Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion.

Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.

Free-space dissemination of time and frequency with 10-19 instability over 113 km.

Networks of optical clocks find applications in precise navigation1,2, in efforts to redefine the fundamental unit of the 'second'3-6 and in gravitational tests7. As the frequency instability for state-of-the-art optical clocks has reached the 10-19 level8,9, the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10-19. However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres10,11. Here we report time-frequency dissemination with an offset of 6.3 × 10-20 ± 3.4 × 10-19 and an instability of less than 4 × 10-19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time-frequency dissemination.

MRSL: a causal network pruning algorithm based on GWAS summary data.

Causal discovery is a powerful tool to disclose underlying structures by analyzing purely observational data. Genetic variants can provide useful complementary information for structure learning. Recently, Mendelian randomization (MR) studies have provided abundant marginal causal relationships of traits. Here, we propose a causal network pruning algorithm MRSL (MR-based structure learning algorithm) based on these marginal causal relationships. MRSL combines the graph theory with multivariable MR to learn the conditional causal structure using only genome-wide association analyses (GWAS) summary statistics. Specifically, MRSL utilizes topological sorting to improve the precision of structure learning. It proposes MR-separation instead of d-separation and three candidates of sufficient separating set for MR-separation. The results of simulations revealed that MRSL had up to 2-fold higher F1 score and 100 times faster computing time than other eight competitive methods. Furthermore, we applied MRSL to 26 biomarkers and 44 International Classification of Diseases 10 (ICD10)-defined diseases using GWAS summary data from UK Biobank. The results cover most of the expected causal links that have biological interpretations and several new links supported by clinical case reports or previous observational literatures.

Pathways of N2O production by marine ammonia-oxidizing archaea determined from dual-isotope labeling.

The ocean is a net source of the greenhouse gas and ozone-depleting substance, nitrous oxide (N2O), to the atmosphere. Most of that N2O is produced as a trace side product during ammonia oxidation, primarily by ammonia-oxidizing archaea (AOA), which numerically dominate the ammonia-oxidizing community in most marine environments. The pathways to N2O production and their kinetics, however, are not completely understood. Here, we use 15N and 18O isotopes to determine the kinetics of N2O production and trace the source of nitrogen (N) and oxygen (O) atoms in N2O produced by a model marine AOA species, Nitrosopumilus maritimus. We find that during ammonia oxidation, the apparent half saturation constants of nitrite and N2O production are comparable, suggesting that both processes are enzymatically controlled and tightly coupled at low ammonia concentrations. The constituent atoms in N2O are derived from ammonia, nitrite, O2, and H2O via multiple pathways. Ammonia is the primary source of N atoms in N2O, but its contribution varies with ammonia to nitrite ratio. The ratio of 45N2O to 46N2O (i.e., single or double labeled N) varies with substrate ratio, leading to widely varying isotopic signatures in the N2O pool. O2 is the primary source for O atoms. In addition to the previously demonstrated hybrid formation pathway, we found a substantial contribution by hydroxylamine oxidation, while nitrite reduction is an insignificant source of N2O. Our study highlights the power of dual 15N-18O isotope labeling to disentangle N2O production pathways in microbes, with implications for interpretation of pathways and regulation of marine N2O sources.

SQSTM1 downregulates avian metapneumovirus subgroup C replication via mediating selective autophagic degradation of viral M2-2 protein.

