Sleep disturbances and incident risk of major depressive disorder in a population-based cohort.

Sleep disturbances are well-known symptoms of major depressive disorder (MDD). However, the prospective risk of MDD in the presence of sleep disturbances in a general population-based cohort is not well known. This study investigated associations between both polysomnography (PSG)-based or subjective sleep features and incident MDD. Participants representative of the general population who had never had MDD completed sleep questionnaires (n = 2000) and/or underwent PSG (n = 717). Over 8 years' follow-up, participants completed psychiatric interviews enabling the diagnosis of MDD. Survival Cox models were used to analyze associations between sleep features and MDD incidence. A higher Epworth Sleepiness Scale and presence of insomnia symptoms were significantly associated with a higher incidence of MDD (hazard ratio [HR] [95 % confidence interval (CI)]: 1.062 [1.022-1.103], p = 0.002 and 1.437 [1.064-1.940], p = 0.018, respectively). Higher density of rapid eye movements in rapid eye movement (REM) sleep was associated with a higher incidence of MDD in men (HR 1.270 [95 % CI 1.064-1.516], p = 0.008). In women, higher delta power spectral density was associated with a lower MDD incidence (HR 0.674 [95 % CI 0.463-0.981], p = 0.039). This study confirmed the associations between subjective and objective sleep features and the incidence of MDD in a large community dwelling cohort.

Integrative Modeling of Accelerometry-Derived Sleep, Physical Activity, and Circadian Rhythm Domains With Current or Remitted Major Depression.

Importance: Accelerometry has been increasingly used as an objective index of sleep, physical activity, and circadian rhythms in people with mood disorders. However, most prior research has focused on sleep or physical activity alone without consideration of the strong within- and cross-domain intercorrelations; and few studies have distinguished between trait and state profiles of accelerometry domains in major depressive disorder (MDD). Objectives: To identify joint and individual components of the domains derived from accelerometry, including sleep, physical activity, and circadian rhythmicity using the Joint and Individual Variation Explained method (JIVE), a novel multimodal integrative dimension-reduction technique; and to examine associations between joint and individual components with current and remitted MDD. Design, Setting, and Participants: This cross-sectional study examined data from the second wave of a population cohort study from Lausanne, Switzerland. Participants included 2317 adults (1164 without MDD, 185 with current MDD, and 968 with remitted MDD) with accelerometry for at least 7 days. Statistical analysis was conducted from January 2021 to June 2023. Main Outcomes and Measures: Features derived from accelerometry for 14 days; current and remitted MDD. Logistic regression adjusted for age, sex, body mass index, and anxiety and substance use disorders. Results: Among 2317 adults included in the study, 1261 (54.42%) were female, and mean (SD) age was 61.79 (9.97) years. JIVE reduced 28 accelerometry features to 3 joint and 6 individual components (1 sleep, 2 physical activity, 3 circadian rhythms). Joint components explained 58.5%, 79.5%, 54.5% of the total variation in sleep, physical activity, and circadian rhythm domains, respectively. Both current and remitted depression were associated with the first 2 joint components that were distinguished by the salience of high-intensity physical activity and amplitude of circadian rhythm and timing of both sleep and physical activity, respectively. MDD had significantly weaker circadian rhythmicity. Conclusions and Relevance: Application of a novel multimodal dimension-reduction technique demonstrates the importance of joint influences of physical activity, circadian rhythms, and timing of both sleep and physical activity with MDD; dampened circadian rhythmicity may constitute a trait marker for MDD. This work illustrates the value of accelerometry as a potential biomarker for subtypes of depression and highlights the importance of consideration of the full 24-hour sleep-wake cycle in future studies.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies.

IMPORTANCE AND OBJECTIVE: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. METHODS: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. RESULTS: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3-5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3-5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. CONCLUSION: Self-reports of no or low caffeine consumption and consumption of more than 3-5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake.

Evaluating the clinical utility of an easily applicable prediction model of suicide attempts, newly developed and validated with a general community sample of adults.

