispersal allows organisms to seek and settle in habitats improving their fitness. Despite the importance of species interactions in determining fitness, a quantitative synthesis of how they affect dispersal is lacking. We present a meta-analysis asking (i) whether the interaction experienced and/or perceived by a focal species (detrimental interaction with predators, competitors, parasites or beneficial interaction with resources, hosts, mutualists) affects its dispersal; and (ii) how the species' ecological and biological background affects the direction and strength of this interaction-dependent dispersal. After a systematic search focusing on actively dispersing species, we extracted 397 effect sizes from 118 empirical studies encompassing 221 species pairs; arthropods were best represented, followed by vertebrates, protists and others. Detrimental species interactions increased the focal species' dispersal (adjusted effect: 0.33 [0.06, 0.60]), while beneficial interactions decreased it (-0.55 [-0.92, -0.17]). The effect depended on the dispersal phase, with detrimental interactors having opposite impacts on emigration and transience. Interaction-dependent dispersal was negatively related to species' interaction strength, and depended on the global community composition, with cues of presence having stronger effects than the presence of the interactor and the ecological complexity of the community. Our work demonstrates the importance of interspecific interactions on dispersal plasticity, with consequences for metacommunity dynamics.This article is part of the theme issue 'Diversity-dependence of dispersal: interspecific interactions determine spatial dynamics'.

Interaction of sedentary behaviour and educational level in breast cancer risk.

OBJECTIVE: This cross-sectional study aims to analyse the relationship between sedentary behaviour and breast cancer (BC) risk from a social perspective. METHODS: Women aged 45-70 who participated in the Valencia Region Breast Cancer Screening Programme (2018-2019) were included, with a total of 121,359 women analysed, including 506 with cancer and 120,853 without cancer. The response variable was BC (screen-detected) and the main explanatory variable was sedentary behaviour (≤2 / >2-≤3 / >3-≤5 / >5 hours/day, h/d). Nested logistic regression models (M) were estimated: M1: sedentary behaviour adjusted for age and family history of BC; M2: M1 + hormonal/reproductive variables (menopausal status, number of pregnancies, hormone replacement therapy; in addition, months of breastfeeding was added for a subsample of women with one or more live births); M3: M2 + lifestyle variables (body mass index, smoking habits); M4: M3 + socioeconomic variables (educational level, occupation); Final model: M4 + gender variables (childcare responsibilities, family size). Interaction between sedentary behaviour and educational level was analysed in the Final model. Moreover, for the whole sample, postmenopausal women and HR+ BC, the Final model was stratified by educational level. RESULTS: Sedentary behaviour was associated with an increased risk of BC with a nearly statistically significant effect in the Final model (>2-≤3 h/d: OR = 1.22 (0.93-1.61); >3-≤5 h/d: OR = 1.14 (0.86-1.52); >5: OR = 1.19 (0.89-1.60)). For women with a low educational level, sitting more than 2 h/d was associated with an increased risk of BC in the whole sample (>2-≤3 h/d OR = 1.93 (1.19-3.21); in postmenopausal women (>2-≤3 h/d, OR = 2.12 (1.18-2.96), >5h/d OR = 1.75 (1.01-3.11)) and in HR+ BC (>2-≤3h/d, OR = 2.15 (1.22-3.99)). Similar results were observed for women with one or more live births. Conclusions Sitting >2 h/d is associated with BC risk in women with low educational level, especially in postmenopausal women and those with live births.

Family centeredness of care: a cross-sectional study in intensive care units part of the European society of intensive care medicine.

PURPOSE: To identify key components and variations in family-centered care practices. METHODS: A cross-sectional study, conducted across ESICM members. Participating ICUs completed a questionnaire covering general ICU characteristics, visitation policies, team-family interactions, and end-of-life decision-making. The primary outcome, self-rated family-centeredness, was assessed using a visual analog scale. Additionally, respondents completed the Maslach Burnout Inventory and the Ethical Decision Making Climate Questionnaire to capture burnout dimensions and assess the ethical decision-making climate. RESULTS: The response rate was 53% (respondents from 359/683 invited ICUs who actually open the email); participating healthcare professionals (HCPs) were from Europe (62%), Asia (9%), South America (6%), North America (5%), Middle East (4%), and Australia/New Zealand (4%). The importance of family-centeredness was ranked high, median 7 (IQR 6-8) of 10 on VAS. Significant differences were observed across quartiles of family centeredness, including in visitation policies availability of a waiting rooms, family rooms, family information leaflet, visiting hours, night visits, sleep in the ICU, and in team-family interactions, including daily information, routine day-3 conference, and willingness to empower nurses and relatives. Higher family centeredness correlated with family involvement in rounds, participation in patient care and end-of-life practices. Burnout symptoms (41% of respondents) were negatively associated with family-centeredness. Ethical climate and willingness to empower nurses were independent predictors of family centeredness. CONCLUSIONS: This study emphasizes the need to prioritize healthcare providers' mental health for enhanced family-centered care. Further research is warranted to assess the impact of improving the ethical climate on family-centeredness.

Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

Coping with unpredictable environments: fine-tune foraging microhabitat use in relation to prey availability in an alpine species.

Microhabitat utilisation holds a pivotal role in shaping a species' ecological dynamics and stands as a crucial concern for effective conservation strategies. Despite its critical importance, microhabitat use has frequently been addressed as static, centering on microhabitat preference. Yet, a dynamic microhabitat use that allows individuals to adjust to fine-scale spatio-temporal prey fluctuations, becomes imperative for species thriving in challenging environments. High-elevation ecosystems, marked by brief growing seasons and distinct abiotic processes like snowmelt, winds, and solar radiation, feature an ephemeral distribution of key resources. To better understand species' strategies in coping with these rapidly changing environments, we delved into the foraging behaviour of the white-winged snowfinch Montifringilla nivalis, an emblematic high-elevation passerine. Through studying microhabitat preferences during breeding while assessing invertebrate prey availability, we unveiled a highly flexible microhabitat use process. Notably, snowfinches exhibited specific microhabitat preferences, favoring grass and melting snow margins, while also responding to local invertebrate availability. This behaviour was particularly evident in snow-associated microhabitats and less pronounced amid tall grass. Moreover, our investigation underscored snowfinches' fidelity to foraging sites, with over half located within 10 m of previous spots. This consistent use prevailed in snow-associated microhabitats and high-prey-density zones. These findings provide the first evidence of dynamic microhabitat use in high-elevation ecosystems and offer further insights into the crucial role of microhabitats for climate-sensitive species. They call for multi-faceted conservation strategies that go beyond identifying and protecting optimal thermal buffering areas in the face of global warming to also encompass locations hosting high invertebrate densities.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Best practices for iatrogenic anaemia prevention in the intensive care unit: Blood-sparing techniques.

Anaemia is a common issue in patients who are admitted to intensive care units and worsens their condition throughout the stay due to the extraction of blood for diagnostic purposes. It is also well-known that an important amount of the carbon dioxide produced by health services is likely attributable to blood donation, testing and manufacture, storage or distribution of blood components. This must be taken into account to perform nursing interventions consistent with the idea of sustainable health care. In this regard, within patient blood management bundles, with the objective of minimizing the use of blood products, it is recommended to use blood-sparing techniques: small volume tubes (SVT) or closed-blood sampling devices (CBSD). Published studies before 2014 (excepting two more recent ones) have shown that by themselves, both techniques reduce drawn volume but do not decrease haemoglobin reduction and/or need of transfusion. Given the lack of cost-effectiveness studies, it may be easier to implement the use of CBSD as it does not require prior consensus on the discard volume or adaptations in the processing of laboratory tests, as is the case with SVT.

SEOM-GEINO clinical guidelines for grade 2 gliomas (2023).

The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.

Combination of Model for End-Stage Liver Disease (MELD) and Sarcopenia predicts mortality after transjugular intrahepatic portosystemic shunt (TIPS).

TIPS is the most effective treatment for portal hypertension. Patient selection remains important to achieving optimal post-TIPS outcomes. The study evaluates 1-year mortality factors in cirrhotic patients receiving TIPS. METHODS: 87 cirrhotic patients received a TIPS between 2015 - 2021. Predictors of 1-year and overall mortality were assessed by estimating cumulative incidence functions and Grey's test to adjust for liver transplantation as a risk competing with mortality. Variables with p < 0.05 were checked for collinearity and included in the multivariate Cox proportional hazards model. Model discrimination was evaluated by calculating the area under the ROC curve. RESULTS: 87 patients were included (68% men; 22% ≥70 years). ALD was the primary cirrhosis cause. Most patients were Child-Pugh class B, MELD-Na score was 13.6 ± 6.0 points. The most frequent indication for TIPS was bleeding (51.7%), followed by refractory ascites (42.5%). The variables positively associated with mortality in univariate analysis were ascites, clinically overt sarcopenia and MELD-Na score, while ongoing nutritional supplementation improved survival. In the multivariate analysis, only clinically overt sarcopenia and MELD-Na score remained independently associated with mortality. A MELD-Na/sarcopenia model demonstrated a good discrimination, AUROC: 0.86 (95% CI 0.77 - 0.95). CONCLUSION: MELD-Na score, and sarcopenia were significantly associated with 1-year survival in cirrhotic patients who received TIPS.

