Miracle-dz/UniFAR-FTUs huggingface dataset:
A schizophrenia risk factor induces marked anatomical deficits at GABAergic‐dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase‐immunogold double labeling, three‐dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3‐month‐old and 14‐month‐old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long‐term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA‐dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long‐term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum‐targeted antipsychotic drugs.
In vitro modulatory effects of ginsenoside compound K, 20(S)-protopanaxadiol and 20(S)-protopanaxatriol on uridine 5′-diphospho-glucuronosyltransferase activity and expression

Abstract We explored the inhibitory effect of ginsenoside compound K (CK), 20(S)-protopanaxadiol (PPD), and 20(S)-protopanaxatriol (PPT) on six uridine 5′-diphospho-glucuronosyltransferase (UGT) enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) activities in human liver microsomes (HLMs) and 10 UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17) activities in recombinant UGT isoforms. PPD was a potent inhibitor of UGT1A3 activity with half-maximal inhibitory concentration values of 5.62 and 3.38 μM in HLMs and recombinant UGT1A3, respectively. UGT1A3 inhibition by CK and PPD was competitive with inhibitory constant (K i) values of 17.4 and 1.21 μM, respectively, and inhibition by PPT was non-competitive with a K i value of 8.07 μM in HLMs. PPD exhibited more than 3.4-fold selectivity for UGT1A3 inhibition compared with other UGT isoforms inhibition, while CK and PPT showed more than 2.16- and 2.21-fold selectivity, respectively. PPD did not significantly increase the mRNA expression of UGT1A1, 1A3, 1A4, 1A9, and 2B7 in hepatocytes. Given the low plasma concentrations of PPD in healthy human subjects and the absence of induction potential on UGT isoforms, we conclude that PPD cause no pharmacokinetic interactions with other co-administered drugs metabolised by UGT1A3.
Hypertension is associated with a variant in the RARRES2 gene in populations of Ouro Preto, Minas Gerais, Brazil: a cross-sectional study.

BACKGROUND Arterial hypertension (AH) is implicated in vascular health and contributes significantly to cardiovascular morbidity and mortality. In addition to the contribution of usual risk factors for AH, elucidating the influence of genetic factors is a promising area of investigation. Therefore, we evaluated the association between AH and cardiovascular risk factors (CVRFs) and genetic polymorphisms in communities in Southeast Brazil. METHODS A total of 515 adults aged 18-91 years, who were cross-sectionally assessed between 2015-2016, were included. Demographic, clinical, behavioral, anthropometric characteristics, and laboratory parameters and 12 single nucleotide polymorphisms in seven candidate genes involved in cardiovascular risk (RARRES2, AGT, NOS3, GNB3, APOE, APOB, APOC3, LDLR, and PPARG) were evaluated, with AH as the outcome. Sex, age, and laboratory parameters were considered the main confounding factors. RESULTS There was a significant association between age >60 years (odds ratio [OR] =6.74), alcohol dependence (OR=3.84), smoking (OR=1.74), overweight (OR=1.74), high plasma triglyceride (TG) levels (OR=1.98) and low high-density lipoprotein (HDL-c) (OR=6.22), diabetes (OR=3.68), and insulin resistance (OR=2.40) and AH. A significant association was observed between rs4721 in RARRES2 and AH. The T allele in homozygosis was a potent chance modifier for AH. The highest chance gradients for AH were characterized by the presence of the TT genotype and DMT2 (OR=9.70), high TG (OR=6.26), low HDL-c (OR=8.20), and age more than 60 years (OR=9.96). CONCLUSION The interaction of the T allele of the rs4721 polymorphism in RARRES2 with CVRFs may predispose carriers to a higher cardiovascular risk.
A quick and low-intensity method for oral administration to large numbers of mice: A possible alternative to oral gavage

Oral administration of medication to experimental animals is a cause of significant stress. When coupled to animals who are already under strenuous circumstances due to the disease being modelled, there is a significant risk for increased morbidity and mortality, thus influencing the results. Faced with these constraints, a low-intensity method for oral administration was developed, based solely on the natural behaviour of the animals and minimal conditioning, in which precise doses of medication were administered in a locally available, standard wheat cookie fragment, providing both a palatable vehicle and an absorbent matrix for the medication. Fast administration to large numbers of animals was thus achieved, safeguarding the animals’ welfare and ensuring ease of handling. This method is a promising alternative to oral gavage in pre-clinical drug studies with laboratory mice.
Constraints on General Relativity Geodesics by a Covariant Geometric Uncertainty Principle

