Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86-1.08; all p-values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

Cells navigate through complex surroundings by following cues from their environment. A prominent example is Dictyostelium, which is directed by chemotaxis towards regions with higher concentrations. In the presence of traveling chemical waves, however, amoebae migrate counter to the running wave. Such behavior, referred to as diffusing wave paradox, suggests the existence of adaptation and directional memory. Here we experimentally investigate the response of phototactic self-propelled microparticles to traveling light-pulses. Despite their entirely memory-less (i.e., strictly local) response to the environment, we observe the same phenomenological behavior, i.e., particle motion counter to the pulse direction. Our findings are supported by a minimal model which considers active particle reorientations within local light gradients. The complex and robust behavior of synthetic active particles to spatially and temporally varying stimuli enables new strategies for achieving collective behavior and can be used for the design of micro-robotic systems with limited signal-processing capabilities.

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5BN642H, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5BN642H in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5BN642H-driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5BN642H patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5BN642H crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5BN642H can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5BN642H, conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5BN642H activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

While shear emulsification is a well understood industrial process, geometrical confinement in microfluidic systems introduces fascinating complexity, so far prohibiting complete understanding of droplet formation. The size of confined droplets is controlled by the ratio between shear and capillary forces when both are of the same order, in a regime known as jetting, while being surprisingly insensitive to this ratio when shear is orders of magnitude smaller than capillary forces, in a regime known as squeezing. Here, we reveal that further reduction of-already negligibly small-shear unexpectedly re-introduces the dependence of droplet size on shear/capillary-force ratio. For the first time we formally account for the flow around forming droplets, to predict and discover experimentally an additional regime-leaking. Our model predicts droplet size and characterizes the transitions from leaking into squeezing and from squeezing into jetting, unifying the description for confined droplet generation, and offering a practical guide for applications.

Speech communication in real-world environments requires adaptation to changing acoustic conditions. How the human auditory cortex adapts as a new noise source appears in or disappears from the acoustic scene remain unclear. Here, we directly measured neural activity in the auditory cortex of six human subjects as they listened to speech with abruptly changing background noises. We report rapid and selective suppression of acoustic features of noise in the neural responses. This suppression results in enhanced representation and perception of speech acoustic features. The degree of adaptation to different background noises varies across neural sites and is predictable from the tuning properties and speech specificity of the sites. Moreover, adaptation to background noise is unaffected by the attentional focus of the listener. The convergence of these neural and perceptual effects reveals the intrinsic dynamic mechanisms that enable a listener to filter out irrelevant sound sources in a changing acoustic scene.

The discovery of superconductivity at 260 K in hydrogen-rich compounds like LaH10 re-invigorated the quest for room temperature superconductivity. Here, we report the temperature dependence of the upper critical fields μ0Hc2(T) of superconducting H3S under a record-high combination of applied pressures up to 160 GPa and fields up to 65 T. We find that Hc2(T) displays a linear dependence on temperature over an extended range as found in multigap or in strongly-coupled superconductors, thus deviating from conventional Werthamer, Helfand, and Hohenberg (WHH) formalism. The best fit of Hc2(T) to the WHH formalism yields negligible values for the Maki parameter α and the spin-orbit scattering constant λSO. However, Hc2(T) is well-described by a model based on strong coupling superconductivity with a coupling constant λ ~ 2. We conclude that H3S behaves as a strong-coupled orbital-limited superconductor over the entire range of temperatures and fields used for our measurements.

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.

Combining anticancer drugs with inorganic nanocrystals to construct multifunctional hybrid nanostructures has become a powerful tool for cancer treatment and tumor suppression. However, it remains a critical challenge to synthesize compact, multifunctional nanostructures with improved functionality and reproducibility. In this study, we report the fabrication of magnetite hybrid nanostructures employing Fe3O4 nanoparticles (NPs) to form multifunctional magnetite nanoclusters (NCs) by combining an oil-in-water microemulsion assembly and a layer-by-layer (LBL) method. The Fe3O4 NCs were firstly prepared via a microemulsion self-assembly technique. Then, polyelectrolyte layers composed of poly(allylamine hydrochloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) and doxorubicin hydrochloride (DOX) were capped on Fe3O4 NCs to construct the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures via LBL method. The as-prepared hybrid nanostructures loaded with DOX demonstrated the pH-responsive drug release and higher cytotoxicity towards human lung cancer (A549) cells in vitro and can serve as T2-weighted magnetic resonance imaging (MRI) contrast agents, which can significantly improve T2 relaxivity and lead to a better cellular MRI contrast effect. The loaded DOX emitting red signals under excitation with 490 nm are suitable for bioimaging applications. This work provides a novel strategy to build a Fe3O4-based multifunctional theranostic nanoplatform with T2-weighted MRI, fluorescence imaging, and drug delivery.

