Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis.

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.

Transcriptome-wide association study identifies multiple genes and pathways associated with thyroid function.

Thyroid dysfunction is a common endocrine disease measured by thyroid-stimulating hormone (TSH) level. Although >70 genetic loci associated with TSH have been reported through genome-wide association studies (GWASs), the variants can only explain a small fraction of the thyroid function heritability. To identify novel candidate genes for thyroid function, we conducted the first large-scale transcriptome-wide association study (TWAS) for thyroid function using GWAS-summary data for TSH levels in up to 119 715 individuals combined with precomputed gene expression weights of six panels from four tissue types. The candidate genes identified by TWAS were further validated by TWAS replication and gene expression profiles. We identified 74 conditionally independent genes significantly associated with thyroid function, such as PDE8B (P = 1.67 × 10-282), PDE10A (P = 7.61 × 10-119), NR3C2 (P = 1.50 × 10-92) and CAPZB (P = 3.13 × 10-79). After TWAS replication using UKBB datasets, 26 genes were replicated for significant associations with thyroid-relevant diseases/traits. Among them, 16 genes were causal for their associations to thyroid-relevant diseases/traits and further validated in differential expression analyses, including two novel genes (MFSD6 and RBM47) that did not implicate in previous GWASs. Enrichment analyses detected several pathways associated with thyroid function, such as the cAMP signaling pathway (P = 7.27 × 10-4), hemostasis (P = 3.74 × 10-4), and platelet activation, signaling and aggregation (P = 9.98 × 10-4). Our study identified multiple candidate genes and pathways associated with thyroid function, providing novel clues for revealing the genetic mechanisms of thyroid function and disease.

Gate-tunable room-temperature ferromagnetism in two-dimensional Fe3GeTe2.

Materials research has driven the development of modern nano-electronic devices. In particular, research in magnetic thin films has revolutionized the development of spintronic devices1,2 because identifying new magnetic materials is key to better device performance and design. Van der Waals crystals retain their chemical stability and structural integrity down to the monolayer and, being atomically thin, are readily tuned by various kinds of gate modulation3,4. Recent experiments have demonstrated that it is possible to obtain two-dimensional ferromagnetic order in insulating Cr2Ge2Te6 (ref. 5) and CrI3 (ref. 6) at low temperatures. Here we develop a device fabrication technique and isolate monolayers from the layered metallic magnet Fe3GeTe2 to study magnetotransport. We find that the itinerant ferromagnetism persists in Fe3GeTe2 down to the monolayer with an out-of-plane magnetocrystalline anisotropy. The ferromagnetic transition temperature, Tc, is suppressed relative to the bulk Tc of 205 kelvin in pristine Fe3GeTe2 thin flakes. An ionic gate, however, raises Tc to room temperature, much higher than the bulk Tc. The gate-tunable room-temperature ferromagnetism in two-dimensional Fe3GeTe2 opens up opportunities for potential voltage-controlled magnetoelectronics7-11 based on atomically thin van der Waals crystals.

Identifying climate refugia for wild yaks (Bos mutus) on the Tibetan Plateau.

Climate change is threatening fragile alpine ecosystems and their resident ungulates, particularly the wild yak (Bos mutus) that inhabits alpine areas between the tree line and glaciers on the Tibetan Plateau. Although wild yaks tend to shift habitats in response to changes in climatic factors, the precise impacts of climate change on their habitat distribution and climate refugia remain unclear. Based on over 1000 occurrence records, the maximum entropy (MaxEnt) algorithm was applied to simulate habitat ranges in the last glacial maximum (LGM), Mid-Holocene, current stage, and three greenhouse gas emission scenarios in 2070. Three habitat patches were identified as climate refugia for wild yaks that have persisted from the LGM to the present and are projected to persist until 2070. These stable areas account for approximately 64% of the current wild yak habitat extent and are sufficiently large to support viable populations. The long-term persistence of these climate refugia areas is primarily attributed to the unique alpine environmental features of the Tibetan Plateau, where relatively stable arid or semi-arid climates are maintained, and a wide range of forage resource supplies are available. However, habitat loss by 2070 caused by insufficient protection is predicted to lead to severe fragmentation in the southeastern and northwestern Kunlun, Hengduan, central-western Qilian, and southern Tanggula-northern Himalaya Mountains. Habitat disturbance has also been caused by increasing anthropogenic effects in the southern Tanggula and northern Himalaya Mountains. We suggest that sufficient protection, transboundary cooperation, and community involvement are required to improve wild yak conservation efforts. Our combined modeling method (MaxEnt-Zonation-Linkage Mapper-FRAGSTAT) can be utilized to identify priority areas and linkages between habitat patches while assessing the conservation efficiency of protected areas and analyzing the coupled relationship between climate change and anthropogenic impacts on the habitat distribution of endangered species.

