The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection.

Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.

A sympathetic view on fat by leptin.

Zeng et al. reveal that the lipolytic effect of the hormone leptin is mediated by sympathetic nerve fibers that directly "envelope" white adipocytes. Local activation of the sympathetic input to the fat opens new venues to circumvent central leptin resistance in obesity.

Size Matters: A Computational Study of Hydrogen Absorption in Ionic Liquids.

We combined both density functional theory and classical molecular dynamics simulations to investigate the molecular mechanisms governing hydrogen solvation in a total of 12 ionic liquids. Overall, the analysis of the structural properties under high temperature and pressure conditions revealed weak interactions between hydrogen and the ionic liquids, with a slight preference of this gas to be placed at the apolar domains. Interestingly, those ionic liquids comprising nitrate anions allow the accommodation of hydrogen molecules also in the polar areas. The study of the hydrogen velocity autocorrelation functions supports this observation. In addition, the structure of all of the tested ionic liquids was almost insensitive to the addition of hydrogen, so the available free volume and cavity formation are presumably the most important factors affecting solubility.

Estimation of modified Zernike coefficients from turbulence-degraded multispectral imagery using deep learning.

We investigate how wavelength diversity affects the performance of a deep-learning model that predicts the modified Zernike coefficients of turbulence-induced wavefront error from multispectral images. The ability to perform accurate predictions of the coefficients from images collected in turbulent conditions has potential applications in image restoration. The source images for this work were a point object and extended objects taken from a character-based dataset, and a wavelength-dependent simulation was developed that applies the effects of isoplanatic atmospheric turbulence to the images. The simulation utilizes a phase screen resampling technique to emulate the simultaneous collection of each band of a multispectral image through the same turbulence realization. Simulated image data were generated for the point and extended objects at various turbulence levels, and a deep neural network architecture based on AlexNet was used to predict the modified Zernike coefficients. Mean squared error results demonstrate a significant improvement in predicting modified Zernike coefficients for both the point object and extended objects as the number of spectral bands is increased. However, the improvement with the number of bands was limited when using extended objects with additive noise.

Estimation of non-uniform motion blur using a patch-based regression convolutional neural network.

The non-uniform blur of atmospheric turbulence can be modeled as a superposition of linear motion blur kernels at a patch level. We propose a regression convolutional neural network (CNN) to predict angle and length of a linear motion blur kernel for varying sized patches. We analyze the robustness of the network for different patch sizes and the performance of the network in regions where the characteristics of the blur are transitioning. Alternating patch sizes per epoch in training, we find coefficient of determination scores across a range of patch sizes of R 2>0.78 for length and R 2>0.94 for angle prediction. We find that blur predictions in regions overlapping two blur characteristics transition between the two characteristics as overlap changes. These results validate the use of such a network for prediction of non-uniform blur characteristics at a patch level.

Deep learning estimation of modified Zernike coefficients and recovery of point spread functions in turbulence.

Recovering the turbulence-degraded point spread function from a single intensity image is important for a variety of imaging applications. Here, a deep learning model based on a convolutional neural network is applied to intensity images to predict a modified set of Zernike polynomial coefficients corresponding to wavefront aberrations in the pupil due to turbulence. The modified set assigns an absolute value to coefficients of even radial orders due to a sign ambiguity associated with this problem and is shown to be sufficient for specifying the intensity point spread function. Simulated image data of a point object and simple extended objects over a range of turbulence and detection noise levels are created for the learning model. The MSE results for the learning model show that the best prediction is found when observing a point object, but it is possible to recover a useful set of modified Zernike coefficients from an extended object image that is subject to detection noise and turbulence.

A Cross-Sectional, Retrospective, and Comparative Study between Delirium and Non-Delirium Psychiatric Disorders in a Psychogeriatric Inpatient Population Referred to Consultation-Liaison Psychiatry Unit.

