Reconstruction and Simulation of Neocortical Microcircuitry.

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

Dynamical arrest transition of a bidisperse two-patchy colloidal dispersion: A dynamic Monte Carlo study.

During the last few years, patchy colloidal dispersions have emerged as ideal candidates of glass-formers of systems composed of particles that interact with non-isotropic potentials. However, from the computational point of view, the characterization of their dynamical properties close to the glass transition via any kind of molecular dynamics simulation technique can be very difficult due to the slowing down of both the rotational and translational dynamics. Although a plethora of dynamical techniques have been developed to account for the dynamics of patchy colloids, new and complementary simulation techniques are required to explore, much faster and more efficiently, the dynamical arrest transition of patchy colloidal dispersions when computer simulation consists of a large number of particles and, due to the slow particle dynamics at the glass transition, an extended time window is explicitly required. Then, in this contribution, by means of the so-called dynamic-Monte Carlo method, we report on the dynamical arrest transition, both rotational and translational, of a bidisperse patchy colloidal dispersion, following three different paths along the density-temperature plane, including high densities and low temperatures. Although this method has not been extensively tested at extreme thermodynamic conditions, we show that even at the dynamical arrest transition, it allows us to extract good dynamical data from a complex system. Therefore, it turns out to be a promising technique to explore the onset of vitrification of anisotropic colloidal particles.

Depletion forces in dense mixtures of spheres and rods.

We evaluate depletion forces in molecular dynamics simulation of a binary mixture of spheres (depleted particles) and rods (depletant particles) for a wide range of densities for both species. This evaluation was carried out using a recently proposed least squares fitting algorithm. We found that the restriction of the rods' rotational degrees of freedom, when the distance between two spheres is less than the rods length, creates a shallow, and apparently linear, attractive force ramp. For intersphere distances smaller than the rods' diameter, a much stronger attractive force is found, and a large repulsive barrier appears between these aforementioned regimes, roughly at the distance of the rods' thickness. The evaluated forces are validated via a comparison of the pairwise correlation functions obtained from molecular dynamics simulation of a mono-disperse sphere fluid, using the evaluated effective forces, against the original (full system) pairwise correlation functions. Agreement is excellent. We also record the angular pairwise correlation function, using the P2(x) Legendre polynomial, and find that for high densities of both species, a local nematic ordering starts to appear. This nematic order may be a factor in the small differences found between original and effective pairwise correlation functions at high densities of rods.

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Do Elderly Patients with Heart Failure and Reduced Ejection Fraction Benefit from Pharmacological Strategies for Prevention of Arrhythmic Events?

BACKGROUND: Heart failure is associated with aging. It is one of the leading causes of morbidity and mortality in Western countries and constitutes the main cause of hospitalization among elderly patients. The pharmacological therapy of patients with heart failure with reduced ejection fraction (HFrEF) has greatly improved during the last years. However, elderly patients less frequently receive recommended medical treatment. SUMMARY: The quadruple therapy (sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) is nowadays the cornerstone of medical treatment since it associates lower risk of heart failure hospitalizations and mortality (also of arrhythmic origin). Cardiac arrhythmias, including sudden cardiac death, are common in patients with HFrEF, entailing worse prognosis. Previous studies addressing the role of blocking the renin-angiotensin-aldosterone system and beta-adrenergic receptors in HFrEF have suggested different beneficial effects on arrhythmia mechanisms. Therefore, the lower mortality associated with the use of the four pillars of HFrEF therapy depends, in part, on lower sudden (mostly arrhythmic) cardiac death. KEY MESSAGES: In this review, we highlight and assess the role of the four pharmacological groups that constitute the central axis of the medical treatment of patients with HFrEF in clinical prognosis and prevention of arrhythmic events, with special focus on the elderly patient, since evidence supports that most benefits provided are irrespective of age, but elderly patients receive less often guideline-recommended medical treatment.

Validation of the Food Purchase Task (FPT) in a clinical sample of smokers with overweight and obesity.