BACKGROUND: A suicide attempt (SA) is a clinically serious action. Researchers have argued that reducing long-term SA risk may be possible, provided that at-risk individuals are identified and receive adequate treatment. Algorithms may accurately identify at-risk individuals. However, the clinical utility of algorithmically estimated long-term SA risk has never been the predominant focus of any study. METHODS: The data of this report stem from CoLaus|PsyCoLaus, a prospective longitudinal study of general community adults from Lausanne, Switzerland. Participants (N = 4,097; Mage = 54 years, range: 36-86; 54% female) were assessed up to four times, starting in 2003, approximately every 4-5 years. Long-term individual SA risk was prospectively predicted, using logistic regression. This algorithm's clinical utility was assessed by net benefit (NB). Clinical utility expresses a tool's benefit after having taken this tool's potential harm into account. Net benefit is obtained, first, by weighing the false positives, e.g., 400 individuals, at the risk threshold, e.g., 1%, using its odds (odds of 1% yields 1/(100-1) = 1/99), then by subtracting the result (400*1/99 = 4.04) from the true positives, e.g., 5 individuals (5-4.04), and by dividing the result (0.96) by the sample size, e.g., 800 (0.96/800). All results are based on 100 internal cross-validations. The predictors used in this study were: lifetime SA, any lifetime mental disorder, sex, and age. RESULTS: SA at any of the three follow-up study assessments was reported by 1.2%. For a range of seven a priori selected threshold probabilities, ranging between 0.5% and 2%, logistic regression showed highest overall NB in 97.4% of all 700 internal cross-validations (100 for each selected threshold probability). CONCLUSION: Despite the strong class imbalance of the outcome (98.8% no, 1.2% yes) and only four predictors, clinical utility was observed. That is, using the logistic regression model for clinical decision making provided the most true positives, without an increase of false positives, compared to all competing decision strategies. Clinical utility is one among several important prerequisites of implementing an algorithm in routine practice, and may possibly guide a clinicians' treatment decision making to reduce long-term individual SA risk. The novel metric NB may become a standard performance measure, because the a priori invested clinical considerations enable clinicians to interpret the results directly.

Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse.

From a cohort of 167 infertile patients suffering from multiple morphological abnormalities of the flagellum (MMAF), pathogenic bi-allelic mutations were identified in the CCDC146 gene. In somatic cells, CCDC146 is located at the centrosome and at multiple microtubule-related organelles during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To decipher the molecular pathogenesis of infertility associated with CCDC146 mutations, a Ccdc146 knock-out (KO) mouse line was created. KO male mice were infertile, and sperm exhibited a phenotype identical to CCDC146 mutated patients. CCDC146 expression starts during late spermiogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets suggests that the protein may be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 impacted all microtubule-based organelles such as the manchette, the head-tail coupling apparatus (HTCA), and the axoneme. Through this study, a new genetic cause of infertility and a new factor in the formation and/or structure of the sperm axoneme were characterized.

Population coding of time-varying sounds in the nonlemniscal inferior colliculus.

The inferior colliculus (IC) of the midbrain is important for complex sound processing, such as discriminating conspecific vocalizations and human speech. The IC's nonlemniscal, dorsal "shell" region is likely important for this process, as neurons in these layers project to higher-order thalamic nuclei that subsequently funnel acoustic signals to the amygdala and nonprimary auditory cortices, forebrain circuits important for vocalization coding in a variety of mammals, including humans. However, the extent to which shell IC neurons transmit acoustic features necessary to discern vocalizations is less clear, owing to the technical difficulty of recording from neurons in the IC's superficial layers via traditional approaches. Here, we use two-photon Ca2+ imaging in mice of either sex to test how shell IC neuron populations encode the rate and depth of amplitude modulation, important sound cues for speech perception. Most shell IC neurons were broadly tuned, with a low neurometric discrimination of amplitude modulation rate; only a subset was highly selective to specific modulation rates. Nevertheless, neural network classifier trained on fluorescence data from shell IC neuron populations accurately classified amplitude modulation rate, and decoding accuracy was only marginally reduced when highly tuned neurons were omitted from training data. Rather, classifier accuracy increased monotonically with the modulation depth of the training data, such that classifiers trained on full-depth modulated sounds had median decoding errors of ∼0.2 octaves. Thus, shell IC neurons may transmit time-varying signals via a population code, with perhaps limited reliance on the discriminative capacity of any individual neuron.NEW & NOTEWORTHY The IC's shell layers originate a "nonlemniscal" pathway important for perceiving vocalization sounds. However, prior studies suggest that individual shell IC neurons are broadly tuned and have high response thresholds, implying a limited reliability of efferent signals. Using Ca2+ imaging, we show that amplitude modulation is accurately represented in the population activity of shell IC neurons. Thus, downstream targets can read out sounds' temporal envelopes from distributed rate codes transmitted by populations of broadly tuned neurons.

