The Impact of COVID-19 on the Response to Hypoxia.

Louis, Alexandre, Charlotte Pröpper, Yann Savina, Corentin Tanne, Guy Duperrex, Paul Robach, Pascal Zellner, Stéphane Doutreleau, Jean-Michel Boulet, Alain Frey, Fabien Pillard, Cristina Pistea, Mathias Poussel, Thomas Thuet, Jean-Paul Richalet, and François Lecoq-Jammes. The impact of COVID-19 on the response to hypoxia. High Alt Med Biol. 24:321-328, 2023. Background: Severe high-altitude illness (SHAI) and coronavirus disease 2019 (COVID-19), while differing in most aspects of pathophysiology, both involve respiratory capacity. We examined the long-term impact of COVID-19 on response to hypoxia in individuals free of symptoms but having tested positive during the pandemic. The need for recommendations for such individuals planning a stay at high altitude are discussed. Methods: This multicenter study recruited participants from the multiSHAI cohort, all of whom had previously undergone a hypoxic exercise test. These participants were classified into two groups depending on whether they had since suffered mild-to-moderate COVID-19 (COVID+) or not (Control) and then asked to retake the test. Primary outcomes were: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise, hypoxic ventilatory response at exercise, and SHAI risk score. Results: A total of 68 participants retook the test, 36 classified in the COVID+ group. Analyses of primary outcomes showed no significant differences between groups. However, the COVID+ group showed significantly increased ventilation (VE) parameters during both hypoxic (p = 0.003) and normoxic exercise (p = 0.007). However, only the VE/oxygen consumption relationship during hypoxic exercise was significantly different. Conclusion: This study demonstrates no negative impact of COVID-19 on response to hypoxia as evaluated by the Richalet test. Clinical Trial Registration: NTC number: NCT05167357.

Contribution of the alternative model for DSM-5 personality disorders to relationship satisfaction.

Introduction: Personality is a central factor associated with relationship discord, conflicts, and separation, as well as with dyadic adjustment and relationship stability. The Alternative Model for Personality Disorders (AMPD) of the DSM-5 offers a hybrid model for understanding personality based on personality dysfunction (Criterion A) and pathological domains and facets (Criterion B). So far, few studies have integrated this model into the understanding of relationship quality. Therefore, the aim of this study was to examine the contribution of Criterion B to relationship satisfaction in individuals involved in an intimate relationship. We also explored the joint contribution of Criteria A and B, as well as their interaction effects, to relationship satisfaction. Methods: Participants were drawn from two clinical samples: patients with personality disorders (PD; N = 101) and clients consulting in private practice clinics (PPC; N = 350). They completed self-report questionnaires assessing relationship satisfaction and AMPD Criteria A (only for PPC sample) and B. Results: Hierarchical regressions showed that, for the PD sample, the Detachment and Negative Affectivity domains, especially the pathological facets of Intimacy Avoidance and Separation Insecurity, explained 22.5% of relationship satisfaction's variance. For PPC clients, Detachment, Negative Affectivity, and Antagonism domains, and especially the pathological facets of Intimacy Avoidance, Anxiousness, and Grandiosity, contribute significantly to relationship satisfaction, explaining 14.8% of its variance. Criterion A elements did not evince incremental value to the regression models in the PPC sample, and no Criteria A and B interaction effects were found. Clinical implications as well as limitations of the study are discussed.

Integrative analysis and prediction of human R-loop binding proteins.

In the past decade, there has been a growing appreciation for R-loop structures as important regulators of the epigenome, telomere maintenance, DNA repair, and replication. Given these numerous functions, dozens, or potentially hundreds, of proteins could serve as direct or indirect regulators of R-loop writing, reading, and erasing. In order to understand common properties shared amongst potential R-loop binding proteins, we mined published proteomic studies and distilled 10 features that were enriched in R-loop binding proteins compared with the rest of the proteome. Applying an easy-ensemble machine learning approach, we used these R-loop binding protein-specific features along with their amino acid composition to create random forest classifiers that predict the likelihood of a protein to bind to R-loops. Known R-loop regulating pathways such as splicing, DNA damage repair and chromatin remodeling are highly enriched in our datasets, and we validate 2 new R-loop binding proteins LIG1 and FXR1 in human cells. Together these datasets provide a reference to pursue analyses of novel R-loop regulatory proteins.

