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Abstract Schizophrenia (SCZ) is a complex psychiatric disorder presenting challenges for characterization. The current study aimed to identify and evaluate disease‐responsive essential genes (DREGs) to enhance the molecular characterization of SCZ. RNA‐sequencing data from PsychENCODE (536 SCZ patients, 832 controls) and peripheral blood transcriptome data from 144 recruited subjects (59 SCZ patients, 6 non‐SCZ psychiatric patients, 79 controls) are analyzed. Shared differential expression genes are obtained using three algorithms. Support vector machine (SVM)‐based recursive feature elimination is employed to identify DREGs. The biological relevance of these DREGs is examined through protein–protein interaction network, pathway enrichment, polygenic scoring, and brain tissue expression. Key DREGs are validated in SCZ animal models. A DREGs‐based machine‐learning model for SCZ characterization is developed and its performance is assessed using multiple datasets. The analysis identified 184 DREGs forming an interconnected network involved in synaptic plasticity, inflammation, neuronal development, and neurotransmission. DREGs exhibited distinct expression in SCZ‐related brain regions and animal models. Their genetic contributions are comparable to genome‐wide polygenic risk scores. The DREG‐based SVM model demonstrated high performance (AUC 85% for SCZ characterization, 79% for specificity). These findings provide new insights into the molecular mechanisms underlying SCZ and emphasize the potential of DREGs in improving SCZ characterization.

We present 850 μ m thermal dust polarization observations with a resolution of 14.″4 (∼0.13 pc) toward an infrared dark cloud G16.96+0.27 using James Clerk Maxwell Telescope/POL-2. The average magnetic field orientation, which roughly agrees with the larger-scale magnetic field orientation traced by the Planck 353 GHz data, is approximately perpendicular to the filament structure. The estimated plane-of-sky magnetic field strength is ∼96 μ G and ∼60 μ G using two variants of the Davis–Chandrasekhar–Fermi methods. We calculate the virial and magnetic critical parameters to evaluate the relative importance of gravity, the magnetic field, and turbulence. The magnetic field and turbulence are both weaker than gravity, but magnetic fields and turbulence together are equal to gravity, suggesting that G16.96+0.27 is in a quasi-equilibrium state. The alignment between the magnetic field and cloud is found to have a trend moving away from perpendicularity in the dense regions, which may serve as a tracer of potential fragmentation in such quiescent filaments.

The internal structure of the prestellar core G208.68-19.02-N2 (G208-N2) in the Orion Molecular Cloud 3 (OMC-3) region has been studied with the Atacama Large Millimeter/submillimeter Array. The dust continuum emission revealed a filamentary structure with a length of ∼5000 au and an average H _2 volume density of ∼6 × 10 ^7 cm ^−3 . At the tip of this filamentary structure, there is a compact object, which we call a nucleus , with a radius of ∼150–200 au and a mass of ∼0.1 M _⊙ . The nucleus has a central density of ∼2 × 10 ^9 cm ^−3 with a radial density profile of r ^−1.87±0.11 . The density scaling of the nucleus is ∼3.7 times higher than that of the singular isothermal sphere (SIS). This as well as the very low virial parameter of 0.39 suggests that the gravity is dominant over the pressure everywhere in the nucleus. However, there is no sign of CO outflow localized to this nucleus. The filamentary structure is traced by the N _2 D ^+ 3–2 emission, but not by the C ^18 O 2–1 emission, implying the significant CO depletion due to high density and cold temperature. Toward the nucleus, the N _2 D ^+ also shows the signature of depletion. This could imply either the depletion of the parent molecule, N _2 , or the presence of the embedded very-low luminosity central source that could sublimate the CO in the very small area. The nucleus in G208-N2 is considered to be a prestellar core on the verge of first hydrostatic core (FHSC) formation or a candidate for the FHSC.