Associations of Depressive and Anxiety Disorders with Pulmonary Disorders in the Community: The PneumoLaus and PsyCoLaus Studies.

INTRODUCTION: Mental health disorders figure among the many comorbidities of obstructive respiratory diseases. The multisystemic characteristics of chronic respiratory disease and its impact on quality of life could affect depressive and/or anxiety disorders. We aimed to evaluate the association of spirometric indices, ventilatory disorders, and self-reported respiratory diseases with psychiatric disorders considering potential confounders. METHODS: We analysed data from CoLaus|PsyCoLaus, a Swiss population-based cohort study, consisting of 2'774 participants (56% women; mean age: 62.3 (standard deviation = ±9.9) years) who performed spirometry and completed semi-structured psychiatric interviews. We defined ventilatory disorders using GLI-2012 references. Major depressive episode (MDE) and anxiety disorders were defined using the DSM-IV (Diagnostic and Statistical Manual). RESULTS: 630 subjects (22.7%) presented a recent MDE. Reversible obstructive ventilatory disorders were associated with recent MDE (OR = 1.94, 95% confidence interval (95% CI) 1.10-3.43) and recent anxiety disorders (2.21 [1.16-4.22]) only in unadjusted model. Self-reported chronic obstructive pulmonary (COPD) and asthma were associated with MDE with ORs of 2.49 (95% CI, 1.19-5.27) and 1.56 (95% CI, 1.04-2.35) after adjustment, respectively. Possible restrictive ventilatory impairment was positively associated with recent anxiety disorders (OR = 2.46, 1.10-5.51). Z-scores of FEV1, FVC, and maximal mid-expiratory flow were not associated with psychiatric disorders. There was no association between ventilatory disorders and MDE in adjusted models. CONCLUSIONS: In this cross-sectional population-based study, the association between respiratory disorders and depressive disorders was observed for self-reported COPD and asthma, but not with objective diagnoses based on spirometry. Lung volumes are not associated with psychiatric disorders. Further prospective studies will be necessary to understand the significance of the association.

Deep Learning Assisted Imaging Methods to Facilitate Access to Ophthalmic Telepathology.

Purpose: To investigate the use of super-resolution imaging techniques to enable telepathology using low-cost commercial cameras. Design: Experimental study. Participants: A total of 139 ophthalmic pathology slides obtained from the Ophthalmic Pathology service at the University of California, Irvine. Methods: Denoising Diffusion Probabilistic Model (DDPM) was developed to predict super-resolution pathology slide images from low-resolution inputs. The model was pretrained using 150 000 images randomly sampled from the ImageNet dataset. Patch aggregation was used to generate large images with DDPM. The performance of DDPM was evaluated against that of generative adversarial networks (GANs) and Robust UNet, which were also trained on the same dataset. Main Outcome Measures: The performance of models trained to generate super-resolution output images from low-resolution input images can be evaluated by using the mean squared error (MSE) and Structural Similarity Index Measure (SSIM), as well as subjective grades provided by expert pathologist graders. Results: In total, our study included 110 training images, 9 validation images, and 20 testing images. The objective performance scores were averaged over patches generated from 20 test images. The DDPM-based approach with pretraining produced the best results, with an MSE score of 1.35e-5 and an SSIM score of 0.8987. A qualitative analysis of super-resolution images was conducted by expert 3 pathologists and 1 expert ophthalmic microscopist, and the average accuracy of identifying the correct ground truth images ranged from 25% to 70% (with an average accuracy of 46.5%) for widefield images and 25% to 60% (with an average accuracy of 38.25%) for individual patches. Conclusions: The DDPM-based approach with pretraining is assessed to be effective at super-resolution prediction for ophthalmic pathology slides both in terms of objective and subjective measures. The proposed methodology is expected to decrease the reliance on costly slide scanners for acquiring high-quality pathology slide images, while also streamlining clinical workflow and expanding the scope of ophthalmic telepathology. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dynamically orthogonal narrow-angle parabolic equations for stochastic underwater sound propagation. Part II: Applications.