Obesity is a major health problem associated with disease burden and mortality. In this context, analyzing food as a powerful reinforcer from a behavioral economics framework could be relevant for the treatment and prevention of obesity. The purposes of this study were to validate a food purchase task (FPT) in a clinical sample of Spanish smokers with overweight and obesity and to assess the internal structure of the FPT. We also analyzed the clinical utility of single-item breakpoint (i.e., commodity price that suppresses demand). A total of 120 smokers [% females: 54.2; Mage = 52.54; SD = 10.34] with overweight and obesity completed the FPT and weight/eating-related variables. Principal component analysis was used to examine the FPT structure, and a set of correlations were used to examine the relationship between the FPT, eating and weight-related variables. The FPT demonstrated robust convergent validity with other measures of eating. Higher food demand was related to higher food craving (r = .33), more binge eating problems (r = .39), more weight gain concerns (r = .35), higher frequency of both controlled (r = .37) and uncontrolled (r = .30) grazing, as well as to an eating style in response to emotions (r = .34) and external eating (r = .34). Of the demand indices, Intensity and Omax showed the highest magnitudes of effects. The FPT factors, persistence and amplitude, do not improve individual FPT indices; and the single-item breakpoint was not related to any eating or weight variable. The FPT is a valid measure of food reinforcement with potential clinical utility in smokers with obesity/overweight.

Post-Cessation Weight Gain among Smokers with Depression Predicts Smoking Relapse.

Objective: Weight gain (WG) is one of the most widespread consequences of smoking cessation, although there is a great variability of post-cessation weight changes among smokers. Its approach is critical because it depicts an important barrier to trying to quit smoking and because it has been considered as a long-term predictor of relapse. Notwithstanding, little is known about post-cessation WG specifically among depressed smokers. The current study sought to: (1) describe the WG at posttreatment and follow-ups in smokers with depression, (2) examine the predictors of posttreatment WG, and (3) analyze whether post-cessation WG predicts smoking relapse at 6-month follow-up. Methods: The sample was comprised of 125 smokers with depression who achieved tobacco abstinence at posttreatment following a psychological smoking cessation intervention. Smoking abstinence was biochemically verified through carbon monoxide and urine cotinine. Multiple linear and hierarchical logistic regressions were conducted to examine predictors of WG at posttreatment and tobacco relapse at 6-month follow-up, respectively. Results: Abstinent participants gained an average of 3.55 kg at 6-month follow-up compared to 1.49 kg among participants who relapsed. Greater nicotine dependence (ß = .372, p = .001) and diastolic pressure at baseline (ß = .252, p = .021) predicted higher WG at end of treatment. WG at posttreatment increased the likelihood of relapse 6 months later (B = .303, OR = 1.354; 95% CI [1.006, 1.822]). Limitations: Weight concerns, disordered eating, and BMI were not recorded, and they could be related to the present findings. Conclusions: These results suggest that individuals with depression during treatment for smoking cessation should be regularly screened and offered treatment to prevent WG.

Mental rotation and schizotypal personality traits: A Bayesian approach.

People diagnosed with schizophrenia exhibit mental rotation differences, suggesting that clinical levels of positive symptoms, such as psychotic hallucinations, are related to disruptions in their monitoring and manipulation of mental representations. According to the psychosis continuum, findings in people with a high level of schizotypal personality traits are expected to be qualitatively similar, but research concerning this topic is scarce. A spared mental imagery manipulation in this population only could suggest that this ability might be a possible protective factor, or that the emergence of clinical-level positive symptoms could be paired with disruptions in this capacity. To explore this issue, 205 undergraduate students (122 women) completed a novel mental rotation task identifying the stimulus that was a 90, 180, or 270° rotation of a black circle with colored portions and were assessed with the Schizotypal Personality Questionnaire. Men performed better in most conditions. No relationship was detected between schizotypal personality traits and accuracy in the task. These results do not support that mental imagery manipulation disruptions may be related to schizotypal personality traits in non-clinical populations. Thus, they might instead be associated with the onset of psychosis disorders as mental representation handling is hindered. However, additional research is required including the general population, as well as those with higher levels of psychotic symptoms and psychosis disorders. Future research could also focus on working memory processes related to mental representation manipulations of different sensory modalities such as auditory mental representations and their relationship with schizotypal personality traits and clinical populations.

Mucinous adenocarcinoma arising from complex perianal fistula: a diagnostic and therapeutic challenge.