Avian metapneumovirus subgroup C (aMPV/C), an important pathogen causing acute respiratory infection in chickens and turkeys, contributes to substantial economic losses in the poultry industry worldwide. aMPV/C has been reported to induce autophagy, which is beneficial to virus replication. Sequestosome 1 (SQSTM1/P62), a selective autophagic receptor, plays a crucial role in viral replication by clearing ubiquitinated proteins. However, the relationship between SQSTM1-mediated selective autophagy and aMPV/C replication is unclear. In this study, we found that the expression of SQSTM1 negatively regulates aMPV/C replication by reducing viral protein expression and viral titers. Further studies revealed that the interaction between SQSTM1 and aMPV/C M2-2 protein is mediated via the Phox and Bem1 (PB1) domain of the former, which recognizes a ubiquitinated lysine at position 67 of the M2-2 protein, and finally degrades M2-2 via SQSTM1-mediated selective autophagy. Collectively, our results reveal that SQSTM1 degrades M2-2 via a process of selective autophagy to suppress aMPV/C replication, thereby providing novel insights for the prevention and control of aMPV/C infection.IMPORTANCEThe selective autophagy plays an important role in virus replication. As an emerging pathogen of avian respiratory virus, clarification of the effect of SQSTM1, a selective autophagic receptor, on aMPV/C replication in host cells enables us to better understand the viral pathogenesis. Previous study showed that aMPV/C infection reduced the SQSTM1 expression accompanied by virus proliferation, but the specific regulatory mechanism between them was still unclear. In this study, we demonstrated for the first time that SQSTM1 recognizes the 67th amino acid of M2-2 protein by the interaction between them, followed by M2-2 degradation via the SQSTM1-mediated selective autophagy, and finally inhibits aMPV/C replication. This information supplies the mechanism by which SQSTM1 negatively regulates viral replication, and provides new insights for preventing and controlling aMPV/C infection.

Impact of nonrandom selection mechanisms on the causal effect estimation for two-sample Mendelian randomization methods.

Nonrandom selection in one-sample Mendelian Randomization (MR) results in biased estimates and inflated type I error rates only when the selection effects are sufficiently large. In two-sample MR, the different selection mechanisms in two samples may more seriously affect the causal effect estimation. Firstly, we propose sufficient conditions for causal effect invariance under different selection mechanisms using two-sample MR methods. In the simulation study, we consider 49 possible selection mechanisms in two-sample MR, which depend on genetic variants (G), exposures (X), outcomes (Y) and their combination. We further compare eight pleiotropy-robust methods under different selection mechanisms. Results of simulation reveal that nonrandom selection in sample II has a larger influence on biases and type I error rates than those in sample I. Furthermore, selections depending on X+Y, G+Y, or G+X+Y in sample II lead to larger biases than other selection mechanisms. Notably, when selection depends on Y, bias of causal estimation for non-zero causal effect is larger than that for null causal effect. Especially, the mode based estimate has the largest standard errors among the eight methods. In the absence of pleiotropy, selections depending on Y or G in sample II show nearly unbiased causal effect estimations when the casual effect is null. In the scenarios of balanced pleiotropy, all eight MR methods, especially MR-Egger, demonstrate large biases because the nonrandom selections result in the violation of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. When directional pleiotropy exists, nonrandom selections have a severe impact on the eight MR methods. Application demonstrates that the nonrandom selection in sample II (coronary heart disease patients) can magnify the causal effect estimation of obesity on HbA1c levels. In conclusion, nonrandom selection in two-sample MR exacerbates the bias of causal effect estimation for pleiotropy-robust MR methods.

Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.

BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

SGCE promotes breast cancer stemness by promoting the transcription of FGF-BP1 by Sp1.

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.

Nitrogen application in pod zone improves yield and quality of two peanut cultivars by modulating nitrogen accumulation and metabolism.

Cultivated peanut (Arachis hypogaea L.) represents one of the most important oil and cash crops world-widely. Unlike many other legumes, peanuts absorb nitrogen through their underground pods. Despite this unique feature, the relationship between yield and nitrogen uptake within the pod zone remains poorly understood. In our pot experiment, we divided the underground peanut part into two zones-pod and root-and investigated the physiological and agronomic traits of two peanut cultivars, SH11 (large seeds, LS) and HY23 (small seeds, SS), at 10 (S1), 20 (S2), and 30 (S3) days after gynophores penetrated the soil, with nitrogen application in the pod zone. Results indicated that nitrogen application increased pod yield, kernel protein content, and nitrogen accumulation in plants. For both LS and SS peanut cultivars, optimal nitrogen content was 60 kg·hm- 2, leading to maximum yield. LS cultivar exhibited higher yield and nitrogen accumulation increases than SS cultivar. Nitrogen application up-regulated the expression of nitrogen metabolism-related genes in the pod, including nitrate reductase (NR), nitrite reductase (NIR), glutamine synthetase (GS), glutamate synthase (NADH-GOGAT), ATP binding cassette (ABC), and nitrate transporter (NRT2). Additionally, nitrogen application increased enzyme activity in the pod, including NR, GS, and GOGAT, consistent with gene expression levels. These nitrogen metabolism traits exhibited higher up-regulations in the large-seeded cultivar than in the small-seeded one and showed a significant correlation with yield in the large-seeded cultivar at S2 and S3. Our findings offer a scientific basis for the judicious application and efficient utilization of nitrogen fertilization in peanuts, laying the groundwork for further elucidating the molecular mechanisms of peanut nitrogen utilization.