Recent Advances in Aerobic Oxidative of C-H Bond by Molecular Oxygen Focus on Heterocycles.

Aerobic oxidative cross-coupling represents one of the most straightforward and atom-economic methods for construction of C-C and C-X (X=N, O, S, or P) bonds using air as a sustainable external oxidant. The oxidative coupling of C-H bonds in heterocyclic compounds can effectively increase their molecular complexity by introducing new functional groups through C-H bond activation, or by formation of new heterocyclic structures through cascade construction of two or more sequential chemical bonds. This is very useful as it can increase the potential applications of these structures in natural products, pharmaceuticals, agricultural chemicals, and functional materials. This is a representative overview of recent progress since 2010 on green oxidative coupling reactions of C-H bond using O2 or air as internal oxidant focus on Heterocycles. It aims to provide a platform for expanding the scope and utility of air as green oxidant, together with a brief discussion on research into the mechanisms behind it.

Efficient Aerobic Oxidative Coupling of Methyl Heteroarenes with Indoles.

Direct oxidative coupling of inert C(sp3 )-H bond has been a great challenge. Herein, an environmentally friendly aerobic oxidative coupling of α-methyl substituted N-heteroarenes with indoles is reported. A variety of diheteroaryl ketones were prepared in good yields (up to 72 %). This protocol features simple operation and broad substrates scope (26 examples). Significantly, a plausible mechanism about catalytic cycle was proposed, and two key intermediates were confirmed by high resolution mass spectrometry.

The effect of magnetic order on the thermal transport properties of the intrinsic two-dimensional magnet 2H-VSe2.

By using first-principles calculations combined with the phonon Boltzmann transport equation, in this work, we systematically investigate the effect of magnetic order on the phonon and thermal transport properties of the intrinsic two dimensional magnet 2H-VSe2. The results show that 2H-VSe2 is dynamically stable in both paramagnetic and ferromagnetic phases, and the obvious discrepancy of characteristic frequencies of Raman-active phonon modes provides a reliable way to identify the magnetic phase. Meanwhile, our calculations also indicate that the magnetic order has a vital effect on the thermal transport properties. Around the Curie temperature (500 K), the thermal conductivity of 2H-VSe2 in the FM phase (16.3 W mK-1) is about four times larger than that in the PM phase (4.3 W mK-1), and such a difference could be maintained even when considering the temperature dependent force constants. By analyzing the phonon mode information and root mean square displacement, we reveal that large atomic interactions and suppressed phonon anharmonicity are the main roots for the enhanced thermal conductivity in the FM phase 2H-VSe2. These results further demonstrate that magnetic materials with a FM phase always host more excellent thermal transport properties than those with a PM phase, and shed light on the great potential applications of thermal switching devices based on 2H-VSe2.

Is social support beneficial for military cadets to accomplish empowerment? Findings from a long-term cross-lagged panel analysis.

Social support and empowerment are central to health and wellbeing. Besides, social support is often the primary means to help students improve their mental health and accomplish empowerment. However, military academies are an atypical form of tertiary education. Is social support still beneficial for military cadets to accomplish empowerment? Or does empowerment influence the extent of social support a person receives? This study sought to examine the reciprocal relationships between social support and empowerment in military academies, as well as to examine the sex differences in this model. A longitudinal panel survey of military cadets was carried out from the years 2019 to 2021. A crosslagged path model design was used on a sample of military cadets (N = 898) measured on three occasions one year apart. The results suggested that no cross-lagged associations between social support and empowerment. The three-year panel data consistently showed that social support does not enhance military cadets' empowerment, whereas empowerment significantly influences their perceived social support. Furthermore, there were no sex differences in this model. Finally, the findings informed practitioners and future research could be pay attention to the particularity in military settings, in order to provide adequate interventions and services for military cadets.

The C(sp3)-H bond functionalization of thioethers with styrenes with insight into the mechanism.