General relativity is a theory for gravitation based on Riemannian geometry, difficult to compatibilize with quantum mechanics. This is evident in relativistic problems in which quantum effects cannot be discarded. For example in quantum gravity, gravitation of zero-point energy or events close to a black hole singularity. Here, we set up a mathematical model to select general relativity geodesics according to compatibility with the uncertainty principle. To achieve this, we derived a geometric expression of the uncertainty principle (GUP). This formulation identified proper space-time length with Planck length by a geodesic-derived scalar. GUP imposed a minimum allowed value for the interval of proper space-time which depended on the particular space-time geometry. GUP forced the introduction of a “zero-point” curvature perturbation over flat Minkowski space, caused exclusively by quantum uncertainty but not to gravitation. When applied to the Schwarzschild metric and choosing radial-dependent geodesics, our mathematical model identified a particle exclusion zone close to the singularity, similar to calculations by loop quantum gravity. For a 2 black hole merger, this exclusion zone was shown to have a radius that cannot go below a value proportional to the energy/mass of the incoming black hole multiplied by Planck length.
Incidence and Risk Factors for Diaphragmatic Herniation Following Esophagectomy for Cancer

Supplemental Digital Content is available in the text Objective: To evaluate the incidence and risk factors of diaphragmatic herniation following esophagectomy for cancer (DHEC), and assess the results of surgical repair. Summary Background data: The current incidence of DHEC is discussed with conflicting data regarding its treatment and natural course. Methods: Monocentric retrospective cohort study (2009–2018). From 902 patients, 719 patients with a complete follow-up of CT scans after transthoracic esophagectomy for cancer were reexamined to identify the occurrence of a DHEC. The incidence of DHEC was estimated using Kalbfleisch and Prentice method and risk factors of DHEC were studied using the Fine and Gray competitive risk regression model by treating death as a competing event. Survival was analyzed. Results: Five-year DHEC incidence was 10.3% [95% CI, 7.8%–13.2%] (n = 59), asymptomatic in 54.2% of cases. In the multivariable analysis, the risk factors for DHEC were: presence of hiatal hernia on preoperative CT scan (HR = 1.72 [1.01–2.94], P = 0.046), previous hiatus surgery (HR = 3.68 [1.61–8.45], P = 0.002), gastroesophageal junction tumor location (HR = 3.51 [1.91–6.45], P < 0.001), neoadjuvant chemoradiotherapy (HR = 4.27 [1.70–10.76], P < 0.001), and minimally invasive abdominal phase (HR = 2.98 [1.60–5.55], P < 0.001). A cure for DHEC was achieved in 55.9%. The postoperative mortality rate was nil, the overall morbidity rate was 12.1%, and the DHEC recurrence rate was 30.3%. Occurrence of DHEC was significantly associated with a lower hazard rate of death in a time-varying Cox's regression analysis (HR = 0.43[0.23–0.81], P = 0.010). Conclusions: The 5-year incidence of DHEC is 10.3% and is associated with a favorable prognosis. Surgical repair of symptomatic or progressive DHEC is associated with an acceptable morbidity. However, the optimal surgical repair technique remains to be determined in view of the large number of recurrences.
Polyclonal antibody–based immunohistochemical detection of intraleukocytic Theileria parasites in roan and sable antelopes

Theileria parasites commonly infect African wild artiodactyls. In rare roan (Hippotragus equinus) and sable (H. niger) antelopes, Theileria sp. (sable)-associated calf mortalities constrain breeding programs. The pathogenicity of most leukocyte-transforming Theileria spp. originates in their invasion of and multiplication in various mononuclear leukocytes, the transformation of both infected and uninfected leukocytes, and their infiltration of multiple organs. Understanding the pathogenesis of theileriosis can be improved by the use of immunohistochemistry (IHC) to identify the localization of the parasites in tissue sections. Our aim was to develop a reproducible IHC assay to detect leukocyte-associated Theileria parasites in formalin-fixed, paraffin-embedded roan and sable tissues. Polyclonal antibodies were purified from the sera of 5 roans from an area endemic for Theileria sp. (sable) and tested for IHC reactivity in 55 infected and 39 control roan and sable antelopes, and for antigen and species cross-reactivity in an additional 58 cases. The 3 strongest antibodies consistently detected intraleukocytic theilerial antigens in known positive cases in roan and sable antelopes, and also detected other Theileria spp. in non-hippotraginid wild artiodactyl tissues. The antibodies did not cross-react with other apicomplexan protozoa, with the exception of Cryptosporidium. Given that PCR on its own cannot determine the significance of theilerial infection in wild ruminants, IHC is a useful laboratory test with which to confirm the diagnosis in these species.
Feasibility of Neural Network Based Virtual Sensor for Vehicle Unsprung Mass Relative Velocity Estimation