Background and objectives: Delirium is the most prevalent psychiatric disorder in inpatient older people. Its presence is associated with higher rates of institutionalization, functional disability and mortality. This study aims to evaluate delirium in a hospitalized psychogeriatric population, focusing on which factors predict the appearance of delirium, the impact it generates and the diagnostic concordance between non-psychiatric physicians and psychiatrists. Material and methods: This is an observational, cross-sectional, retrospective, and comparative study. We obtained data from a sample of 1017 patients (≥65 years) admitted to general hospital and referred from different services to the consultation-liaison psychiatry (CLP) unit. Logistic regression was performed using delirium as the dependent variable. To estimate the concordance of the diagnoses, the Kappa coefficient was used. To assess the impact of delirium, an ordinal regression, Wilcoxon median test and Fisher's test were performed. Results: Delirium is associated with a higher number of visits, OR 3.04 (95% CI 2.38-3.88), longer length of stay and mortality, OR 2.07 (95% CI, 1.05 to 4.10). The model to predict delirium shows that being >75 years old has an OR of 2.1 (95% CI, 1.59-2.79), physical disability has an OR of 1.66 (95% CI, 1.25-2.20), history of delirium has an OR of 10.56 (95% CI, 5.26-21.18) and no use of benzodiazepines has an OR of 4.24 (95% CI, 2.92-6.14). The concordance between the referring physician's psychiatric diagnosis and the psychiatrist CLP unit showed a kappa of 0.30. When analysing depression and delirium, the concordance showed Kappa = 0.46. Conclusions: Delirium is a highly prevalent psychiatric disorder, but it is still underdiagnosed, with low diagnostic concordance between non-psychiatric doctors and psychiatrists from CLP units. There are multiple risk factors associated with the appearance of delirium, which must be managed to reduce its appearance.

A Differentiable Neural-Network Force Field for Ionic Liquids.

We present NeuralIL, a model for the potential energy of an ionic liquid that accurately reproduces first-principles results with orders-of-magnitude savings in computational cost. Built on the basis of a multilayer perceptron and spherical Bessel descriptors of the atomic environments, NeuralIL is implemented in such a way as to be fully automatically differentiable. It can thus be trained on ab initio forces instead of just energies, to make the most out of the available data, and can efficiently predict arbitrary derivatives of the potential energy. Using ethylammonium nitrate as the test system, we obtain out-of-sample accuracies better than 2 meV atom-1 (<0.05 kcal mol-1) in the energies and 70 meV Å-1 in the forces. We show that encoding the element-specific density in the spherical Bessel descriptors is key to achieving this. Harnessing the information provided by the forces drastically reduces the amount of atomic configurations required to train a neural network force field based on atom-centered descriptors. We choose the Swish-1 activation function and discuss the role of this choice in keeping the neural network differentiable. Furthermore, the possibility of training on small data sets allows for an ensemble-learning approach to the detection of extrapolation. Finally, we find that a separate treatment of long-range interactions is not required to achieve a high-quality representation of the potential energy surface of these dense ionic systems.

Universal healthcare coverage for first episode of schizophrenia-spectrum disorders in Chile: analysis of the administrative database.

Aim of the study was to analyse the Ministry of Health's (MINSAL) administrative database of the Universal Health Coverage (UHC) program for First Episode of Schizophrenia Spectrum Disorders (FEP-SSD). The database included every case registered in the program between 2004 and 2017. According to the timeframes established for permanence in the program, cases were defined as Suspected, FEP in diagnostic observation and FEP-SSD. Only first registers were analysed. We compared gender, age at entry, level of care and region where the case was registered. Denominator data for estimation of incidence rates were obtained from the last census. We adjusted incidence rate ratios by age, gender, and region. During the studied period, 33.207 suspected cases were registered. 27.006 (81%) were confirmed as FEP and after 6-month follow-up, 22.701 (68%) were confirmed as FEP-SSD. The median age at entry was 24 years, males entering at younger age. Male proportion was higher than female in all groups. 46.9% of all cases were detected in primary care. FEP-SSD cases were six years younger and had a higher proportion of males than discarded cases (62.6 vs 53.2%). During 169.4 million person-years at risk, crude incidence for suspected cases was 19.58 per 100.000 person-years; for FEP, 15.92 per 100.000 person-years and for FEP-SSD, 13.38 per 100.000 person-years. Chile has lower incidence of FEP-SSD compared to current world estimations but gender proportions are comparable. This UHC program has allowed early access through the integration of mental health to the health network at all levels of care.