Preliminary Steps Toward Extracting the Specific Alternative Model for Personality Disorders Diagnoses From Criteria A and B Self-Reports.

The Alternative DSM-5 Model for Personality Disorders (AMPD) retains six specific personality disorders (PDs) that can be diagnosed based on Criterion A level of impairment and Criterion B maladaptive facets. Those specific diagnoses are still underresearched, despite the preference expressed by most PD scholars for a mixed/hybrid classification. This study explores the possibility of using Criterion A and B self-report questionnaires to extract the specific AMPD diagnoses. Plausible prevalence estimates were found in three samples (outpatient PD, private practice, community; N = 766) using the facet score ≥ 2 and t score > 65 methods for determining the presence of a Criterion B facet; diagnoses had meaningful correlations with external variables. This study provides evidence-albeit preliminary-that the extraction of the specific AMPD PDs from self-report questionnaires might be a viable avenue. Ultimately, it could promote the use and dissemination of those diagnoses for screening purposes in clinical and research settings.

ARID1A regulates R-loop associated DNA replication stress.

ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

Dynamic flows create potentially habitable conditions in Antarctic subglacial lakes.

Trapped beneath the Antarctic ice sheet lie over 400 subglacial lakes, which are considered to be extreme, isolated, yet viable habitats for microbial life. The physical conditions within subglacial lakes are critical to evaluating how and where life may best exist. Here, we propose that Earth's geothermal flux provides efficient stirring of Antarctic subglacial lake water. We demonstrate that most lakes are in a regime of vigorous turbulent vertical convection, enabling suspension of spherical particulates with diameters up to 36 micrometers. Thus, dynamic conditions support efficient mixing of nutrient- and oxygen-enriched meltwater derived from the overlying ice, which is essential for biome support within the water column. We caution that accreted ice analysis cannot always be used as a proxy for water sampling of lakes beneath a thin (<3.166 kilometers) ice cover, because a stable layer isolates the well-mixed bulk water from the ice-water interface where freezing may occur.

Improved phase-field models of melting and dissolution in multi-component flows.

We develop and analyse the first second-order phase-field model to combine melting and dissolution in multi-component flows. This provides a simple and accurate way to simulate challenging phase-change problems in existing codes. Phase-field models simplify computation by describing separate regions using a smoothed phase field. The phase field eliminates the need for complicated discretizations that track the moving phase boundary. However, standard phase-field models are only first-order accurate. They often incur an error proportional to the thickness of the diffuse interface. We eliminate this dominant error by developing a general framework for asymptotic analysis of diffuse-interface methods in arbitrary geometries. With this framework, we can consistently unify previous second-order phase-field models of melting and dissolution and the volume-penalty method for fluid-solid interaction. We finally validate second-order convergence of our model in two comprehensive benchmark problems using the open-source spectral code Dedalus.

MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts.

Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors including the MRE11-RAD50-NBS1 (MRN) complex. While MRN has been shown to promote R-loops at DNA double-strand breaks, we show that it suppresses R-loops and associated DNA damage at transcription-replication conflicts. This occurs through a non-nucleolytic function of MRE11 that is important for R-loop suppression by the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms at transcription-replication conflicts.

Chromatin as a Platform for Modulating the Replication Stress Response.

Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart.

Order Out of Chaos: Slowly Reversing Mean Flows Emerge from Turbulently Generated Internal Waves.

We demonstrate via direct numerical simulations that a periodic, oscillating mean flow spontaneously develops from turbulently generated internal waves. We consider a minimal physical model where the fluid self-organizes in a convective layer adjacent to a stably stratified one. Internal waves are excited by turbulent convective motions, then nonlinearly interact to produce a mean flow reversing on timescales much longer than the waves' period. Our results demonstrate for the first time that the three-scale dynamics due to convection, waves, and mean flow is generic and hence can occur in many astrophysical and geophysical fluids. We discuss efforts to reproduce the mean flow in reduced models, where the turbulence is bypassed. We demonstrate that wave intermittency, resulting from the chaotic nature of convection, plays a key role in the mean-flow dynamics, which thus cannot be captured using only second-order statistics of the turbulent motions.