The stochastic dynamically orthogonal (DO) narrow-angle parabolic equations (NAPEs) are exemplified and their properties and capabilities are described using three new two-dimensional stochastic range-independent and range-dependent test cases with uncertain sound speed field, bathymetry, and source location. We validate results against ground-truth deterministic analytical solutions and direct Monte Carlo (MC) predictions of acoustic pressure and transmission loss fields. We verify the stochastic convergence and computational advantages of the DO-NAPEs and discuss the differences with normal mode approaches. Results show that a single DO-NAPE simulation can accurately predict stochastic range-dependent acoustic fields and their non-Gaussian probability distributions, with computational savings of several orders of magnitude when compared to direct MC methods. With their coupling properties and their adaptation in range to the dominant uncertainties, the DO-NAPEs are shown to predict accurate statistics, from mean and variance to multiple modes and full probability distributions, and to provide excellent reconstructed realizations, from amplitudes and phases to other specific properties of complex realization fields.

Dynamically orthogonal narrow-angle parabolic equations for stochastic underwater sound propagation. Part I: Theory and schemes.

Robust informative acoustic predictions require precise knowledge of ocean physics, bathymetry, seabed, and acoustic parameters. However, in realistic applications, this information is uncertain due to sparse and heterogeneous measurements and complex ocean physics. Efficient techniques are thus needed to quantify these uncertainties and predict the stochastic acoustic wave fields. In this work, we derive and implement new stochastic differential equations that predict the acoustic pressure fields and their probability distributions. We start from the stochastic acoustic parabolic equation (PE) and employ the instantaneously-optimal Dynamically Orthogonal (DO) equations theory. We derive stochastic DO-PEs that dynamically reduce and march the dominant multi-dimensional uncertainties respecting the nonlinear governing equations and non-Gaussian statistics. We develop the dynamical reduced-order DO-PEs theory for the Narrow-Angle parabolic equation and implement numerical schemes for discretizing and integrating the stochastic acoustic fields.

Subtypes of major depressive disorders and objectively measured physical activity and sedentary behaviors in the community.

BACKGROUND: Lack of physical activity (PA) and high sedentary behavior (SB) may enhance mental health problems, including depression, and are associated with increased mortality. Aside from a large body of research on major depressive disorder (MDD) assessed as an entity and either PA or SB, few studies have examined associations among subtypes of MDD and both PA and SB simultaneously derived from wrist-worn accelerometers. Accordingly, our aim was to explore the associations among MDD subtypes (atypical, melancholic, combined atypical-melancholic and unspecified) and four actigraphy-derived behaviors combining the levels of PA and SB. METHODS: The sample stemmed from CoLaus|PsyCoLaus, a population-based cohort study, consisting of 2375 participants (55.1% women; mean age: 62.4 years) who wore an accelorometer for 14 days after a physical exam and subsequently completed a semi-structured psychiatric interview. Activity behaviors were defined according to the combination of the levels of moderate-to-vigorous intensity PA and SB. Associations of remitted MDD subtypes, current MDD and physical inactivity behaviors were assessed using multinomial logistic regression, adjusted for socio-demographic characteristics, a history of anxiety, alcohol and drug use disorders and cardiovascular risk factors. RESULTS: In the fully adjusted model, participants with the remitted combined atypical-melancholic subtype had a higher risk of being more physically inactive. CONCLUSIONS: Our findings suggest that low PA and high SB are not restricted to the duration of depressive episodes in people with atypical and melancholic episodes. The lack of PA and high SB in this group of depressive patients exposes them to an additional long-term cardiovascular risk and measures to increase PA may be particularly fruitful in this MDD subgroup.

CCDC65, encoding a component of the axonemal Nexin-Dynein regulatory complex, is required for sperm flagellum structure in humans.