A metal-free inactive C(sp3)-H bond functionalization of thioethers with styrenes using TBHP as an initiator and DBU as a base has been developed. This transformation has broken through the low activity of thioethers and realized moderate yields. Herein extended experiments were conducted to confirm the radical relay process, reaction energy and intermediate transformations.

A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Shwachman-Diamond Syndrome With Congenital Myogenic Ptosis: Case Report of a Rare Association?

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a multisystem disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. There is considerable variation in the phenotypes of SDS. We present a case of an infant presenting with SDS and left-sided ptosis. OBSERVATION: We report a case of an infant who presented with 2 episodes of severe sepsis and cytopenia, without overt symptoms of exocrine pancreatic deficiency or skeletal abnormalities. Persistent left-sided ptosis was noted in both presentations. Genetic testing confirmed the diagnosis of SDS. The left-sided ptosis was diagnosed as congenital myogenic ptosis. CONCLUSION: The association of ptosis and other congenital bone marrow failure syndromes is well established, but this is the first description of SDS with ptosis. This association may expand our understanding of SDS phenotypes if similar cases are reported in the future.

Multimodal Assessments of Altered Sensation after Transoral Endoscopic Thyroidectomy.

BACKGROUND: Transoral endoscopic thyroidectomy, a novel technique, uses oral vestibule as the entry point and leaves no scar on the body surface. However, because the incisions are close to the mental nerve, nerve damage and the associated sensory impairment are concerning. Herein, we evaluated sensory alteration after transoral endoscopic thyroidectomy and determined factors associated with the prolonged sensory alteration. METHODS: Patients who underwent transoral endoscopic thyroidectomy were enrolled. Sensation over the lower lip, chin, and neck was evaluated before and after the surgery. A self-assessment questionnaire, Semmes-Weinstein monofilament test, and two-point discrimination test were used to subjectively and objectively evaluate sensory changes. RESULTS: Fifty-one patients were enrolled; most of them reported altered sensation, with chin (72.5%) being the most common site, followed by lower lip (52.9%), upper neck (33.3%), and lower neck (5.9%) on postoperative day 2. The sensory disturbance resolved within 3 months. Factors associated with prolonged sensory alteration are male sex and old age. Fourteen patients (27.5%) experienced mild drooling from the mouth, which was usually self-limiting in 1 month. Sensory impairments in light touch pressure threshold and two-point discrimination were significant in the chin and neck on postoperative day 2 and at 1 week. The ability to discern two-point was also compromised in the lower lip on postoperative day 2. All these significant changes normalized to preoperative baseline at 1 month. CONCLUSIONS: There was an altered sensation after transoral endoscopic thyroidectomy with the most common and disturbed in the chin. Sensory impairment was usually transient and recovered in 3 months.

Modeling circRNA expression pattern with integrated sequence and epigenetic features demonstrates the potential involvement of H3K79me2 in circRNA expression.

MOTIVATION: CircRNAs are an abundant class of non-coding RNAs with widespread, cell-/tissue-specific patterns. Previous work suggested that epigenetic features might be related to circRNA expression. However, the contribution of epigenetic changes to circRNA expression has not been investigated systematically. Here, we built a machine learning framework named CIRCScan, to predict circRNA expression in various cell lines based on the sequence and epigenetic features. RESULTS: The predicted accuracy of the expression status models was high with area under the curve of receiver operating characteristic (ROC) values of 0.89-0.92 and the false-positive rates of 0.17-0.25. Predicted expressed circRNAs were further validated by RNA-seq data. The performance of expression-level prediction models was also good with normalized root-mean-square errors of 0.28-0.30 and Pearson's correlation coefficient r over 0.4 in all cell lines, along with Spearman's correlation coefficient ρ of 0.33-0.46. Noteworthy, H3K79me2 was highly ranked in modeling both circRNA expression status and levels across different cells. Further analysis in additional nine cell lines demonstrated a significant enrichment of H3K79me2 in circRNA flanking intron regions, supporting the potential involvement of H3K79me2 in circRNA expression regulation. AVAILABILITY AND IMPLEMENTATION: The CIRCScan assembler is freely available online for academic use at https://github.com/johnlcd/CIRCScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Development and preliminary testing of a probe-based duplex real-time PCR assay for the detection of African swine fever virus.