Hydrogen Bonding Competition Mediated Phase Separation with Abnormal Moisture-Induced Stiffness Boosting.

Moisture usually deteriorates polymers' mechanical performance owing to its plasticizing effect, causing side effects in their practical load-bearing applications. Herein, a simple binary ionogel consisting of an amphiphilic polymer network and a hydrophobic ionic liquid (IL) is developed with remarkable stiffening effect after moisture absorption, demonstrating a complete contrast to water-induced softening effect of most polymer materials. Such a moisture-induced stiffening behavior is induced by phase separation after hydration of this binary ionogel. Specifically, it is revealed that hydrogen (H)-bonding structures play a dominant role in the humidity-responsive behavior of the ionogel, where water will preferentially interact with polymer chains through H-bonding and break the polymer-IL H-bonds, thus leading to phase separation structures with modulus boosting. This work may provide a facile and effective molecular engineering route to construct mechanically adaptive polymers with water-induced dramatic stiffening for diverse applications.

Ubiquitination-dependent degradation of nucleolin mediated by porcine circovirus type 3 capsid protein.

IMPORTANCE: Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes multisystem disease in pigs and poses a severe threat to the swine industry. However, the mechanisms of how PCV3 uses host proteins to regulate its own life cycle are not well understood. In this study, we found that PCV3 capsid protein interacts with nucleolin and degrades it. Degradation of nucleolin by the PCV3 capsid protein requires recruitment of the enzyme RNF34, which is transported to the nucleolus from the cytoplasm in the presence of the PCV3 capsid protein. Nucleolin also decreases PCV3 replication by promoting the release of interferon ß. These findings clarify the mechanism by which nucleolin modulates PCV3 replication in cells, thereby facilitating to provide an important strategy for preventing and controlling PCV3 infection.

Seneca valley virus 3C protease blocks EphA2-Mediated mTOR activation to facilitate viral replication.

The Seneca Valley virus (SVV) is a recently discovered porcine pathogen that causes vesicular diseases and poses a significant threat to the pig industry worldwide. Erythropoietin-producing hepatoma receptor A2 (EphA2) is involved in the activation of the AKT/mTOR signaling pathway, which is involved in autophagy. However, the regulatory relationship between SVV and EphA2 remains unclear. In this study, we demonstrated that EphA2 is proteolysed in SVV-infected BHK-21 and PK-15 cells. Overexpression of EphA2 significantly inhibited SVV replication, as evidenced by decreased viral protein expression, viral titers, and viral load, suggesting an antiviral function of EphA2. Subsequently, viral proteins involved in the proteolysis of EphA2 were screened, and the SVV 3C protease (3Cpro) was found to be responsible for this cleavage, depending on its protease activity. However, the protease activity sites of 3Cpro did not affect the interactions between 3Cpro and EphA2. We further determined that EphA2 overexpression inhibited autophagy by activating the mTOR pathway and suppressing SVV replication. Taken together, these results indicate that SVV 3Cpro targets EphA2 for cleavage to impair its EphA2-mediated antiviral activity and emphasize the potential of the molecular interactions involved in developing antiviral strategies against SVV infection.

Temperature-dependent charge carrier behavior in phosphorene quantum dots probed by terahertz time-domain spectroscopy.