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases.

The sigma-1 receptor (σ-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two σ-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (Δ31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The σ-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K(+) channel Kir2.1, compared with the wild-type σ-1R. Thus, these σ-1R mutants have different functional properties that could contribute to their disease phenotypes.

Fabry-Perot resonance of water waves.

We show that significant water wave amplification is obtained in a water resonator consisting of two spatially separated patches of small-amplitude sinusoidal corrugations on an otherwise flat seabed. The corrugations reflect the incident waves according to the so-called Bragg reflection mechanism, and the distance between the two sets controls whether the trapped reflected waves experience constructive or destructive interference within the resonator. The resulting amplification or suppression is enhanced with increasing number of ripples and is most effective for specific resonator lengths and at the Bragg frequency, which is determined by the corrugation period. Our analysis draws on the analogous mechanism that occurs between two partially reflecting mirrors in optics, a phenomenon named after its discoverers Charles Fabry and Alfred Perot.

Feeling but not caring: empathic alteration in narcissistic men with high psychopathic traits.

Psychopathy is a personality disorder characterized by specific interpersonal-affective deficits and social deviance often marked by reduced empathy and decreased affective response to the suffering of others. However, recent findings in community samples suggest that the somatosensory resonance to other's pain measured with electroencephalography (EEG) is increased by psychopathic traits. This study aimed at comparing both the response to physical pain and the observation of pain being inflicted to another person in individuals with clinically significant psychopathic traits, namely patients with severe narcissistic personality disorder (NPD, n=11), and community controls (CC, n=13). The gating of somatosensory responses to a tactile steady-state stimulation (25 Hz) during the observation of pain-evoking and non-painful visual stimuli of hands was measured using EEG. Pain thresholds were assessed with a quantitative sensory testing (QST) battery. NPD compared with CC subjects showed similar thermal pain thresholds, but significantly higher pain pressure thresholds (PPT). Significantly greater somatosensory gating (SG) during the anticipation and the observation of pain in others was observed in NPD compared with CC subjects, but this difference was not associated with differences in self-pain perception. SG to pain observation was positively correlated with the Impulsivity-Egocentricity (IE) dimension of psychopathy. These findings demonstrated a stronger somatosensory resonance in the high psychopathic trait NPD group that suggests an increased somatic representation of observed pain despite lower dispositional empathy.

The modulation of somatosensory resonance by psychopathic traits and empathy.

A large number of neuroimaging studies have shown neural overlaps between first-hand experiences of pain and the perception of pain in others. This shared neural representation of vicarious pain is thought to involve both affective and sensorimotor systems. A number of individual factors are thought to modulate the cerebral response to other's pain. The goal of this study was to investigate the impact of psychopathic traits on the relation between sensorimotor resonance to other's pain and self-reported empathy. Our group has previously shown that a steady-state response to non-painful stimulation is modulated by the observation of other people's bodily pain. This change in somatosensory response was interpreted as a form of somatosensory gating (SG). Here, using the same technique, SG was compared between two groups of 15 young adult males: one scoring very high on a self-reported measure of psychopathic traits [60.8 ± 4.98; Levenson's Self-Report Psychopathy Scale (LSRP)] and one scoring very low (42.7 ± 2.94). The results showed a significantly greater reduction of SG to pain observation for the high psychopathic traits group compared to the low psychopathic traits group. SG to pain observation was positively correlated with affective and interpersonal facet of psychopathy in the whole sample. The high psychopathic traits group also reported lower empathic concern (EC) scores than the low psychopathic traits group. Importantly, primary psychopathy, as assessed by the LSRP, mediated the relation between EC and SG to pain observation. Together, these results suggest that increase somatosensory resonance to other's pain is not exclusively explained by trait empathy and may be linked to other personality dimensions, such as psychopathic traits.