We present a case of a 64-year-old male with a history of perianal abscesses that have been surgically treated on 10 occasions. Eight months after the last drainage procedure, he presented with a new abscess. Drainage was performed, revealing a cavity with smooth walls, a chronic appearance, filled with mucoid material. An internal fistulous opening was identified at the 6 o'clock position above the anorectal line, which communicated with the described cavity, forming a trans-sphincteric fistula to the mid-anal canal. Biopsy with pathological anatomy showed a mucinous adenocarcinoma with possible intestinal origin (CK20+, CDX2+, TTF1-, CK7+). After completing the evaluation, he was diagnosed with T4N1M0 rectal neoplasia. A diverting colostomy was performed, followed by neoadjuvant therapy, and subsequently, a laparoscopic abdominoperineal amputation. Pathological anatomy revealed residual adenocarcinoma ypT2N0 N0V0L0, R0. This case is notable for both the rarity of a mucinous adenocarcinoma originating in a perianal fistula and the nonspecific clinical presentation of such tumors. Clinical suspicion is crucial, especially in cases of recurrent abscesses with the discharge of mucoid material through fistulous openings, prompting the need for biopsies to ensure proper diagnosis and subsequent optimal treatment.

Association between e-cigarette and conventional cigarette use among Spanish adolescents. / Asociación entre el uso de cigarrillos electrónicos y cigarrillos convencionales en adolescentes españoles.

In recent years, studies have highlighted the upward trend in electronic cigarette use among adolescents, as well as the potential of e-cigarette use to lead to subsequent conventional cigarette use. The study's aims were two-fold: 1) to examine the progression from e-cigarette use to conventional cigarette use; and 2) to analyze the differences in the severity of smoking pattern among dual users (i.e., e-cigarette and conventional cigarette use), cigarette-only smokers, and e-cigarette-only users in a Spanish adolescent population. Data were obtained from the ESTUDES, a representative survey of addictive behaviors of Spanish adolescents aged 14-18, which was comprised of 38,010 adolescents (Mage = 15.69; SD = 1.19; 51.35% females). Results indicate that lifetime e-cigarette use increased the prevalence of subsequent conventional cigarette use by 1.86 times (95% CI 1.74, 1.99), and the prevalence of conventional cigarette use in the last month by 2.38 times (95% CI 2.19, 2.58), independently of whether the e-cigarette contains nicotine or not. Dual users showed a higher percentage of daily smokers, and a greater number of cigarettes per day, a higher use of e-cigarettes with nicotine, and an earlier age of smoking onset. Regarding risk perception, e-cigarette-only users perceived both conventional tobacco and e-cigarettes as less harmful (all p-values < .001). These findings document the strength of association between e-cigarette and conventional cigarettes, and underscore the importance of developing legal restrictions and prevention strategies aimed at reducing e-cigarette use, which in turn would reduce tobacco use.

En los últimos años, algunos estudios han destacado la tendencia ascendente en el uso del cigarrillo electrónico entre adolescentes, así como el potencial para el posterior consumo de cigarrillos convencionales. Este estudio tuvo dos objetivos: 1) examinar la progresión del cigarrillo electrónico al cigarrillo convencional; y 2) analizar las diferencias en el patrón de gravedad del tabaquismo entre consumidores duales (i.e., cigarrillos electrónicos y convencionales), fumadores de cigarrillos y consumidores de cigarrillos electrónicos. Los datos se obtuvieron de la encuesta ESTUDES, una encuesta nacional que recoge información de conductas adictivas en adolescentes entre 14 y 18 años, la cual consta de 38 010 personas (Medad = 15,69; DT = 1,19; 51,35% mujeres). Los resultados indicaron que haber usado alguna vez un cigarrillo electrónico incrementó la probabilidad de un consumo posterior de cigarrillos 1,86 veces (IC 95% 1,74-1,99), y la probabilidad de consumir tabaco en el último mes 2,38 veces (IC 95% 2,19-2,58), independientemente de si los cigarrillos electrónicos contienen o no nicotina. Los consumidores duales mostraron un mayor porcentaje de fumadores diarios, un mayor número de cigarrillos al día, un mayor uso de cigarrillos electrónicos con nicotina y una edad de inicio más temprana. Con respecto a la percepción de riesgo, los adolescentes que han usado solo cigarrillos electrónicos percibían tanto el tabaco como los cigarrillos electrónicos como menos dañinos (todos los valores p < ,001). Estos hallazgos indican la fuerte asociación entre los cigarrillos electrónicos y los convencionales, y subrayan la importancia de desarrollar restricciones legales y estrategias preventivas dirigidas al cigarrillo electrónico, lo que reduciría a su vez el consumo de tabaco.