Although phosphorene quantum dots (PQDs) have gained significant attention in optoelectronics and physics due to their unique optical responses, the low-frequency electromagnetic properties of PQDs and the effects of temperature still remain largely unexplored. Herein, we investigate the temperature-dependent terahertz (THz) response of PQDs by using THz time-domain spectroscopy. Effective THz conductivity of the PQD sample is extracted based on THz measurements to analyze the charge carrier behavior. It is shown that the carriers in the PQDs can be approximated as a weakly confined Drude gas of classical and noninteracting charge particles, which are described by the modified Drude-Smith formula. Then, we also obtain the temperature dependences of the effective characteristic parameters for the charge carriers. As the temperature increases, the plasma frequency linearly enhances whereas both of the carrier diffusion time and the momentum scattering time decrease, which are akin to conventional semiconductors to a large extent. In addition, the confinement factor is closed to 1 and nearly insensitive to temperature. These results are helpful to gain an in-depth understanding of the low-frequency electromagnetic response of charge carriers in PQDs and to explore new applications in photonics and optoelectronics.

Non-Line-of-Sight Imaging and Vibrometry Using a Comb-Calibrated Coherent Sensor.

Non-line-of-sight (NLOS) imaging has the ability to reconstruct hidden objects, allowing a wide range of applications. Existing NLOS systems rely on pulsed lasers and time-resolved single-photon detectors to capture the information encoded in the time of flight of scattered photons. Despite remarkable advances, the pulsed time-of-flight LIDAR approach has limited temporal resolution and struggles to detect the frequency-associated information directly. Here, we propose and demonstrate the coherent scheme-frequency-modulated continuous wave calibrated by optical frequency comb-for high-resolution NLOS imaging, velocimetry, and vibrometry. Our comb-calibrated coherent sensor presents a system temporal resolution at subpicosecond and its superior signal-to-noise ratio permits NLOS imaging of complex scenes under strong ambient light. We show the capability of NLOS localization and 3D imaging at submillimeter scale and demonstrate NLOS vibrometry sensing at an accuracy of dozen Hertz. Our approach unlocks the coherent LIDAR techniques for widespread use in imaging science and optical sensing.

High-density bin-based genetic map reveals a 530-kb chromosome segment derived from wild peanut contributing to late leaf spot resistance.

KEY MESSAGE: Twenty-eight QTLs for LLS disease resistance were identified using an amphidiploid constructed mapping population, a favorable 530-kb chromosome segment derived from wild species contributes to the LLS resistance. Late leaf spot (LLS) is one of the major foliar diseases of peanut, causing serious yield loss and affecting the quality of kernel and forage. Some wild Arachis species possess higher resistance to LLS as compared with cultivated peanut; however, ploidy level differences restrict utilization of wild species. In this study, a synthetic amphidiploid (Ipadur) of wild peanuts with high LLS resistance was used to cross with Tifrunner to construct TI population. In total, 200 recombinant inbred lines were collected for whole-genome resequencing. A high-density bin-based genetic linkage map was constructed, which includes 4,809 bin markers with an average inter-bin distance of 0.43 cM. The recombination across cultivated and wild species was unevenly distributed, providing a novel recombination landscape for cultivated-wild Arachis species. Using phenotyping data collected across three environments, 28 QTLs for LLS disease resistance were identified, explaining 4.35-20.42% of phenotypic variation. The major QTL located on chromosome 14, qLLS14.1, could be consistently detected in 2021 Jiyang and 2022 Henan with 20.42% and 12.12% PVE, respectively. A favorable 530-kb chromosome segment derived from Ipadur was identified in the region of qLLS14.1, in which 23 disease resistance proteins were located and six of them showed significant sequence variations between Tifrunner and Ipadur. Allelic variation analysis indicating the 530-kb segment of wild species might contribute to the disease resistance of LLS. These associate genomic regions and candidate resistance genes are of great significance for peanut breeding programs for bringing durable resistance through pyramiding such multiple LLS resistance loci into peanut cultivars.

Trastuzumab deruxtecan (DS8201) for advanced non-small cell lung cancer with HER2 exon 20 insertion mutation: a case report.