Very slow search and reach: failure to maximize expected gain in an eye-hand coordination task.

We examined an eye-hand coordination task where optimal visual search and hand movement strategies were inter-related. Observers were asked to find and touch a target among five distractors on a touch screen. Their reward for touching the target was reduced by an amount proportional to how long they took to locate and reach to it. Coordinating the eye and the hand appropriately would markedly reduce the search-reach time. Using statistical decision theory we derived the sequence of interrelated eye and hand movements that would maximize expected gain and we predicted how hand movements should change as the eye gathered further information about target location. We recorded human observers' eye movements and hand movements and compared them with the optimal strategy that would have maximized expected gain. We found that most observers failed to adopt the optimal search-reach strategy. We analyze and describe the strategies they did adopt.

Characterization of genes encoding for acquired bacitracin resistance in Clostridium perfringens.

Phenotypic bacitracin resistance has been reported in Clostridium perfringens. However, the genes responsible for the resistance have not yet been characterized. Ninety-nine C. perfringens isolates recovered from broilers and turkeys were tested for phenotypic bacitracin resistance. Bacitracin MIC(90) (>256 µg/ml) was identical for both turkey and chicken isolates; whereas MIC(50) was higher in turkey isolates (6 µg/ml) than in chicken isolates (3 µg/ml). Twenty-four of the 99 isolates showed high-level bacitracin resistance (MIC breakpoint >256 µg/ml) and the genes encoding for this resistance were characterized in C. perfringens c1261_A strain using primer walking. Sequence analysis and percentages of amino acid identity revealed putative genes encoding for both an ABC transporter and an overproduced undecaprenol kinase in C. perfringens c1261_A strain. These two mechanisms were shown to be both encoded by the putative bcrABD operon under the control of a regulatory gene, bcrR. Efflux pump inhibitor thioridazine was shown to increase significantly the susceptibility of strain c1261_A to bacitracin. Upstream and downstream from the bcr cluster was an IS1216-like element, which may play a role in the dissemination of this resistance determinant. Pulsed-field gel electrophoresis with prior double digestion with I-CeuI/MluI enzymes followed by hybridization analyses revealed that the bacitracin resistance genes bcrABDR were located on the chromosome. Semi-quantitative RT-PCR demonstrated that this gene cluster is expressed under bacitracin stress. Microarray analysis revealed the presence of these genes in all bacitracin resistant strains. This study reports the discovery of genes encoding for a putative ABC transporter and an overproduced undecaprenol kinase associated with high-level bacitracin resistance in C. perfringens isolates from turkeys and broiler chickens.

I am touched by your pain: limb-specific modulation of the cortical response to a tactile stimulation during pain observation.

UNLABELLED: The observation of pain in other individuals is known to impact the cerebral activity in regions dedicated to one's nociception, as well as the behavior toward the person in pain. However, it remains unclear whether this shared representation for pain modulates somatosensory processing to nonpainful stimuli and whether this modulation is limb specific. Twenty right-handed healthy participants viewed a series of pictures depicting right hands or right feet in painful or nonpainful situations while light repetitive (25 Hz) mechanical stimuli were applied to the hand. The cortical excitability to these nonpainful stimuli was measured through the energy in the 25-Hz frequency band of electroencephalographic data. Following picture onset, a combination of nonspecific and specific modulation of cortical excitability was found. The former was widespread over the parieto-central region and likely related to factors such as attention. The latter was mostly restricted to 3 electrodes over the parietal cortex contralateral to the stimulation of the hand, and was specifically associated with the observation of others' hand in painful scenarios. This result confirms that the observation of pain can modulate somatosensory cortical excitability in an effector-specific way. The findings add to the accumulating evidence that other people's somatic pain is mapped onto the observer's sensori-motor system and offers a new paradigm to investigate potential neurophysiological changes in care providers who are often overexposed to others' pain. PERSPECTIVE: This electroencephalography study demonstrates with a quick, easily implementable, and noninvasive paradigm that the change in cortical somatosensory excitability during pain observation is limb-specific, and confirms from a neuroscience perspective that being exposed to others' pain implies more than the sharing of an affective experience.