An outbreak of African swine fever (ASF) in China in 2018 caused substantial economic losses to the swine industry. To accurately diagnose clinical infection with ASF virus (ASFV), we developed a TaqMan probe-based duplex real-time PCR that simultaneously detected two discontinuous genes in the virus genome, thereby preventing the inaccurate results obtained with only one reaction. Two sets of ASFV gene-specific primers, along with two fluorescent TaqMan probes were designed to target conserved regions of the B646L and B438L genes. This method had high sensitivity and specificity, with a limit of detection of 10 copies/µL, and it did not cross-react with the genomes of other viral pathogens that affect pigs (i.e., CSFV, PRRSV, PEDV, PRV, PPV and PCV2). Overall, 180 clinical samples from ASFV-infected pig farms were used to compare this method with a commercial kit, which yielded excellent consistency (98.3%). This new diagnostic method should greatly improve the efficiency of ASFV surveillance and reduce economic losses, providing benefits for both animal and public health.

Change of soluble acid invertase gene (SAI-1) haplotype in hybrid sorghum breeding program in China.

Sugar metabolism is the most important and core one which drives plant growth and development. Invertases are key enzymes that regulate sugar metabolism. A still-growing number of studies have revealed that invertases play a crucial role in various aspects of plant growth and development. Crop yield is the product of sugar metabolism; it could be deduced that invertase also regulated the yield formation. So we have done a series of research on soluble acid invertase in sweet sorghum from enzyme activity to gene cloning and functional marker development. In this paper, we sequenced full length of SAI-1 gene in 69 grain sorghum parent lines, trying to see how it differs in their gene sequences and their distribution in related hybrid varieties released in the past. To our surprise, the result showed that B-lines and restore lines (R-line) have almost different SAI-1 haplotype distribution. The change of haplotype of SAI-1 gene is associated with yield gain as with grain sorghum breeding progress, which proved that SAI-1 may take a very important role in yield formation. And we also found the SAI-1 gene tends to become shorter as with the breeding advance, which means short sequence in introns, while exon remains unchanged leading to higher gene efficiency. The best SAI-1 haplotype combination of sorghum hybrid was also found for different planting regions. These findings are of great significance for improving breeding efficiency, understanding heterosis, and germplasm enhancement. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01231-2.

Outcome Comparison between Endoscopic Transoral and Bilateral Axillo-Breast Approach Thyroidectomy Performed by a Single Surgeon.

BACKGROUND: The transoral approach and the bilateral axillo-breast approach (BABA) are remote access approaches for endoscopic thyroidectomy. Both follow a symmetric design and use CO2 insufflation to maintain the working space. The outcome differences between the techniques are rarely compared in the literature. METHODS: All patients who underwent endoscopic transoral (n = 72) and BABA (n = 63) thyroidectomy between October 2018 and August 2020 by a single surgeon were retrospectively reviewed. The following peri-operative data were collected and compared: operative time, blood loss, postoperative drainage amount, hospital stay, pain score, number of retrieved lymph nodes, and complications. RESULTS: Patients in the transoral group were younger (44.7 vs. 49.3 years, p = 0.022) and had smaller tumors (2.4 vs. 2.8 cm, p = 0.020) than those in the BABA group. The operative times were significantly longer in the transoral group than in the BABA group (lobectomy, 194.1 vs. 177.0 min, p = 0.026; total thyroidectomy, 246.0 vs. 214.3 min, p = 0.042). Nevertheless, the time difference became insignificant after completing the initial 20 cases of transoral thyroidectomy. The drainage fluid collected after the surgery was serosanguinous, and a lower drainage volume was observed in the transoral group than that in the BABA group (64.9 vs. 78.5 ml, p = 0.017). However, there was no significant difference regarding the blood loss, hospital stay, postoperative pain score, and lymph nodes retrieved. The rate of postoperative complications, such as hypoparathyroidism and vocal cord palsy was comparable between the two groups. CONCLUSIONS: Transoral approach and BABA are comparable with regard to surgical outcomes. Selected patients may choose either technique based on their preferences.

Vocal cord granuloma after transoral thyroidectomy using oral endotracheal intubation: two case reports.