The development of pesticide resistance in insects and recent bans on pesticides call for the identification of natural sources of resistance in crops. Here, we used natural variation in pepper (Capsicum spp.) resistance combined with an untargeted metabolomics approach to detect secondary metabolites related to thrips (Frankliniella occidentalis) resistance. Using leaf disc choice assays, we tested 11 Capsicum accessions of C. annuum and C. chinense in both vegetative and flowering stages for thrips resistance. Metabolites in the leaves of these 11 accessions were analyzed using LC-MS based untargeted metabolomics. The choice assays showed significant differences among the accessions in thrips feeding damage. The level of resistance depended on plant developmental stage. Metabolomics analyses showed differences in metabolomes among the Capsicum species and plant developmental stages. Moreover, metabolomic profiles of resistant and susceptible accessions differed. Monomer and dimer acyclic diterpene glycosides (capsianosides) were pinpointed as metabolites that were related to thrips resistance. Sucrose and malonylated flavone glycosides were related to susceptibility. To our knowledge, this is the first time that dimer capsianosides of pepper have been linked to insect resistance. Our results show the potential of untargeted metabolomics as a tool for discovering metabolites that are important in plant - insect interactions.

Intermitted fasting or every-other-day feeding (EOD) has many positive effects in rodents and humans. Our goal was to describe how EOD influences bone mineral composition in female and male mice under prolonged EOD feeding. Male and female adult mice were fed EOD for 9 months. After this time, we used a direct method of measurement of mineral components in ashes of long bones (humerus and radius) to estimate the content of calcium (Ca), phosphorus (P), potassium (K), magnesium (Mg), and sodium (Na). We also performed histological analysis of sections of long bones. We found no significant changes in mineral composition between ad libitum and EOD fed males and females. We noted higher Ca and P contents in control males vs. females and lower content of Mg in control males vs. females. We observed the presence of marrow adipose tissue (MAT) in sections of EOD-fed females. EOD without supplementation during feeding days did not increase loss of mineral content of bones in C57BL/6J mice, but the presence of MAT only in EOD females indicates a gender-dependent response to EOD treatment in C57BL/6J mice.

BACKGROUND The aim of this study was to explore the expression levels of family with sequence similarity 83, member A (FAM83A) in lung adenocarcinoma (LUAD) and investigate its clinical prognostic value. MATERIAL AND METHODS Bioinformatics mining methods were used to predict the differential expression levels of FAM83A mRNA in LUAD and normal lung tissues based on the TCGA and Oncomine databases. Immunohistochemical staining was performed to demonstrate the FAM83A protein expression levels in 83 cases of LUAD combined with paired normal lung tissues. The correlation between clinicopathologic factors and FAM83A differential expression levels in LUAD was explored by the chi-square test. Kaplan-Meier univariate and Cox multivariate survival analyses were performed to investigate the clinical prognostic value of FAM83A expression in LUAD patients. RESULTS Results from TCGA and Oncomine databases revealed that FAM83A mRNA expression level was significantly higher in LUAD than that in normal lung tissues (both P<0.05). Immunohistochemical findings demonstrated that the high positive rate of FAM83A in LUAD was 73.49% (61/83), while that of matched normal lung tissues was only 22.89% (19/83). Moreover, LUAD patients with FAM83A mRNA or high protein levels had dramatically lower OS times than those with FAM83A mRNA or low protein levels (All P<0.05). Lastly, Cox multivariate survival analysis showed that FAM83A differential expression level (low vs. high) was the only independent factor predicting the prognosis of LUAD patients (P=0.001). CONCLUSIONS FAM83A was overexpressed in LUAD, and FAM83A overexpression could be used as an independent factor of poor prognosis in LUAD patients.