Determining depletion interactions by contracting forces.

Depletion forces are fundamental for determining the phase behavior of a vast number of materials and colloidal dispersions and have been used for the manipulation of in- and out-of-equilibrium thermodynamic states. The entropic nature of depletion forces is well understood; however, most theoretical approaches, and also molecular simulations, work quantitatively at moderate size ratios in much diluted systems since large size asymmetries and high particle concentrations are difficult to deal with. The existing approaches for integrating out the degrees of freedom of the depletant species may fail under these extreme physical conditions. Thus, the main goal of this contribution is to introduce a general physical formulation for obtaining the depletion forces even in those cases where the concentration of all species is relevant. We show that the contraction of the bare forces uniquely determines depletion interactions. Our formulation is tested by studying depletion forces in binary and ternary colloidal mixtures. We report here results for dense systems with total packing fractions of 45% and 55%. Our results open up the possibility of finding an efficient route to determine effective interactions at a finite concentration, even under non-equilibrium thermodynamic conditions.

Obstructive jaundice secondary to a pseudoaneurysm of the superior mesenteric artery.

Superior mesenteric arteries pseudoaneurysms are rare entity, usually asymptomatic but they can appear as an abdominal pain, throbbing mass or shock, being jaundice an exceptional type of presentation. Diagnosis is made by imaging tests (CT) and currently the endovascular approach is the most widespread, reserving open surgery in selected cases. We describe the case of a patient with an 86mm SMA pseudoaneurysm with compression of the extrahepatic bile duct.

Characteristics and impact of sex in a cohort of patients with primary sclerosing cholangitis: Experience of a transplant center in the Mediterranean basin. / Características e impacto del sexo en una cohorte de pacientes con colangitis esclerosante primaria: experiencia de un centro trasplantador de la cuenca mediterránea.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease that typically affects middle-aged men with ulcerative colitis (UC). However, recent studies point out to epidemiological changes. Our aim was to determine if the epidemiology, clinical course and outcome of patients with PSC followed at a reference hepatology center resemble what is described in the literature. PATIENTS AND METHOD: Retrospective search of patients with a diagnosis of PSC treated in our center between 2000 and 2019. RESULTS: Cohort of 55 patients (mean age: 37 years), 44% women. Most were large duct type (79%). Most diagnoses were made after 2011. At time of diagnosis, 63% of patients were asymptomatic. The median time from suspicion to diagnosis was 2 years. After a mean follow-up time of 7 years, one third developed cirrhosis, and 25% required liver transplantation (LT); among these, the disease recurred in almost half. Inflammatory bowel disease (IBD) was present in 45%, especially UC. Although statistical significance was not reached, PSC in women was characterized by higher rate of asymptomatic presentation and more frequent association with UC versus other forms of IBD. Women also had more frequently cirrhosis at diagnosis and required LT more often than men. CONCLUSION: The epidemiology of PSC is changing. The number of women affected is greater than what was expected from the literature, with a recent increase in incidence. There seems to be differences between sexes in the form of presentation and disease course that should be confirmed in subsequent studies.

Nonlinear Analysis of Rotational Springs to Model Semi-Rigid Frames.