BACKGROUND: Transoral thyroidectomy can be performed using nasal or oral intubation. Recently, we encountered two cases of vocal cord granuloma that were suspected to result from intraoperative compression by the oral endotracheal tube. CASES PRESENTATION: Two women underwent transoral endoscopic thyroidectomy with oral endotracheal tubes fixed at the mouth angle. Their initial postoperative recovery was uneventful, but they developed hoarseness 2 months after the surgery. Subsequent strobolaryngoscopy revealed vocal cord granulomas at the side of contact of the endotracheal tube. One patient received medication and voice therapy, and her granuloma shrank significantly one month later. The other patient underwent granuloma resection. Thereafter, the symptoms improved in both the patients. CONCLUSIONS: Oral intubation with tube placement at the mouth angle might result in the formation of vocal cord granulomas. Therefore, we suggest positioning the tube at the midline to avoid excessive irritation on one side of the vocal cord.

Fluorescent pattern recognition of metal ions by nanoparticles of bovine serum albumin as a chemical nose/tongue.

A sensor array mimicking a chemical nose/tongue based on bovine serum albumin nanoparticles (BSANsn) has been developed for the fluorescence pattern recognition of metal ions in biofluids. Three types of BSANsn (BSANs10, BSANs20, and BSANs40) show the same excitation/emission peak at 478/526 nm. According to the differential fluorescence variation, the sensor array shows particular fluorescence response patterns depending upon metal ions. Upon principal component analysis (PCA), it was found that the sensor array can distinguish 18 metal ions clearly at a concentration of as low as 10 µM. Moreover, different concentrations of metal ions and mixed metal ions of diverse kinds or valence states can be differentiated by the sensor in biofluids. In addition, the results were well consistent with those obtained with the traditional ICP-AES method.

Crystal Structures of the C-Terminally Truncated Endoglucanase Cel9Q from Clostridium thermocellum Complexed with Cellodextrins and Tris.

Endoglucanase CtCel9Q is one of the enzyme components of the cellulosome, which is an active cellulase system in the thermophile Clostridium thermocellum. The precursor form of CtCel9Q comprises a signal peptide, a glycoside hydrolase family 9 catalytic domain, a type 3c carbohydrate-binding module (CBM), and a type I dockerin domain. Here, we report the crystal structures of C-terminally truncated CtCel9Q (CtCel9QΔc) complexed with Tris, Tris+cellobiose, cellobiose+cellotriose, cellotriose, and cellotetraose at resolutions of 1.50, 1.70, 2.05, 2.05 and 1.75 Å, respectively. CtCel9QΔc forms a V-shaped homodimer through residues Lys529-Glu542 on the type 3c CBM, which pairs two ß-strands (ß4 and ß5 of the CBM). In addition, a disulfide bond was formed between the two Cys535 residues of the protein monomers in the asymmetric unit. The structures allow the identification of four minus (-) subsites and two plus (+) subsites; this is important for further understanding the structural basis of cellulose binding and hydrolysis. In the oligosaccharide-free and cellobiose-bound CtCel9QΔc structures, a Tris molecule was found to be bound to three catalytic residues of CtCel9Q and occupied subsite -1 of the CtCel9Q active-site cleft. Moreover, the enzyme activity assay in the presence of 100 mm Tris showed that the Tris almost completely suppressed CtCel9Q hydrolase activity.

Quantum Hall Effect in Electron-Doped Black Phosphorus Field-Effect Transistors.

The advent of black phosphorus field-effect transistors (FETs) has brought new possibilities in the study of two-dimensional (2D) electron systems. In a black phosphorus FET, the gate induces highly anisotropic 2D electron and hole gases. Although the 2D hole gas in black phosphorus has reached high carrier mobilities that led to the observation of the integer quantum Hall effect, the improvement in the sample quality of the 2D electron gas (2DEG) has however been only moderate; quantum Hall effect remained elusive. Here, we obtain high quality black phosphorus 2DEG by defining the 2DEG region with a prepatterned graphite local gate. The graphite local gate screens the impurity potential in the 2DEG. More importantly, it electrostatically defines the edge of the 2DEG, which facilitates the formation of well-defined edge channels in the quantum Hall regime. The improvements enable us to observe precisely quantized Hall plateaus in electron-doped black phosphorus FET. Magneto-transport measurements under high magnetic fields further revealed a large effective mass and an enhanced Landé g-factor, which points to strong electron-electron interaction in black phosphorus 2DEG. Such strong interaction may lead to exotic many-body quantum states in the fractional quantum Hall regime.