Healthcare resource utilization and costs among patients with heart failure with preserved, mildly reduced, and reduced ejection fraction in Spain.

AIMS: To describe healthcare resource utilization (HCRU) of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain.  METHODS: Adults with ≥ 1 HF diagnosis and ≥ 1 year of continuous enrolment before the corresponding index date (1/January/2016) were identified through the BIG-PAC database. Rate per 100 person-years of all-cause and HF-related HCRU during the year after the index date were estimated using bootstrapping with replacement. RESULTS: Twenty-one thousand two hundred ninety-seven patients were included, of whom 48.5% had HFrEF, 38.6% HFpEF and 4.2% HFmrEF, with the rest being of unknown EF. Mean age was 78.8 ± 11.8 years, 53.0% were men and 83.0% were in NYHA functional class II/III. At index, 67.3% of patients were taking renin angiotensin system inhibitors, 61.2% beta blockers, 23.4% aldosterone antagonists and 5.2% SGLT2 inhibitors. Rates of HF-related outpatient visits and hospitalization were 968.8 and 51.6 per 100 person-years, respectively. Overall, 31.23% of patients were hospitalized, mainly because of HF (87.88% of total hospitalizations); HF hospitalization length 21.06 ± 17.49 days (median 16; 25th, 75th percentile 9-27). HF hospitalizations were the main cost component: inpatient 73.64%, pharmacy 9.67%, outpatient 9.43%, and indirect cost 7.25%. Rates of all-cause and HF-related HCRU and healthcare cost were substantial across all HF subgroups, being higher among HFrEF compared to HFmrEF and HFpEF patients. CONCLUSIONS: HCRU and cost associated with HF are high in Spain, HF hospitalizations being the main determinant. Medication cost represented only a small proportion of total costs, suggesting that an optimization of HF therapy may reduce HF burden.

Al3+ solvation in solutions of aluminum nitrate in a protic ionic liquid: Nuclear magnetic resonance verification of the solvation shell composition.

The closest environment of Al3+ cations was analyzed in detail in solutions of aluminum nitrate in the prototypical protic ionic liquid ethyl ammonium nitrate (EAN) using 1 H and 14 N nuclear magnetic resonance (NMR) spectra. For Al (NO3 )3 -EAN mixtures with different water content, a quantitative analysis of the integral intensities of the 1 H and 14 N signals was carried out and the composition of the first solvation shell of the aluminum cation was refined.

Oncogenic Pathways in Neurodegenerative Diseases.

Cancer and neurodegenerative diseases are two of the leading causes of premature death in modern societies. Their incidence continues to increase, and in the near future, it is believed that cancer will kill more than 20 million people per year, and neurodegenerative diseases, due to the aging of the world population, will double their prevalence. The onset and the progression of both diseases are defined by dysregulation of the same molecular signaling pathways. However, whereas in cancer, these alterations lead to cell survival and proliferation, neurodegenerative diseases trigger cell death and apoptosis. The study of the mechanisms underlying these opposite final responses to the same molecular trigger is key to providing a better understanding of the diseases and finding more accurate treatments. Here, we review the ten most common signaling pathways altered in cancer and analyze them in the context of different neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases.

Influence of Metal Salts Addition on Physical and Electrochemical Properties of Ethyl and Propylammonium Nitrate.