With the automotive industry moving towards automated driving, sensing is becoming an increasingly important part of enabling technology. The virtual sensors allow data fusion from various vehicle sensors and provide a prediction for measurement that is hard or too expensive to measure in another way or in the case of demand on continuous detection. In this paper, virtual sensing is discussed for the case of vehicle suspension control, where information about the relative velocity of the unsprung mass for each vehicle corner is required. The corresponding goal can be identified as a regression task with multi-input sequence input. The hypothesis is that the state-ofart method of Bidirectional Long-Short Term Memory (BiLSMT) can solve it. In this paper, a virtual sensor has been proposed and developed by training a neural network model. The simulations have been performed using an experimentally validated full vehicle model in IPG Carmaker. Simulations provided the reference data which was used for Neural Network (NN) training. The extensive dataset covering 26 scenarios has been used to obtain training, validation and testing data. The Bayesian Search was used to select the best neural network structure using root mean square error as a metric. The best network is made of 167 BiLSTM, 256 fully connected hidden units and 4 output units. Error histograms and spectral analysis of the predicted signal compared to the reference signal are presented. The results demonstrate the good applicability of neural network-based virtual sensors for the estimation of vehicle unsprung mass relative velocity.
T OPIC -A WARE C ONTEXTUALIZED T RANSFORMERS

Training on disjoint fixed-length segments, Transformers successfully transform static word embeddings into contextualized word representations. However, they often restrict the context of a token to the segment it resides in and hence neglect the flow of contextual information across segments, failing to capture longer-term dependencies beyond the predefined segment length. This paper uses a probabilistic deep topic model to provide contextualized embeddings at both the token and segment levels. It also introduces a contextual next-word embedding guided topic attention module, injecting contextualized topic information into Transformerbased architectures. The proposed method not only captures global semantic coherence of all segments and word concurrence patterns, but also enriches the representation of each token by adapting it to its local context, which goes beyond the segment it resides in and can be flexibly defined according to the target task while maintaining control over memory footprint and computational time. Experiments on various corpora show that adding only a few extra parameters, the proposed topic-aware contextualized transformers consistently outperform their conventional counterparts, and can be used to generate coherent sentences and paragraphs.
A review of machine learning for cardiology.

This paper reviews recent cardiology literature and reports how Artificial Intelligence Tools (specifically, Machine Learning techniques) are being used by physicians in the field. Each technique is introduced with enough details to allow the understanding of how it works and its intent, but without delving into details that do not add immediate benefits and require expertise in the field. We specifically focus on the principal Machine Learning based risk scores used in cardiovascular research. After introducing them and summarizing their assumptions and biases, we discuss their merits and shortcomings. We report on how frequently they are adopted in the field and suggest why this is the case based on our expertise in Machine Learning. We complete the analysis by reviewing how corresponding statistical approaches compare with them. Finally, we discuss the main open issues in applying Machine Learning tools to cardiology tasks, also drafting possible future directions. Despite the growing interest in these tools, we argue that there are many still underutilized techniques: while Neural Networks are slowly being incorporated in cardiovascular research, other important techniques such as Semi-Supervised Learning and Federated Learning are still underutilized. The former would allow practitioners to harness the information contained in large datasets that are only partially labeled, while the latter would foster collaboration between institutions allowing building larger and better models.
Co-use of Tobacco Products and Cannabis among Veterans: A Preliminary Investigation of Prevalence and Associations with Mental Health Outcomes

ABSTRACT While tobacco product (such as combustible cigarettes and nicotine vaping products) and cannabis use rates remain high in the general United States (U.S.) population, veterans from the conflicts in Iraq and Afghanistan (i.e., OEF/OIF veterans) are at high risk of high rates of cannabis and tobacco use. Co-use of tobacco and cannabis (i.e., using both substances within a specified period of time or combining the drugs within the same device for use) is of growing prevalence in the U.S. However, little is understood about the prevalence rates of tobacco and cannabis co-use among U.S. veterans and its associations with mental health symptomatology. The current study conducted a preliminary analysis of co-use patterns of tobacco and cannabis and associated mental health outcomes among a sample of OEF/OIF veterans (N = 1,230). Results indicated high rates of lifetime and past 30-day use of both substances. Past 30-day co-users endorsed significantly higher levels of stress, PTSD, depression, and anxiety compared to singular product users. Results suggest that the addition of cannabis use in conjunction with tobacco use may be associated with greater mental health symptoms among veterans. Findings indicate veteran tobacco and cannabis co-users may benefit from mental health care to help mitigate poor mental health symptoms.
Identification and molecular characterization of propionylcholinesterase, a novel pseudocholinesterase in rice