Magnetic fields of molecular clouds in the central molecular zone (CMZ) have been relatively under-observed at sub-parsec resolution. Here, we report JCMT/POL2 observations of polarized dust emission in the CMZ, which reveal magnetic field structures in dense gas at ∼0.5 pc resolution. The 11 molecular clouds in our sample include two in the western part of the CMZ (Sgr C and a farside cloud candidate), four around the Galactic longitude 0 (the 50 km s ^−1 cloud, CO 0.02−0.02, the Stone , and the Sticks and Straw among the Three Little Pigs), and five along the Dust Ridge (G0.253+0.016, clouds b, c, d, and e/f), for each of which we estimate the magnetic field strength using the angular dispersion function method. The morphologies of magnetic fields in the clouds suggest potential imprints of feedback from expanding H ii regions and young massive star clusters. A moderate correlation between the total viral parameter versus the star formation rate (SFR) and the dense gas fraction of the clouds is found. A weak correlation between the mass-to-flux ratio and the SFR, and a weak anticorrelation between the magnetic field and the dense gas fraction are also found. Comparisons between magnetic fields and other dynamic components in clouds suggest a more dominant role of self-gravity and turbulence in determining the dynamical states of the clouds and affecting star formation at the studied scales.

We observe the magnetic field morphology toward a nearby star-forming filamentary cloud, G202.3+2.5, using James Clerk Maxwell Telescope/POL-2 850 μ m thermal dust polarization observations with an angular resolution of 14.″4 (∼0.053 pc). The average magnetic field orientation is found to be perpendicular to the filaments, while showing different behaviors in the four subregions, suggesting various effects from the filaments’ collision in these subregions. With the kinematics obtained by the ${{{\rm{N}}}_{2}{\rm{H}}}^{+}$ observation by IRAM, we estimate the plane-of-sky magnetic field strength by two methods, the classical Davis–Chandrasekhar–Fermi (DCF) method and the angular dispersion function (ADF) method, giving B _pos,dcf and B _pos,adf of ∼90 and ∼53 μ G. We study the relative importance between the gravity ( G ), magnetic field ( B ), and turbulence ( T ) in the four subregions, and find G > T > B , G ≥ T > B , G ∼ T > B , and T > G > B in the north tail, west trunk, south root, and east wing, respectively. In addition, we investigate the projection effects on the DCF and ADF methods, based on a similar simulation case, and find the 3D magnetic field strength may be underestimated by a factor of ∼3 if applying the widely used statistical B _pos -to- B _3D factor when using the DCF or ADF methods, which may further underestimate/overestimate the related parameters.

Filamentary structures are ubiquitously found in high-mass star-forming clouds. To investigate the relationship between filaments and star formation, we carry out the INFANT (Investigations of Massive Filaments and Sar Formation) survey, a multiscale, multiwavelength survey of massive filamentary clouds with Atacama Large Millimeter/submillimeter Array (ALMA) band 3/band 6 and Very Large Array K band. In this first paper, we present the ALMA band 6 continuum observations toward a sample of eight high-mass star-forming filaments. We covered each target with an approximately rectangular mosaic field of view with two 12 m array configurations, achieving an angular resolution of ∼0.″6 (2700 au at 4.5 kpc) and a continuum rms of ∼0.1 mJy beam ^−1 (∼0.06 M _⊙ in gas mass assuming 15 K). We identify cores using the getsf and astrodendro and find the former is more robust in terms of both identification and measuring flux densities. We identify in total 183 dense cores (15–36 cores in each cloud) and classify their star formation states via outflow and warm gas tracers. The protostellar cores are statistically more massive than the prestellar cores, possibly indicating further accretion onto cores after the formation of protostars. For the high-mass end ( ${M}_{\mathrm{core}}$ > 1.5 M _⊙ ) of the core mass function (CMF) we derive a power-law index of −1.15 ± 0.12 for the whole sample and −1.70 ± 0.25 for the prestellar population. We also find a steepening trend in CMF with cloud evolution (−0.89 ± 0.15 for the young group versus. −1.44 ± 0.25 for the evolved group) and discuss its implications for cluster formation.

Background: Education and cognition demonstrate consistent inverse associations with Alzheimer’s disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites reflect the end point of biological processes and are accessible and malleable. Identifying metabolites with etiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms. Methods: Using data from the largest metabolomics genome-wide association study (N ≈ 24,925) and three independent AD cohorts (N = 4725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization interrogated univariable causal relationships between 1) metabolites and AD; 2) education and cognition; 3) metabolites, education, and cognition; and 4) education, cognition, and AD. Mediating relationships were computed using multivariable Mendelian randomization. Results: Thirty-four metabolites were genetically associated with AD at p < .05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins demonstrated a protective causal effect (glutamine: 95% confidence interval [CI], 0.70 to 0.92; free cholesterol in extra-large high-density lipoproteins: 95% CI, 0.75 to 0.92). An AD-protective effect was also observed for education (95% CI, 0.61 to 0.85) and cognition (95% CI, 0.60 to 0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice versa, however. No evidence of mediation via any metabolite was found. Conclusions: Glutamine and free cholesterol in extra-large high-density lipoproteins show protective causal effects on AD. Education and cognition also demonstrate protection, though education’s effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multimodal work and progressing toward effective intervention strategies.