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Strain Elastography Fat-to-Lesion Index Is Associated with Mammography BI-RADS Grading, Biopsy, and Molecular Phenotype in Breast Cancer.

Breast cancer (BC) affects millions of women worldwide, causing over 500,000 deaths annually. It is the leading cause of cancer mortality in women, with 70% of deaths occurring in developing countries. Elastography, which evaluates tissue stiffness, is a promising real-time minimally invasive technique for BC diagnosis. This study assessed strain elastography (SE) and the fat-to-lesion (F/L) index for BC diagnosis. This prospective study included 216 women who underwent SE, ultrasound, mammography, and breast biopsy (108 malignant, 108 benign). Three expert radiologists performed imaging and biopsies. Mean F/L index was 3.70 ± 2.57 for benign biopsies and 18.10 ± 17.01 for malignant. We developed two predictive models: a logistic regression model with AUC 0.893, 79.63% sensitivity, 87.62% specificity, 86.9% positive predictive value (+PV), and 80.7% negative predictive value (-PV); and a neural network with AUC 0.902, 80.56% sensitivity, 88.57% specificity, 87.9% +PV, and 81.6% -PV. The optimal Youden F/L index cutoff was >5.76, with 84.26% sensitivity and specificity. The F/L index positively correlated with BI-RADS (Spearman's r = 0.073, p < 0.001) and differed among molecular subtypes (Kruskal-Wallis, p = 0.002). SE complements mammography for BC diagnosis. With adequate predictive capacity, SE is fast, minimally invasive, and useful when mammography is contraindicated.

Pleiotropic Effects of PhaR Regulator in Bradyrhizobium diazoefficiens Microaerobic Metabolism.

Bradyrhizobium diazoefficiens can live inside soybean root nodules and in free-living conditions. In both states, when oxygen levels decrease, cells adjust their protein pools by gene transcription modulation. PhaR is a transcription factor involved in polyhydroxyalkanoate (PHA) metabolism but also plays a role in the microaerobic network of this bacterium. To deeply uncover the function of PhaR, we applied a multipronged approach, including the expression profile of a phaR mutant at the transcriptional and protein levels under microaerobic conditions, and the identification of direct targets and of proteins associated with PHA granules. Our results confirmed a pleiotropic function of PhaR, affecting several phenotypes, in addition to PHA cycle control. These include growth deficiency, regulation of carbon and nitrogen allocation, and bacterial motility. Interestingly, PhaR may also modulate the microoxic-responsive regulatory network by activating the expression of fixK2 and repressing nifA, both encoding two transcription factors relevant for microaerobic regulation. At the molecular level, two PhaR-binding motifs were predicted and direct control mediated by PhaR determined by protein-interaction assays revealed seven new direct targets for PhaR. Finally, among the proteins associated with PHA granules, we found PhaR, phasins, and other proteins, confirming a dual function of PhaR in microoxia.

Influence of seasonality and biological activity on infection by helminths in Cantabrian bear.

This study aimed to investigate the variations of parasites in the feces of brown bears Ursus arctos inhabiting the Cantabrian Mountains (NW Spain). A total of 248 bear fecal samples were collected throughout one year, spanning from August 2018 to September 2019, at an approximate frequency of 20 samples per month. The results were analyzed in relation to both the season and the biological activity of the brown bears, i.e., hibernation, mating and hyperphagia. Among the examined samples, eggs of Dicrocoelium dendriticum (32.2%; 95% Confidence Interval: 26.4-38.1), Baylisascaris sp. (44.8%; 38.5-50.9), ancylostomatids (probably belonging to Uncinaria spp.) (16.5%; 11.9-21.1) and Trichuris sp. (1.2%; 0-2.6) were observed. Significant seasonal differences were noted for Baylisascaris and ancylostomatids (χ2 = 21.02, P = 0.001 and χ2 = 34.41, P = 0.001, respectively). Furthermore, the presence of helminth eggs was correlated with the activity phase of the brown bears. Dicrocoelium attained the highest prevalence during the mating phase, while Baylisascaris and ancylostomatids were more frequent during hyperphagia. Notably, the highest egg-output counts for Dicrocoelium and Baylisascaris sp. were recorded during the mating phase and hibernation, respectively, whereas ancylostomatids eggs peaked during hyperphagia. Additionally, variations in egg-output counts were significant for all helminths concerning the season, with the exception of Trichuris sp., and for Dicrocoelium and Baylisascaris sp. According to bear activity. It is concluded that infection by gastrointestinal helminths depends on the season and the biological activity of the bears from the Cantabrian Mountains, and their health status could result influenced.