In this work, we deepen in the characterization of two protic ionic liquids (PILs), ethylammonium nitrate (EAN) and propylammonium nitrate (PAN). With this aim, we determined the influence of inorganic nitrate salts addition on their physical properties and their electrochemical potential window (EPW). Thus, experimental measurements of electrical conductivity, density, viscosity, refractive index and surface tension of mixtures of {EAN or PAN + LiNO3, Ca(NO3)2, Mg(NO3)2 or Al(NO3)3} at a temperature range between 5 and 95 °C are presented first, except for the last two properties which were measured at 25 °C. In the second part, the corresponding EPWs were determined at 25 °C by linear sweep voltammetry using three different electrochemical cells. Effect of the salt addition was associated mainly with the metal cation characteristics, so, generally, LiNO3 showed the lower influence, followed by Ca(NO3)2, Mg(NO3)2 or Al(NO3)3. The results obtained for the EAN + LiNO3 mixtures, along with those from a previous work, allowed us to develop novel predictive equations for most of the presented physical properties as functions of the lithium salt concentration, the temperature and the water content. Electrochemical results showed that a general order of EPW can be established for both PILs, although exceptions related to measurement conditions and the properties of the mixtures were found.

A New Solid-State Proton Conductor: The Salt Hydrate Based on Imidazolium and 12-Tungstophosphate.

We report the structure and charge transport properties of a novel solid-state proton conductor obtained by acid-base chemistry via proton transfer from 12-tungstophosphoric acid to imidazole. The resulting material (henceforth named Imid3WP) is a solid salt hydrate that, at room temperature, includes four water molecules per structural unit. To our knowledge, this is the first attempt to tune the properties of a heteropolyacid-based solid-state proton conductor by means of a mixture of water and imidazole, interpolating between water-based and ionic liquid-based proton conductors of high thermal and electrochemical stability. The proton conductivity of Imid3WP·4H2O measured at truly anhydrous conditions reads 0.8 × 10-6 S cm-1 at 322 K, which is higher than the conductivity reported for any other related salt hydrate, despite the lower hydration. In the pseudoanhydrous state, that is, for Imid3WP·2H2O, the proton conductivity is still remarkable and, judging from the low activation energy (Ea = 0.26 eV), attributed to structural diffusion of protons. From complementary X-ray diffraction data, vibrational spectroscopy, and solid-state NMR experiments, the local structure of this salt hydrate was resolved, with imidazolium cations preferably orienting flat on the surface of the tungstophosphate anions, thus achieving a densely packed solid material, and water molecules of hydration that establish extremely strong hydrogen bonds. Computational results confirm these structural details and also evidence that the path of lowest energy for the proton transfer involves primarily imidazole and water molecules, while the proximate Keggin anion contributes with reducing the energy barrier for this particular pathway.

Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide ß-endorphin. CB1R activation selectively increases ß-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

Attachment styles moderate Theory of Mind differences between persons with schizophrenia, first-degree relatives and controls.

OBJECTIVES: Theory of Mind (ToM) plays a role in social functioning and is impaired in patients with schizophrenia and to a lesser degree in first-degree relatives, compared to healthy controls. This study investigates whether attachment styles moderate these observed group differences in ToM. METHODS: This cross-sectional study included a sample of 51 patients, 23 first-degree relatives, and 49 controls who completed assessments of anxious and avoidant attachment (Psychosis Attachment Measure), ToM (Reading the Mind in the Eyes Test), and estimated cognitive ability. Patients' symptoms were assessed with the Positive and Negative Syndrome Scale. RESULTS: Patients differed from controls and relatives in ToM performance but not in attachment avoidance or attachment anxiety. Attachment anxiety showed an interaction with group over ToM. The interaction was significant only between patients and controls but not between patients and relatives or relatives and controls. Post-hoc analysis showed that patients and controls showed differential ToM performance at average and high attachment anxiety. In patients, symptom levels did not moderate the association between attachment and ToM. CONCLUSIONS: Attachment anxiety is related to poorer levels of ToM in patients, suggesting this may have a contributory role in schizophrenia. The findings stress the need for longitudinal research into the directionality of the relationship between ToM and attachment anxiety. PRACTITIONER POINTS: Relationships with significant others might be a factor that influences the way in which social information is processed by persons with a diagnosis of a psychotic disorder. In patients, higher levels of attachment anxiety - that is, low self-worth, fear of abandonment and rejection, continuous vigilance of threat-related cues - were associated with a lower ability to understand the mental states of others. However, at lower levels of attachment anxiety, their ToM performance was comparable to that of relatives and controls. This effect was not influenced by symptom severity. Further research is required to confirm the potential influence of attachment insecurity on ToM ability as the latter is strongly related to patient's functional outcomes.