The Atacama Large Millimeter/submillimeter Array (ALMA) Survey of Star Formation and Evolution in Massive Protoclusters with Blue Profiles (ASSEMBLE) aims to investigate the process of mass assembly and its connection to high-mass star formation theories in protoclusters in a dynamic view. We observed 11 massive ( M _clump ≳ 10 ^3 M _⊙ ), luminous ( L _bol ≳ 10 ^4 L _⊙ ), and blue-profile (infall signature) clumps by ALMA with resolution of ∼2200–5500 au (median value of 3500 au) at 350 GHz (870 μ m). We identified 248 dense cores, including 106 cores showing protostellar signatures and 142 prestellar core candidates. Compared to early stage infrared dark clouds (IRDCs) by ASHES, the core mass and surface density within the ASSEMBLE clumps exhibited a significant increment, suggesting concurrent core accretion during the evolution of the clumps. The maximum mass of prestellar cores was found to be 2 times larger than that in IRDCs, indicating that evolved protoclusters have the potential to harbor massive prestellar cores. The mass relation between clumps and their most massive core (MMCs) is observed in ASSEMBLE but not in IRDCs, which is suggested to be regulated by multiscale mass accretion. The mass correlation between the core clusters and their MMCs has a steeper slope compared to that observed in stellar clusters, which can be due to fragmentation of the MMC and stellar multiplicity. We observe a decrease in core separation and an increase in central concentration as protoclusters evolve. We confirm primordial mass segregation in the ASSEMBLE protoclusters, possibly resulting from gravitational concentration and/or gas accretion.

Abstract SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8–90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (P = 5.8 × 10–29). Exome sequencing excluded the involvement of other BA metabolism-associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in SLC10A1 is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in SLC10A1 are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP.

Background Newborns affected with congenital pulmonary airway malformations (CPAMs) may present with severe respiratory distress or remain asymptomatic. While surgical resection is the definitive treatment for symptomatic CPAMs, prophylactic elective surgery may be recommended for asymptomatic CPAMs owing to the risk of tumour development. However, the implementation of prophylactic surgery is quite controversial on the grounds that more evidence linking CPAMs and cancer is needed. The large gap in knowledge of CPAM pathogenesis results in uncertainties and controversies in disease management. As developmental genes control postnatal cell growth and contribute to cancer development, we hypothesised that CPAMs may be underlain by germline mutations in genes governing airways development. Methods Sequencing of the exome of 19 patients and their unaffected parents. Results A more than expected number of mutations in cancer genes (false discovery rate q-value

Urbanization is one of the most significant contributing factors to anthropogenic climate change. However, a lack of projected city land use data has posed significant challenges to factoring urbanization into climate change modeling. Thus, the results from current models may contain considerable errors in estimating future climate scenarios. The Pearl River Delta region was selected as a case study to provide insight into how large-scale urbanization and different climate change scenarios impact the local climate. This study adopts projected land use data from freely available satellite imagery and applies dynamic simulation land use results to the Weather Research and Forecasting Model (WRF). The simulation periods cover the summer periods in 2010 and 2029–2031, the latter of which is averaged to represent the year 2030. The WRF simulation used the observed local climate conditions in 2010 to represent the current scenario and the projected local climate changes for 2030 as the future scenario. Under all three future climate change scenarios, the warming trend is prominent (around 1–2 °C increase), with a widespread reduction in wind speed in inland areas (1–2 ms−1). The vulnerability of human health to thermal stress was evaluated by adopting the wet-bulb globe temperature (WBGT). The results from the future scenarios suggest a high public health risk due to rising temperatures in the future. This study provides a methodology for a more comprehensive understanding of future urbanization and its impact on regional climate by using freely available satellite images and WRF simulation tools. The simulated temperature and WBGT results can serve local governments and stakeholders in city planning and the creation of action plans that will reduce the potential vulnerability of human health to excessive heat.