An antibody-drug conjugate (ADC) of human epidermal growth factor receptor-2 (HER2) provides effective treatment for patients with HER2-positive non-small cell lung cancer (NSCLC). Exon 20 insertion mutations are the most common among HER2 mutations. This mutant subtype is highly drug-resistant, and patients receiving conventional treatment often have a poor prognosis. Trastuzumab deruxtecan (T-DXd), a novel anti-HER2 ADC, has emerged as a novel treatment option for HER2-positive (mutated, expressed, amplified, alternated) NSCLC, based on several studies and reported results. Herein, we report a case of stage IV NSCLC with HER2 exon 20 mutation in a 52-year-old male patient whose tumor recurred after radical resection of pulmonary carcinoma, who could not tolerate chemotherapy, and presented with bone metastasis. After treatment with T-DXd, the tumor significantly regressed and bone metastasis improved, maintaining a state of no progression for 21 months. This case report evidences the use of T-DXd in the treatment of NSCLC with HER2 exon 20 insertion mutation.

AX·(H2SeO3)n (A = K, Cs; X = Cl, Br; n = 1, 2): A Series of Ionic Cocrystals as Promising UV Birefringent Materials with Large Birefringence and Wide Band Gap.

The design and syntheses of new birefringent crystals will be of great importance in commercial applications and materials science. A series of ultraviolet (UV) birefringent crystals, AX·(H2SeO3)n (A = K, Cs; X = Cl, Br; n = 1, 2), with large sizes up to 23 × 6 × 3 mm3, was successfully synthesized by simple aqueous solution method. These four compounds belong to three different space groups. Isomorphic KCl·(H2SeO3)2 and CsCl·(H2SeO3)2 crystallize in the P1¯ space group, while CsBr·(H2SeO3)2 and CsCl·H2SeO3 crystallize in the P21/m and P21/c space groups, respectively. They exhibit cocrystal structures composed of [2(H2SeO3)]∞ and [AX]∞ frameworks, ingeniously inheriting the large optical anisotropy of selenite and the wide band gap of alkali metal halide. And it proves that these compounds indeed possess large birefringence (0.1-0.17 at 532 nm) and short UV cutoff edges (227-239 nm), achieving a balance of optical properties. This research affords a simple and viable strategy for the design and syntheses of new UV birefringent crystals. Besides, it is also found that the n value and ionic size (A and X ions) have important influences on the crystal structures and optical properties of AX·(H2SeO3)n. And this will promote further understanding of the alkali metal halide selenite family.

Design of Eu3+-Doped Fluoride Phosphor with Zero Thermal Quenching Property Based on Density Functional Theory.

Although being applied in various fields, white light emitting diodes (WLEDs) still have drawbacks that urgently need to be conquered: the luminescent intensity of commercial phosphors sharply decreases at working temperature. In this study, we calculated the forming energy of defects and confirmed that the VNa defect state can stably exist in ß-NaGdF4, by density functional theory (DFT) calculation. Furthermore, we predicted that the VNa vacancies would provide a zero thermal quenching (ZTQ) property for the ß-NaGdF4-based red-light phosphor. Then, a series of ß-NaGdF4:xEu3+ and ß-NaGdF4:0.25Eu3+,yYb3+ red-light phosphors were synthesized by the hydrothermal method. We found that ß-NaGdF4:0.25Eu3+ and ß-NaGdF4:0.25Eu3+,0.005Yb3+ phosphors possess ZTQ properties at a temperature range between 303-483 K and 303-523 K, respectively. The thermoluminescence (TL) spectra were employed to calculate the depth and density of the VNa vacancies in ß-NaGdF4:0.25Eu3+ and ß-NaGdF4:0.25Eu3+,0.005Yb3+. Combining the DFT calculation with characterization results of TL spectra, it is concluded that electrons stored in VNa vacancies are excited to the exited state of Eu3+ to compensate for the loss of Eu3+ luminescent intensity. This will lead to an increase of luminescent intensity at high temperatures and facilitate the samples to improve ZTQ properties. WLEDs were obtained with CRI = 83.0, 81.6 and CCT = 5393, 5149 K, respectively, when phosphors of ß-NaGdF4:0.25Eu3+ and ß-NaGdF4:0.25Eu3+,0.005Yb3+ were utilized as the red-light source. These results indicate that these two phosphors may become reliable red-light sources with high antithermal quenching properties for WLEDs.