Influence of Small Quantities of Water on the Physical Properties of Alkylammonium Nitrate Ionic Liquids.

This paper presents a comprehensive study of two alkylammonium nitrate ionic liquids. As part of this family of materials, mainly ethylammonium nitrate (EAN) and also propylammonium nitrate (PAN) have attracted a great deal of attention during the last decades due to their potential applications in many fields. Although there have been numerous publications focused on the measurement of their physical properties, a great dispersion can be observed in the results obtained for the same magnitude. One of the critical points to be taken into account in their physical characterization is their water content. Thus, the main objective of this work was to determine the degree of influence of the presence of small quantities of water in EAN and PAN on the measurement of density, viscosity, electrical conductivity, refractive index and surface tension. For this purpose, the first three properties were determined in samples of EAN and PAN with water contents below 30,000 ppm in a wide range of temperatures, between 5 and 95 °C, while the last two were obtained at 25 °C. As a result of this study, it has been concluded that the presence of water is critical in those physical properties that involve mass or charge transport processes, resulting in the finding that the absolute value of the average percentage change in both viscosity and electrical conductivity is above 40%. Meanwhile, refractive index (≤0.3%), density (≤0.5%) and surface tension (≤2%) present much less significant changes.

Clinical Profile and Length of Hospital Stay in a Sample of Psychogeriatric Patients Referred to Consultation Liaison Psychiatric Unit.

Background and objectives: There has been a recent increase in older patients admitted to general hospitals. A significant percentage of hospitalized older patients are ≥75 years old, which differ from the patients aged 65 to 74 years old in terms of functional status at patient discharge. This study aims to compare sociodemographic, clinical features, and factors associated with length of hospital stay in youngest-old and oldest-old populations of inpatients referred to the consultation liaison psychiatry unit. Material and methods: This is an observational, cross-sectional, retrospective, and comparative study. We obtained data from a sample of 1017 patients (≥65 years) admitted to a general hospital and referred from different services (medicine, surgery, etc.) to the consultation liaison psychiatry unit. The sample was divided into two groups of patients: youngest-old (65-74 years) and oldest-old (≥75 years). Psychiatric evaluations were performed while the patients were on wards at the hospital. Psychopharmacs were started as needed. A comparative analysis was carried out and predictive factors related to length of hospital stay were calculated. Results: The reference rate to consultation liaison psychiatry unit was 1.45% of the total older patients hospitalized. Our study demonstrates differences between the groups of older people: the oldest-old group were mainly female (p < 0.001), had more previous psychiatric diagnoses (p < 0.001), physical disabilities (p = 0.02), and neurocognitive disorders (p < 0.001), they used more antipsychotics (p < 0.001), and more frequently had a discharge disposition to a nursing home (p = 0.036). The presence of physical disability (beta = 0.07, p < 0.001) and logtime to referral to consultation liaison psychiatry unit (beta = 0.58, p < 0.001) were associated with increased length of hospital stay. Conclusions: Youngest-old and oldest-old people should be considered as two different types of patients when we consider clinical features. The time to referral to consultation liaison psychiatry unit seems to be a relevant factor associated with length of hospital stay.