The majority of cognitive bias research has been conducted in Western cultures. We examined cross-cultural differences in cognitive biases, comparing Westerners' and East Asians' performance and acculturation following migration to the opposite culture. Two local (UK, Hong Kong) and four migrant (short-term and long-term migrants to each culture) samples completed culturally validated tasks measuring attentional and interpretation bias. Hong Kong residents were more positively biased than people living in the UK on several measures, consistent with the lower prevalence of psychological disorders in East Asia. Migrants to the UK had reduced positive biases on some tasks, while migrants to Hong Kong were more positive, compared to their respective home counterparts, consistent with acculturation in attention and interpretation biases. These data illustrate the importance of cultural validation of findings and, if replicated, would have implications for the mental health and well-being of migrants.

BackgroundAlthough altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.Methods and findingsWe included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n=10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at pConclusionsGenetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors' Summary.

Nasopharyngeal carcinoma (NPC) is a malignancy of epithelial origin. The etiology of NPC is complex and includes multiple genetic and environmental factors. We employed case-control analysis to study the association of chromosome 6p regions with NPC. In total, 360 subjects and 360 healthy controls were included, and 233 single nucleotide polymorphisms (SNPs) on 6p were examined. Significant single-marker associations were found for SNPs rs2267633 (p = 4.49 × 10(-5)), rs2076483 (most significant, p = 3.36 × 10(-5)), and rs29230 (p=1.43 × 10(-4)). The highly associated genes were the gamma-amino butyric acid B receptor 1 (GABBR1), human leukocyte antigen (HLA-A), and HLA complex group 9 (HCG9). Haplotypic associations were found for haplotypes AAA (located within GABBR1, p-value = 6.46 × 10(-5)) and TT (located within HLA-A, p = 0.0014). Further investigation of the homozygous genotype frequencies between cases and controls suggested that micro-deletion regions occur in GABBR1 and neural precursor cell expressed developmentally down-regulated 9 (NEDD9). Quantitative real-time polymerase chain reaction (qPCR) using 11 pairs of NPC biopsy samples confirmed the significant decline in GABBR1 and NEDD9 mRNA expression in the cancer tissues compared to the adjacent non-tumor tissue (p

BACKGROUND: Maternal immune activation (MIA) during prenatal life is a risk factor for neurodevelopmental disorders including schizophrenia and autism. Such conditions are associated with alterations in fronto-subcortical circuits, but their molecular basis is far from clear. METHODOLOGY/PRINCIPAL FINDINGS: Using two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry, with targeted western blot analyses for confirmation, we investigated the impact of MIA on the prefrontal and striatal proteome from an established MIA mouse model generated in C57B6 mice, by administering the viral analogue PolyI:C or saline vehicle (control) intravenously on gestation day (GD) 9. In striatum, 11 proteins were up-regulated and 4 proteins were down-regulated in the PolyI:C mice, while 10 proteins were up-regulated and 7 proteins down-regulated in prefrontal cortex (PFC). These were proteins involved in the mitogen-activated protein kinase (MAPK) signaling pathway, oxidation and auto-immune targets, including dual specificity mitogen-activated protein kinase kinase 1 (MEK), eukaryotic initiation factor (eIF) 4A-II, creatine kinase (CK)-B, L-lactate dehydrogenase (LDH)-B, WD repeat-containing protein and NADH dehydrogenase in the striatum; and guanine nucleotide-binding protein (G-protein), 14-3-3 protein, alpha-enolase, olfactory maker protein and heat shock proteins (HSP) 60, and 90-beta in the PFC. CONCLUSIONS/SIGNIFICANCE: This data fits with emerging evidence for disruption of critical converging intracellular pathways involving MAPK pathways in neurodevelopmental conditions and it shows considerable overlap with protein pathways identified by genetic modeling and clinical post-mortem studies. This has implications for understanding causality and may offer potential biomarkers and novel treatment targets for neurodevelopmental conditions.

Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD) and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE), 313 foci were extracted from 25 voxel-based studies comprising 660 participants (308 ASD, 352 first-episode schizophrenia) and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures.