Sperm flagella share an evolutionary conserved microtubule-based structure with motile cilia expressed at the surface of several cell types, such as the airways epithelial cells. As a result, male infertility can be observed as an isolated condition or a syndromic trait, illustrated by Primary Cilia Dyskinesia (PCD). We report two unrelated patients showing multiple morphological abnormalities of the sperm flagella (MMAF) and carrying distinct homozygous truncating variants in the PCD-associated gene CCDC65. We characterized one of the identified variants (c.1208del; p.Asn403Ilefs*9), which induces the near absence of CCDC65 protein in patient sperm. In Chlamydomonas, CCDC65 ortholog (DRC2, FAP250) is a component of the Nexin-Dynein Regulatory complex (N-DRC), which interconnects microtubule doublets and coordinates dynein arms activity. In sperm cells from the patient, we also show the loss of GAS8, another component of the N-DRC, supporting a structural/functional link between the two proteins. Our work indicates that, similarly to ciliary axoneme, CCDC65 is required for sperm flagellum structure. Importantly, our work provides first evidence that mutations in the PCD-associated gene CCDC65 also cause asthenozoospermia.

Calcium-Sensitive Subthreshold Oscillations and Electrical Coupling in Principal Cells of Mouse Dorsal Cochlear Nucleus.

In higher sensory brain regions, slow oscillations (0.5-5 Hz) associated with quiet wakefulness and attention modulate multisensory integration, predictive coding, and perception. Although often assumed to originate via thalamocortical mechanisms, the extent to which subcortical sensory pathways are independently capable of slow oscillatory activity is unclear. We find that in the first station for auditory processing, the cochlear nucleus, fusiform cells from juvenile mice (of either sex) generate robust 1-2 Hz oscillations in membrane potential and exhibit electrical resonance. Such oscillations were absent prior to the onset of hearing, intrinsically generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) and persistent Na+ conductances (NaP) interacting with passive membrane properties, and reflected the intrinsic resonance properties of fusiform cells. Cx36-containing gap junctions facilitated oscillation strength and promoted pairwise synchrony of oscillations between neighboring neurons. The strength of oscillations were strikingly sensitive to external Ca2+, disappearing at concentrations >1.7 mM, due in part to the shunting effect of small-conductance calcium-activated potassium (SK) channels. This effect explains their apparent absence in previous in vitro studies of cochlear nucleus which routinely employed high-Ca2+ extracellular solution. In contrast, oscillations were amplified in reduced Ca2+ solutions, due to relief of suppression by Ca2+ of Na+ channel gating. Our results thus reveal mechanisms for synchronous oscillatory activity in auditory brainstem, suggesting that slow oscillations, and by extension their perceptual effects, may originate at the earliest stages of sensory processing.

A splice donor variant of GAS8 induces structural disorganization of the axoneme in sperm flagella and leads to nonsyndromic male infertility.

Motile cilia and flagella are closely related organelles structured around a highly conserved axoneme whose formation and maintenance involve proteins from hundreds of genes. Defects in many of these genes have been described to induce primary ciliary dyskinesia (PCD) mainly characterized by chronic respiratory infections, situs inversus and/or infertility. In men, cilia/flagella-related infertility is usually caused by asthenozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). Here, we investigated a cohort of 196 infertile men displaying a typical MMAF phenotype without any other PCD symptoms. Analysis of WES data identified a single case carrying a deleterious homozygous GAS8 variant altering a splice donor consensus site. This gene, also known as DRC4, encodes a subunit of the Nexin-Dynein Regulatory Complex (N-DRC), and has been already associated to male infertility and mild PCD. Confirming the deleterious effect of the candidate variant, GAS8 staining by immunofluorescence did not evidence any signal from the patient's spermatozoa whereas a strong signal was present along the whole flagella length in control cells. Concordant with its role in the N-DRC, transmission electron microscopy evidenced peripheral microtubule doublets misalignments. We confirm here the importance of GAS8 in the N-DRC and observed that its absence induces a typical MMAF phenotype not necessarily accompanied by other PCD symptoms.