Transient Synaptic Enhancement Triggered by Exogenously Supplied Monocarboxylate in Drosophila Motoneuron Synapse.

Current evidence suggests that glial cells provide C3 carbon sources to fuel neuronal activity; however, this notion has become challenged by biosensor studies carried out in acute brain slices or in vivo, showing that neuronal activity does not rely on the import of astrocyte-produced L-lactate. Rather, stimulated neurons become net lactate exporters, as it was also shown in Drosophila neurons, in which astrocyte-provided lactate returns as lipid droplets to be stored in glial cells. In this view, we investigate whether exogenously supplied monocarboxylates can support Drosophila motoneuron neurotransmitter release (NTR). By assessing the excitatory post-synaptic current (EPSC) amplitude under voltage-clamp as NTR indicative, we found that both pyruvate and L-lactate, as the only carbon sources in the synapses bathing-solution, cause a large transient NTR enhancement, which declines to reach a synaptic depression state, from which the synapses do not recover. The FM1-43 pre-synaptic loading ability, however, is maintained under monocarboxylate, suggesting that SV cycling should not contribute to the synaptic depression state. The NTR recovery was reached by supplementing the monocarboxylate medium with sucrose. However, monocarboxylate addition to sucrose medium does not enhance NTR, but it does when the disaccharide concentration becomes too reduced. Thus, when pyruvate concentrations become too reduced, exogenously supplied L-lactate could be converted to pyruvate and metabolized by the neural mitochondria, triggering the NTR enhancement. SIGNIFICANCE STATEMENT: The question of whether monocarboxylic acids can fuel the Drosophila motoneuron NTR was challenged. Our findings show that exogenously supplied monocarboxylates trigger a large transient synaptic enhancement just under extreme glycolysis reduction but fail to maintain NTR under sustained synaptic demand, still at low frequency stimulation, driven to the synapses to a synaptic depression state. Glycolysis activation, by adding sucrose to the monocarboxylate bath solution, restores the motoneuron NTR ability, giving place to a hexoses role in SV recruitment. Moreover these results suggest exogenously supplied C3 carbon sources could have an additional role beyond providing energetic support for neural activity.

Prevalence and clinical characteristics of uveitic glaucoma: multicentric study in Bogotá, Colombia.

OBJECTIVES: To describe the clinical features of patients diagnosed with uveitic glaucoma (UG) and ocular hypertension secondary to uveitis (OHT-SU). METHODS: A multicentric cross-sectional study using medical records of patients with uveitis between 2013 and 2021. Uveitis and glaucoma specialists examined all patients. Variables were analyzed using the chi-square or Fisher's exact test for categorical variables. Additionally, t test, Mann-Whitney, and Kruskal-Wallis variance analysis were used for continuous variables. Finally, a Kaplan-Meier survival analysis for UG and OHT-SU development over time was done. RESULTS: Of the 660 clinical records reviewed of patients with uveitis, 191 (28.9%) had OHT-SU in at least one visit, and 108 (16.4%) of them developed UG. In all ages, females were more affected than males. Anterior uveitis was the main anatomic localisation, and non-granulomatous, recurrent, and inactive uveitis were the most frequent clinical features. The mean final visual acuity was 0.3 (0.0-1.0) LogMAR. Also, 95.8% of the patients had additional sequelae related to uveitis regardless of UG and OHT-SU. Interestingly, males had earlier affection, with statistical significance in OHT for adults (P = 0.036) and UG for children (P = 0.04). Of all patients, 81.1% received topical hypotensive treatment and 29.8% required a surgical procedure. CONCLUSIONS: UG and OHT-SU are common complications of uveitis in the Colombian population. These sight-threatening conditions were more common and appeared sooner in men at any age. Our results suggest that earlier and more aggressive treatment with topical hypotensive agents could positively influence the visual outcomes and the requirement of surgical procedures.