This paper explains the mathematical foundations of a method for modelling semi-rigid unions. The unions are modelled using rotational rather than linear springs. A nonlinear second-order analysis is required, which includes both the effects of the flexibility of the connections as well as the geometrical nonlinearity of the elements. The first task in the implementation of a 2D Beam element with semi-rigid unions in a nonlinear finite element method (FEM) is to define the vector of internal forces and the tangent stiffness matrix. After defining the formula for this vector and matrix in the context of a semi-rigid steel frame, an iterative adjustment of the springs is proposed. This setting allows a moment-rotation relationship for some given load parameters, dimensions, and unions. Modelling semi-rigid connections is performed using Frye and Morris' polynomial model. The polynomial model has been used for type-4 semi-rigid joints (end plates without column stiffeners), which are typically semi-rigid with moderate structural complexity and intermediate stiffness characteristics. For each step in a non-linear analysis required to adjust the matrix of tangent stiffness, an additional adjustment of the springs with their own iterative process subsumed in the overall process is required. Loops are used in the proposed computational technique. Other types of connections, dimensions, and other parameters can be used with this method. Several examples are shown in a correlated analysis to demonstrate the efficacy of the design process for semi-rigid joints, and this is the work's application content. It is demonstrated that using the mathematical method presented in this paper, semi-rigid connections may be implemented in the designs while the stiffness of the connection is verified.

Area-Specific Synapse Structure in Branched Posterior Nucleus Axons Reveals a New Level of Complexity in Thalamocortical Networks.

Thalamocortical posterior nucleus (Po) axons innervating the vibrissal somatosensory (S1) and motor (MC) cortices are key links in the brain neuronal network that allows rodents to explore the environment whisking with their motile snout vibrissae. Here, using fine-scale high-end 3D electron microscopy, we demonstrate in adult male C57BL/6 wild-type mice marked differences between MC versus S1 Po synapses in (1) bouton and active zone size, (2) neurotransmitter vesicle pool size, (3) distribution of mitochondria around synapses, and (4) proportion of synapses established on dendritic spines and dendritic shafts. These differences are as large, or even more pronounced, than those between Po and ventro-posterior thalamic nucleus synapses in S1. Moreover, using single-axon transfection labeling, we demonstrate that the above differences actually occur on the MC versus the S1 branches of individual Po cell axons that innervate both areas. Along with recently-discovered divergences in efficacy and plasticity, the synaptic structure differences reported here thus reveal a new subcellular level of complexity. This is a finding that upends current models of thalamocortical circuitry, and that might as well illuminate the functional logic of other branched projection axon systems.SIGNIFICANCE STATEMENT Many long-distance brain connections depend on neurons whose branched axons target separate regions. Using 3D electron microscopy and single-cell transfection, we investigated the mouse Posterior thalamic nucleus (Po) cell axons that simultaneously innervate motor and sensory areas of the cerebral cortex involved in whisker movement control. We demonstrate significant differences in the size of the boutons made in each area by individual Po axons, as well as in functionally-relevant parameters in the composition of their synapses. In addition, we found similarly large differences between the synapses of Po versus ventral posteromedial thalamic nucleus axons in the whisker sensory cortex. Area-specific synapse structure in individual axons implies a new, unsuspected level of complexity in long-distance brain connections.

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Identification of a Plasma MicroRNA Profile Associated With Venous Thrombosis.

OBJECTIVE: Venous thrombosis (VT) is a complex condition with a highly heritable genetic component that predisposes one to its development. Certain microRNAs (miRNAs) might be used as biomarkers of VT, but few studies have examined miRNA expression in this respect. The aim of the present work was to identify a plasma miRNA profile associated with VT. Approach and Results: miRNAs were analyzed by quantitative polymerase chain reaction in plasma samples from members of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) population (n=935). A discovery phase involving the screening of 752 miRNAs from a subset of 104 GAIT-2 subjects was followed by an internal validation phase in which the selected miRNAs were quantified in the whole GAIT-2 population. In the discovery phase, 16 miRNAs were selected, including 9 associated with VT and 7 that correlated with an intermediate phenotype of VT. In the next phase, 4 miRNAs were validated as differentially expressed (false discovery rate, <0.1) in VT: hsa-miR-126-3p, hsa-miR-885-5p, hsa-miR-194-5p, and hsa-miR-192-5p. The 4 miRNAs each returned a significant (P<0.05) odds ratio for VT (range of 1.3-1.8). A risk model including the 4 miRNAs, age, and sex returned an area under the receiver operating characteristic curve of 0.77. Moreover, all 4 miRNAs showed significant correlations with intermediate phenotypes of VT (eg, protein S and factor VII). The targets of the miRNAs in the blood coagulation pathway and their interactions are also discussed. CONCLUSIONS: The present results suggest a 4-miRNA plasma profile associated with VT is of potential use in predicting the risk of this condition.

Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile.

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.