Plant WRKY transcription factors are responsible for biotic and abiotic stresses and play an important role in enhancing their adaptability. The AtWRKY33 is a gene that functions in response to abiotic stresses such as low temperature, drought, salinity, etc. In this study, a recombinant vector YG8198-ZmWRKY53 carrying the ZmWRKY53, an interspecific homolog of the dicotyledonous AtWRKY33, was transferred to rice plants by Agrobacterium mediated transformation. The ectopic expression of the ZmWRKY53 in transgenic rice plants conferred cold tolerance with a higher accumulation of free proline and water-soluble sugars, an increase in chlorophyll content, a decrease in electrolyte leakage rate and MDA levels compared to control plants. This result suggests that ZmWRKY53 may confer cold tolerance in rice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Three-party authentication key exchange is a protocol that allows two users to set up a session key for encrypted communication by the help of a trusted remote server. Providing user anonymity and mutual authentication in the authentication key exchange is important security requirements to protect users' privacy and enhance its security performance. Recently Li proposed a chaotic maps-based authentication key exchange protocol which attempts to provide mutual authentication and user anonymity, but we found that there were some faults in the key exchange phase and password change phase of his scheme. We prove that Li's scheme does not provide user anonymity and that the user's privacy information is disclosed, and propose enhanced three-party authentication key exchange protocol that provides user anonymity and we analyse its security properties and verify its validity based on BAN logic and AVISPA tool., Competing Interests: The authors have declared that no competing interests exist.

A yellow bacterial strain, designated LRZ-2 T , was isolated from High Arctic tundra near the settlement Ny-Ålesund in the Svalbard Archipelago, Norway. The cells were Gram-stain-positive, aerobic and non-sporulating. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain LRZ-2 T represented a novel member of the suborder Micrococcineae . Its nearest phylogenetic neighbours were the members of the genus Luteimicrobium , with 16S rRNA gene sequence similarity of 95.3-96.9 %. The average nucleotide identity and digital DNA-DNA hybridization values between the genomes of strain LRZ-2 T and its closely related strains were 77.4-74.3 % and 21.4-19.6 %, respectively. The DNA G+C content was 72.4 mol%. The peptidoglycan type of the isolate was A4β with an interpeptide bridge comprising l-ornithine and d-glutamic acid. The predominant menaquinone was MK-9 (H 4 ) and the major fatty acids were anteiso-C 15 : 0 , C 16 : 0 , anteiso-C 15 : 1 A, anteiso-C 17 : 0 and iso-C 15 : 0 . The polar lipids were diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, phosphatidylinositol dimannoside, unidentified phosphoglycolipid, four unidentified phospholipids and two unidentified polar lipids. Strain LRZ-2 T showed a 16S rRNA gene signature pattern consisting of nucleotides at positions 120 (A), 131-231 (C-G), 196 (C), 342-347 (C-G), 444-490 (A-U), 580-761 (C-G), 602-636 (C-G), 670-736 (A-U), 822-878 (G-C), 823-877 (G-C), 826-874 (C-G), 827 (U), 843 (C), 950-1231 (U-A), 1047-1210 (G-C), 1109 (C), 1145 (G), 1309-1328 (G-C), 1361 (G) and 1383 (C), which clearly distinguished it from all genera previously reported in the suborder Micrococcineae . On the basis of the phylogenetic, phenotypic and chemotaxonomic data, strain LRZ-2 T is considered to represent a novel species of a new genus, for which the name Pengzhenrongella sicca gen. nov., sp. nov. is proposed. The type strain of Pengzhenrongella sicca is LRZ-2 T (=CCTCC AB 2012163 T =DSM 100332 T ).

Bacillus circulans 528 produces a restriction endonuclease, Bci528I which is an isoschizomer of EcoRI. We purified the enzyme, using Sephadex G-150, Phospho-cellulose, DEAE-cellulose, Hepharin-Sepharose CL-6B chromatography. The specific activity of Bci528I was 29,400 U/mg·protein. Bci528I recognizes 5'-GAATTC-3' in dsDNA and cleaves between G and A of the recognition sequence, producing a symmetric four base 5'overhang.