The delivery of DNA vaccines is the principle impediment for implementation of DNA vaccination on a mass scale. In this study, we report a temperature induced conditionally expressed phage PhiX174 gene E mediated lysis of Salmonella under in vivo conditions that can increase the immunogenicity of a DNA vaccine delivered via Salmonella carrier system. We electroporated gene E encoding lysis plasmid pJHL187 along with the pcDNA-HA plasmid encoding H1N1 HA into attenuated Salmonella Typhimurium, strain JOL1893. Using C57BL/6 mice as the model, we showed that the mice intragastrically vaccinated with JOL1893 induced significant production of HA-specific humoral and cell mediated immune responses compared to the JOL1837, which carry pcDNA-HA plasmid alone. Furthermore, mice vaccinated with JOL1893 vaccine were fully protected against the lethal H1N1 challenge compared to the JOL1837 strain, which showed 90% protection only. However, none of the animals survived treated with either the PBS or the Salmonella carrying empty vector. Taken together, our results indicate that mucosal immunization with conditional lysis enabled live attenuated S. Typhimurium as a DNA vaccine carrier can induce efficient systemic and mucosal immune responses, and improves immune protection against a highly pathogenic H1N1 infection in mice model.

Latex proteins from P. pudica (LPPp) have anti-inflammatory activity. In the present study, LPPp was evaluated to protect animals against inflammatory ulcerative colitis (UC). UC was induced by intracolonic instillation of a 6% acetic acid solution and the animals received LPPp (10, 20 or 40 mg/kg) by intraperitoneal route 1 h before and 17 h after acetic acid injection. Eighteen hours after instillation of acetic acid, the mice were euthanized and the colons were excised to determine the wet weight, macroscopic and microscopic lesion scores, myeloperoxidase (MPO) activity, IL1-β levels, glutathione (GSH) and malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity. The results revealed that LPPp treatment (40 mg/kg) had a protective effect on acetic acid-induced colitis by reducing the wet weight, macroscopic and microscopic scores of intestinal lesions and colonic MPO activity. Additionally, LPPp inhibited tissue oxidative stress, since decreases in GSH consumption, MDA concentration and SOD activity were observed. The treatment with LPPp reduced the levels of cytokine IL-1β, contributing to the reduction of colon inflammation. Biochemical investigation showed that LPPp comprises a mixture of proteins containing proteinases, chitinases and proteinase inhibitors. These data suggest that LPPp has a protective effect against intestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration, cytokine release and oxidative stress.

Concrete words have been shown to have a processing advantage over abstract words, yet theoretical accounts and neural correlates underlying the distinction between concrete and abstract concepts are still unresolved. In an fMRI study, participants performed a property verification task on abstract and concrete concepts. Property comparisons of concrete concepts were predominantly based on either visual or haptic features. Multivariate pattern analysis successfully distinguished between abstract and concrete stimulus comparisons at the whole brain level. Multivariate searchlight analyses showed that posterior and middle cingulate cortices contained information that distinguished abstract from concrete concepts regardless of feature dominance. These results support the view that supramodal convergence zones play an important role in representation of concrete and abstract concepts.

Alanine and proline-rich protein (Apa) is a secreted antigen of Mycobacterium spp. which involves in stimulating immune responses and adhering to host cells by binding to fibronectin (Fn). Here, we report the crystal structure of Apa from Mycobacterium tuberculosis (Mtb) and its Fn-binding characteristics.