Influence of the Use of Irrigation Solution Inhibitors in Improving Dentine Adhesion: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review examined the effect of neutralizing agents on bond strength after irrigation with sodium hypochlorite and their existing protocols in literature. METHODS: This present study adhered to the PRISMA guidelines and was registered at PROSPERO. Five electronic databases were searched (sept-2020/jan-2021) in English, Spanish, and Portuguese, without any restrictions on publication date. Cases reports, editorials and literature reviews were not included. The risk of bias was assessed using the Cochrane Collaboration tool. From the initial 7,147 studies, 2,745 were removed as duplicates and 4,382 were excluded after a title/abstract screen. RESULTS: Seventeen in vitro studies were included. The results showed that the higher the concentration of sodium hypochlorite, the lower the bond strength at dentine/restoration interface (p⟨0.01). Among the studies, sodium ascorbate was the most widely used neutralizer and showed the most significant results in increasing bond strength (p⟨0.01). The bond strength values were found to increase with longer application time of the neutralizing substances (p⟨0.01). CONCLUSIONS: The use of sodium ascorbate as a neutralizing agent can reverse the negative effects of the sodium hypochlorite and improve the bond strength between dentine and resin cement, however, it isn't possible to determine the best protocol for use.

Auditory Corticofugal Neurons Transmit Auditory and Non-auditory Information During Behavior.

Layer 5 pyramidal neurons of sensory cortices project "corticofugal" axons to myriad sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: these long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca2+ imaging of auditory corticofugal dendrites as mice of either sex engage in a GO/NO-GO sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by behaviorally relevant sounds under our conditions. Task related dendritic activity instead mostly followed sound cue termination and co-occurred with mice's instrumental licking during the answer period of behavioral trials, irrespective of reward consumption. Temporally selective, optogenetic silencing of corticofugal neurons during the trial answer period impaired auditory discrimination learning. Thus, auditory corticofugal systems' contribution to learning and plasticity may be partially nonsensory in nature.

Risk factors for mood disorders among offspring of parents with bipolar disorder: Findings from a discordant-sibling study.

The purpose of this naturalistic, prospective study was to identify risk factors for mood disorders in offspring of parents with bipolar disorder (BPD) using the discordant-sibling design by comparing premorbid psychopathology or symptoms, temperament, personality traits and coping style as well as the perception of family-related characteristics among affected and unaffected siblings within the same family. This approach controls for confounding by unmeasured genetic and environmental factors shared within families. Our sample comprised 24 families of a parent with BPD with at least one child that developed BPD or major depressive disorder (n = 31), and at least one child who did not. Offspring were followed for a mean duration of 16.2 (s.d: 4.6) years. Information was collected from the offspring themselves. Generalized linear mixed models only revealed differences in three dimensions of the Dimension of Temperament Survey-Revised (DOTS-R) version: Offspring with mood disorders scored higher on "Approach-withdrawal", "Rhythmicity for daily habits", and "Task orientation" than their unaffected siblings. The higher scores, and not lower scores as expected, on these temperament dimensions observed in offspring that subsequently developed mood disorders may reflect increased vulnerability, but they could also mirror premorbid mood swings or strategies to cope with them.

Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function.

Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygous ZMYND12 variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using the Trypanosoma brucei model. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygous ZMYND12 variants. Co-immunoprecipitation and ultrastructure expansion microscopy in T. brucei revealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples from Trypanosoma and Ttc29 KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.

Observing the universal screening of a Kondo impurity.

The Kondo effect, deriving from a local magnetic impurity mediating electron-electron interactions, constitutes a flourishing basis for understanding a large variety of intricate many-body problems. Its experimental implementation in tunable circuits has made possible important advances through well-controlled investigations. However, these have mostly concerned transport properties, whereas thermodynamic observations - notably the fundamental measurement of the spin of the Kondo impurity - remain elusive in test-bed circuits. Here, with a novel combination of a 'charge' Kondo circuit with a charge sensor, we directly observe the state of the impurity and its progressive screening. We establish the universal renormalization flow from a single free spin to a screened singlet, the associated reduction in the magnetization, and the relationship between scaling Kondo temperature and microscopic parameters. In our device, a Kondo pseudospin is realized by two degenerate charge states of a metallic island, which we measure with a non-invasive, capacitively coupled charge sensor. Such pseudospin probe of an engineered Kondo system opens the way to the thermodynamic investigation of many exotic quantum states, including the clear observation of Majorana zero modes through their fractional entropy.