Numerous links exist between inflammation and tumor development. Toll-like receptor 4 (TLR4) expression by tumor cells can be a contributing factor that promotes tumor cell proliferation, survival, migration, and metastasis. In this study, we explored the impact of TLR4 inhibition using TAK-242, a specific inhibitor of TLR4, on the invasion properties of ovarian (A2780CP, 2008C13, SKOV3, and A2780S) and breast (MCF7, SKBR3, MDA-MB-231, and BT-474) cancer cell lines. Six out of eight cell lines expressed TLR4 and its downstream mediators (MyD88, NF-ĸB1, and RELB), indicating that these cell lines could be proper candidates for the TLR4 inhibition. TAK-242 induced a cytotoxic effect on all tested cell lines; however, a different cell sensitivity pattern was noticeable. Interestingly, in the TLR4-expressing cell lines, there was a significant correlation between the TLR4/MyD88 expressions and the cancer cell response to TAK-242: the higher the expression, the higher the IC 50 . To the best of our knowledge, no study has addressed the effects of TAK-242 on invasive abilities of cancer cells and our study suggests for the first time that TAK-242 could considerably decrease invasion properties of ovarian and breast cancer cell lines. We found that not only did TAK-242 reduce the enzymatic activity of MMP2 and MMP9, but also down-regulated gene expressions of epithelial-mesenchymal transition (EMT)-related genes. In sum, it seems that targeting TLR4 using TAK-242 possesses novel promising potential in cancer treatment strategies and may prevent invasion in patients suffering from ovarian and breast cancers, especially in those with over-expression of TLR4., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Inguinal hernia repair and general anesthesia (GA) are known risk factors for urinary retention. Paravertebral blocks (PVBs) have been utilized to facilitate enhanced recovery after surgery. We evaluate the benefit of incorporating PVBs into our anesthetic technique in a large cohort of ambulatory patients undergoing inguinal hernia repair., Methods: Records of 619 adults scheduled for ambulatory inguinal hernia repair between 2010 and 2015 were reviewed and categorized based on anesthetic and surgical approach [GA and open (GAO), GA and laparoscopic (GAL), PVB and open (PVBO), and GA/PVB and open (GA/PVBO)]. Patients were excluded for missing data, self-catheterization, chronic opioid tolerance, and additional surgical procedures coinciding with hernia repair. Risk factors associated with the primary outcome of urinary retention were examined using logistic regression., Results: PVBO (n = 136) had significantly lower odds than GAO of experiencing urinary retention (odds ratio 0.16; 95% CI 0.05-0.51); overall (P < .01), with 4.4% (n = 6) of the patients in the PVBO group having urinary retention versus 22.6% (n = 7) with GAO. Expressed as intravenous morphine equivalences, the PVBO group had the lowest median opioid use (5 mg), followed by GA, PVB, and open (7.5 mg); GAO 25 mg; and GAL 25 mg. Also, 30% (n = 41) of the PVBO group required no opioid analgesia in the postanesthesia care unit., Conclusions: PVBs as the primary anesthetic or an adjunct to GA is the preferred anesthetic technique for open inguinal hernia repair as it facilitates enhanced recovery after surgery by decreasing risk of urinary retention, opioid requirements, and length of stay.

Hsp90α is a molecular chaperone protein involved in the structural maturation of oncogenic signaling proteins. Hsp90 was recently identified as an anticancer target; various studies are ongoing to find ways for managing cancer through Hsp90α. However, this approach is limited by reported side-effects. Hypoxia is a hallmark of solid tumors, including those of breast cancer and the extent of tumor hypoxia is associated with resistance to treatment and poor prognosis. One of the major signaling pathways in cancer cells, the Jak2/STAT5b pathway, has been found to be closely correlated with hypoxia. The objective of this study was to investigate the role of Jak2/STAT5b in the regulation of Hsp90α expression so that Hsp90α targeting can be achieved indirectly by modulating the Jak2/STAT5b pathway. We examined the role of the Jak2/STAT5b pathway in the expression of Hsp90α under hypoxic conditions by immunoblotting, reporter gene assays, EMSA and RNA interference analysis. With the help of in vivo models, we also analyzed the expression of Hsp90α in different parts of solid tumor tissues. We found a close association between hypoxic stress and Hsp90α expression. We also determined that STAT5b regulates the expression of Hsp90α during hypoxic stimulation. Under hypoxic conditions the expression of Hsp90α and STAT5b were proportional. siRNA analysis and nucleotide analysis showed that the promoter of Hsp90α has a STAT5b binding domain. Our work confirmed that STAT5b is one of the transcription factors that regulate Hsp90α. We, therefore, concluded that under hypoxic conditions, the Jak2/STAT5b pathway regulates Hsp90α expression and it could serve as a promising target for the treatment of solid tumors.