Dexmedetomidine (DEX), an imidazole compound, is an anesthetic drug used perioperatively. In the current study, we investigated the effects of DEX on androgen production in rat immature Leydig cells in vitro. Leydig cells isolated from pubertal Sprague Dawley rats were treated with various concentrations of DEX (0.015-1.5 µM) for 3 h and medium 5α-androstanediol and testosterone levels and the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1 and Akr1c14 in Leydig cells were determined. At 0.015-1.5 μM, DEX concentration-dependently inhibited androgen secretion and downregulated Cyp17a1 and Srd5a1 mRNA levels. DEX equally blocked the LH- and cAMP-stimulated secretion of androgens. Using the steroid substrates, 22R-hydroxycholesterol (for cytochrome P450 cholesterol side chain cleavage), pregnenolone (for 3β-hydroxysteroid dehydrogenase 1), progesterone (for cytochrome P450 17α-hydroxylase/C17,C20-lyase), androstenedione (for 17β-hydroxysteroid dehydrogenase 3), testosterone (for steroid 5α-reductase 1), and dihydrotestosterone (for 3α-hydroxysteroid dehydrogenase), it was demonstrated that DEX inhibited 22R-hydroxycholesterol, pregnenolone, progesterone, and testosterone-mediated 5α-androstanediol formation at 1.5 μM. Further study demonstrated that DEX also directly inhibited rat testis cholesterol side chain cleavage, 3β-hydroxysteroid dehydrogenation, and 17α-hydroxylation at 1.5 μM. DEX induced ROS production and increased apoptosis rate in immature Leydig cells after 24-h treatment at ≥0.15 μM. In conclusion, DEX directly inhibits the activities of some steroidogenic enzymes and downregulates the expression of Cyp17a1 and Srd5a1, and increases ROS production, thus leading to lower production of androgens in immature Leydig cells.

Problems of stability were found for biomarkers of alcohol consumption: ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanols (PEths), and fatty acid ethyl esters (FAEEs) in whole blood. The purpose of this study was to establish a method for the determination of these four kinds of ethanol's non-oxidative metabolites in dried blood spots (DBS) by liquid chromatography tandem mass spectrometry (LC-MS/MS), and to evaluate their stability. In this method, 50 μL of human blood was spotted onto a filter paper for DBS analysis. Samples were extracted by methanol, reconstituted by 2-propanol, and injected into the LC-MS/MS system. Limits of detection were among 0.5-50 ng/mL, and deviations in accuracy and precision were all lower than 15% at three quality control levels. The stability of the four kinds of ethanol non-oxidative metabolites in DBS was investigated during a 90-day range under three temperatures, -20 °C, 4 °C, and 25 °C. EtG and EtS showed a high level of stability in DBS in the 90-day range, regardless of the temperature. FAEEs were unstable after three days. PEths showed stability within 15 days in postmortem DBS and 60 days in antemortem DBS, respectively, at all temperatures.

Lysine formylation is a newly discovered post-translational modification in histones, which plays a crucial role in epigenetics of chromatin function and DNA binding. In this study, a novel bioinformatics tool named CKSAAP_FormSite is proposed to predict lysine formylation sites. An effective feature extraction method, the composition of k-spaced amino acid pairs, is employed to encode formylation sites. Moreover, a biased support vector machine algorithm is proposed to solve the class imbalance problem in the prediction of formylation sites. As illustrated by 10-fold cross-validation, CKSAAP_FormSite achieves an satisfactory performance with an AUC of 0.8234. Therefore, CKSAAP_FormSite can be a useful bioinformatics tool for the prediction of formylation sites. Feature analysis shows that some amino acid pairs, such as 'KA', 'SxxxxK' and 'SxxxA' around formylation sites may play an important role in the prediction. The results of analysis and prediction could offer useful information for elucidating the molecular mechanisms of formylation.

The Ganoderma genus represents clear biotechnological potential, due to the large quantity of molecules with biological activity that could be explored. However, available information regarding the biotechnological importance of species within Ganoderma, other than G. lucidum, is quite limited. Genomic studies of little-known species can contribute to the knowledge thereof, as well as the search for metabolic pathways and the identification of genes which code for proteins that may be of biotechnological relevance. Therefore, the objective of the present study was to obtain the G. australe genome, through the use of new sequencing technologies. Genomic DNA from G. australe was sequenced with the PacBio Sequel system, to a depth of 100×. The genome was assembled de novo with the Canu assembly tool, and gene prediction and annotation were performed with a funannotate pipeline. An assembled 84 Mb genome was obtained, and 22,756 putative protein-coding sequences were predicted in the G. australe genome. Ganoderic acid pathways were annotated and listed in the funannotate pipeline, and were recognized using Pfam and Antismash signals. Thus, the G. australe genome shows great potential, mainly, due to the annotation of putative sequences that could be employed in biotechnological approaches.