ABSTRACT Cholinesterase is consisting of acetylcholinesterase (AChE) and pseudocholinesterase in vertebrates and invertebrates. AChE gene has been identified in several plant species, while pseudocholinesterase gene has not yet been found in any plant species. In this study, we report that the AChE gene paralog encodes propionylcholinesterase (PChE), a pseudocholinesterase in rice. PChE was found to be located adjacent to AChE (Os07g0586200) on rice chromosome 7 and designated as Os07g0586100. Phylogenetic tree analysis showed a close relationship between rice AChE and PChE. PChE-overexpressing rice had higher hydrolytic activity toward propionylthiocholine than acetylthiocholine and showed extremely low activity against butyrylthiocholine. Therefore, the PChE gene product was characterized as a propionylcholinesterase, a pseudocholinesterase. The rice PChE displayed lower sensitivity to the cholinesterase inhibitor, neostigmine bromide, than electric eel, maize, and rice AChEs. The recombinant PChE functions as a 171 kDa homotetramer. PChE was expressed during the later developmental stage, and it was found be localized in the extracellular spaces of the rice leaf tissue. These results suggest that the rice plant possesses PChE, which functions in the extracellular spaces at a later developmental stage. To the best of our knowledge, this study provides the first direct evidence and molecular characterization of PChE in plants.
Murine Irgm Paralogs Regulate Nonredundant Functions To Execute Host Defense to Toxoplasma gondii

Gamma interferon (IFN-γ)-induced immunity-related GTPases (IRGs) confer cell-autonomous immunity to the intracellular protozoan pathogen Toxoplasma gondii. Effector IRGs are loaded onto the Toxoplasma-containing parasitophorous vacuole (PV), where they recruit ubiquitin ligases, ubiquitin-binding proteins, and IFN-γ-inducible guanylate-binding proteins (Gbps), prompting PV lysis and parasite destruction. ABSTRACT Gamma interferon (IFN-γ)-induced immunity-related GTPases (IRGs) confer cell-autonomous immunity to the intracellular protozoan pathogen Toxoplasma gondii. Effector IRGs are loaded onto the Toxoplasma-containing parasitophorous vacuole (PV), where they recruit ubiquitin ligases, ubiquitin-binding proteins, and IFN-γ-inducible guanylate-binding proteins (Gbps), prompting PV lysis and parasite destruction. Host cells lacking the regulatory IRGs Irgm1 and Irgm3 fail to load effector IRGs, ubiquitin, and Gbps onto the PV and are consequently defective for cell-autonomous immunity to Toxoplasma. However, the role of the third regulatory IRG, Irgm2, in cell-autonomous immunity to Toxoplasma has remained unexplored. Here, we report that Irgm2 unexpectedly plays a limited role in the targeting of effector IRGs, ubiquitin, and Gbps to the Toxoplasma PV. Instead, Irgm2 is instrumental in the decoration of PVs with γ-aminobutyric acid receptor-associated protein-like 2 (GabarapL2). Cells lacking Irgm2 are as defective for cell-autonomous host defense to Toxoplasma as pan-Irgm−/− cells lacking all three Irgm proteins, and Irgm2−/− mice succumb to Toxoplasma infections as readily as pan-Irgm−/− mice. These findings demonstrate that, relative to Irgm1 and Irgm3, Irgm2 plays a distinct but critically important role in host resistance to Toxoplasma.
Choline and docosahexaenoic acid during the first 1000 days and children’s health and development in low- and middle-income countries

Abstract Choline and DHA are nutrients that, when provided during the first 1000 days from conception to age 2 years, may have beneficial effects on child neurodevelopment as well as related health factors, including birth outcomes and child growth, morbidity, and inflammation. Because these nutrients are found mainly in animal-source foods, they may be lacking in the diets of pregnant and lactating women and young children in low- and middle-income countries, potentially putting children at risk for suboptimal development and health. Prior reviews of these nutrients have mainly focused on studies from high-income countries. Here, a narrative review is presented of studies describing the pre- and postnatal roles of choline, docosahexaenoic acid, and a combination of the 2 nutrients on child neurodevelopment, birth outcomes, growth, morbidity, and inflammation in low- and middle-income countries. More studies are needed to understand the specific, long-term effects of perinatal choline and docosahexaenoic acid intake in various contexts.