Background: Human enteroviruses (HEVs) are a major cause of herpangina, HFMD (hand, foot, and mouth disease), and other neurological diseases in Seoul, Korea., Methods: A total of 56 specimens from hospitalized patients collected from February to December 2009 (37 females and 19 males) in Seoul were tested for HEV from stool, throat swab, and vesicle swab samples taken from patients with herpangina or HFMD using cell culture and RT-PCR in 2009. By the 1D gene, encoding the VP1 capsid protein, seven different HEV genotypes were detected with Coxsackievirus A2, A4, A5, A9, A16 (CA), Coxsackievirus B1 (CB), and Enterovirus 71 (EV71). The most prevalent genotype was CA16 (6, 10.7%), followed by CA2 (4, 7.1%), CA5 (4, 7.1%), EV71 (2, 3.6%), CA4 (1, 1.8%), CA9 (1, 1.8%), and CB1 (1, 1.8%). The 1D gene sequences of two EV71 strains were closely related with one another (98.5% nucleotide similarity) and belonged to the C4 genotype., Conclusions: It is important to continuously survey the genetic characteristics of EV71 and CA16 from patients, which will provide useful data that aids in our understanding of HFMD infections in Seoul, Korea and may contribute to future control.

We studied the effects of angiotensin II receptor blockade with losartan on thirst and sodium appetite in pregnant Wistar rats and on their adult female offspring. During maternal adaptation to pregnancy, average daily total water intake increased by 63% (P<0.01); NaCl intake by 214% (P<0.001). These changes were not blocked by daily s.c. injections of losartan (50 mg/kg bw i.p.) from gestation day (GD) 2 until GD 19 which implied that maternal AT(1) receptors were not involved in the up regulation of thirst and sodium appetite during pregnancy. Losartan blockade during gestation led to a significant and continued increase in thirst and sodium appetite in the adult female offspring. Daily water intakes were greater in the losartan (LO) group than in the vehicle-injected control group (CO), leading to a total water intake of 1114 +/- 80.6 ml/kg bw compared with 738 +/- 56.7 ml/kg bw (P<0.05) during the 8-day period of observation. Daily sodium intakes were usually 2-3 times greater in the LO group compared with the CO group, amounting to a final cumulative intake of 232 +/- 33 mmol/kg bw compared with 93.8 +/- 16.5 mmol/kg bw (P<0.05) in 8 days. These elevated sodium and water intakes were nearly counterbalanced by the increased renal excretion of water and sodium by fully functional kidneys that were not injured by the drug. Body weights were 10% lower in the LO group at the start but remained unchanged relative to the CO group during the entire 8-day period of observation. Plasma electrolytes, blood hematocrit and carotid MABP in the LO group did not differ from the CO group.

A peptide derived from the human papillomavirus L2 protein is recognized by a myelin basic protein (MBP)-specific T cell clone from a multiple sclerosis patient and by MBP-specific autoantibodies purified from multiple sclerosis brain tissue. We now show in mice that low doses of this papillomavirus peptide were optimal in selecting a subpopulation of papillomavirus peptide-specific T cells that cross-reacted with MBP(87-99) and with an unrelated viral peptide derived from the BSLF1 protein of Epstein-Barr virus (EBV). These low dose viral peptide- specific T cell lines were highly encephalitogenic. Splenocytes from mice transferred with viral peptide-specific T cells showed a vigorous response to both the papillomavirus and MBP peptides, indicating that viral antigen-specific T cells survived for a prolonged time in vivo. The EBV peptide, unable to prime and select an autoreactive T cell population, could still activate the low dose papillomavirus peptide-specific cells and induce central nervous system (CNS) autoimmunity. Cytokine profiles of papillomavirus peptide-specific encephalitogenic T cells and histopathology of CNS lesions resembled those induced by MBP. These results demonstrate conserved aspects in the recognition of the self-antigen and a cross-reactive viral peptide by human and murine MBP-specific T cell receptors. We demonstrate that a viral antigen, depending on its nature, dose, and number of exposures, may select autoantigen-specific T cells that survive in vivo and can trigger autoimmune disease after adoptive transfer.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelination. Retinoids regulate cell differentiation and growth by binding to and activating retinoic acid receptors, which seem to be nuclear transcription factors. The effect of retinoids on chronic relapsing EAE produced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MBP-specific LNC activation resulted in a considerable increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-gamma was decreased. Increased IL-4 also was detected in culture supernatants. However, the presence of a neutralizing Ab to IL-4 (11B11) during MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given after disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 phenotype, which, in turn, might be responsible for the decrease in the encephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which the protective cytokines of Th2-like cells predominate may have potential relevance for human demyelinating diseases such as multiple sclerosis.