Rare complication of rheumatoid arthritis: Charcot Neuro-osteoarthropathy.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease.However, there are few cases of Charcot Neuro-osteoarthropathy (CN) caused by rheumatoid diseases in clinical reports. It is not easy to pay attention to the diagnosis of CN in the complications of rheumatoid disease, which greatly increases the probability of misdiagnosis and missed diagnosis. This case reported a rare complication of rheumatoid arthritis, Charcot arthritis, and the molecular mechanism and diagnosis and treatment of CN caused by RA were systematically discussed. CASE PRESENTATION: The patient, a 79-year-old woman, was hospitalized due to bilateral shoulder pain, limited activity for half a year, aggravated for 4 months to the hospital. During this period, the symptoms did not improve after treatment with acupuncture and Chinese medicine. The patient was previously diagnosed with rheumatoid arthritis for more than 3 years and intermittent irregular use of methylprednisolone and methotrexate for 2 years. She had a history of osteoporosis. PHYSICAL EXAMINATION: symmetrical malformed swelling of the finger joints of both hands; Bilateral supraspinatus and deltoid muscle atrophy, tenderness at the acromion, and attachment of the long head tendon of the biceps brachii were observed. The left Dugas test and the right Dugas test were positive.Blood test: anti-cyclic citrullinated peptide antibody (A-CCP) 33.10U/ml (normal range: 0-5RU/ml); antinuclear antibody quantification (ANA) 47.40AU/ml (normal range: Negative or < 32); anti-double stranded DNA IgG antibody quantification (dsDNA) 31.00 IU/ml (normal range: 0-100 IU/ml); D-Dimer 6.43 µg/ml (normal range: 0-0.5 mg/L); erythrocyte sedimentation rate (ESR) was 27 mm/h (normal range: < 20 mm/60 min). C-reactive protein (CRP) 39.06 mg/L(0.068-8 mg/L).MRI 3.0 T enhancement of bilateral shoulder joints, cervical spine and thoracic spine showed: 1.Large bone destruction, cartilage injury, multiple effusion, synovitis, obvious on the right side. 2.Intervertebral disc degeneration, cervical 3/4, 4/5, 5/6, 6/7 disc herniation, with cervical 3/4 obvious, posterior central herniation; CONCLUSIONS: Rheumatoid arthritis complicated with Charcot's joint is rare. Clinically, patients with rheumatoid diseases should not ignore Charcot's joint complications because of rareness. Early blood inflammatory markers, neuro electrophysiology, and imaging MRI of rheumatoid CN are of great significance for the diagnosis of this mild or early neurovascular inflammation. Early diagnosis and treatment are helpful to prevent further joint injury. The clinical diagnosis, treatment, and molecular mechanism of osteolysis in RA and peripheral sensory nerve injury remain to be further revealed.

The Association Between Thymidylate Synthase Gene Polymorphisms and the Risk of Ischemic Stroke in Chinese Han Population.

Family history of hypertension, smoking, diabetes and alcohol consumption and atherosclerotic plaque were identified as common risk factors in IS. We aimed at investigating the relationship between Thymidylate Synthase (TS) gene polymorphisms and ischemic stroke (IS).This case-control research selected and genotyped three single nucleotide polymorphisms (SNPs)of TS( rs699517, rs2790, and rs151264360) with Sanger sequencing in Chinese Han population. We also adopted logistic regression analysis in genetic models for calculating odds ratios and 95% confidence intervals. Genotype-Tissue Expression(GTEx) database analyzed the tissue-specific expression and TS polymorphisms. The ischemic stroke patients showed higher low-density lipoprotein cholesterol and total homocysteine (tHcy). It was found that patients with the TT genotype of rs699517 and GG genotype of rs2790 had larger degrees of tHcy than those with CC + CT genotypes and AA + AG genotypes, respectively. The genotype distribution of the three SNPs did not deviate from Hardy-Weinberg equilibrium (HWE). Haplotype analysis showed that T-G-del was the major haplotype in IS, and C-A-ins was the major haplotype in controls. GTEx database indicated that the rs699517 and rs2790 increased the expression of TS in healthy human and associated with TS expression level in a single tissue. In conclusion: This study has shown that TS rs699517 and rs2790 were significantly related to ischemic stroke patients.