ABSTRACT
Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque (PP), generalized pustular (GPP), and erythrodermic (EP) psoriasis who have had an inadequate response to conventional systemic therapies. This approval is based on results from the global phase 3 POETYK PSO-1 and PSO-2 trials in which deucravacitinib was associated with significantly improved efficacy outcomes compared with placebo in adults with moderate to severe plaque psoriasis, and results described here from POETYK PSO-4, an open-label, single-arm, phase 3 trial (NCT03924427), which evaluated the efficacy and safety of deucravacitinib 6 mg once daily in adult Japanese patients with PP, GPP, or EP. The coprimary endpoints were the proportion of patients achieving a ≥75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with at least a two-point improvement from baseline at week 16. Nonresponder imputation was used for missing data. Efficacy responses, adverse events (AEs), and serious AEs (SAEs) were recorded for up to 52 weeks. Seventy-four patients were treated (PP, n = 63; GPP, n = 3; EP, n = 8). At week 16, 76.2%, 66.7%, and 37.5% of patients with PP, GPP, and EP, respectively, had achieved PASI 75, and 82.5%, 0.0%, and 50.0% had achieved sPGA 0/1. Responses were overall maintained through week 52. AEs occurred in 74.6% of patients with PP, 100% of patients with GPP, and 87.5% of patients with EP. The most common AEs were nasopharyngitis and acne. Rates of SAEs and discontinuations were low. There were no deaths. Deucravacitinib was effective and well tolerated in Japanese patients with moderate to severe PP and in a limited number of patients with GPP or EP.
Subject(s)
Exanthema , Heterocyclic Compounds , Psoriasis , Skin Diseases, Vesiculobullous , Adult , Humans , Japan , TYK2 Kinase/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Treatment Outcome , Severity of Illness Index , Psoriasis/drug therapy , Psoriasis/chemically induced , Chronic Disease , Acute Disease , Exanthema/drug therapy , Skin Diseases, Vesiculobullous/drug therapy , Double-Blind MethodABSTRACT
Antibiotics and heavy metals added to livestock and poultry feed are excreted in manure, which is added to agricultural soil and causes severe pollution. However, the effects of oxytetracycline (OTC) and zinc (Zn), which are present at relatively high levels in feed additives, on antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), and microbial communities have not been comprehensively studied. This study evaluated the effects of OTC and Zn on environmental factors, microorganisms, MGEs, and ARGs. The expression of MGEs in soil was stimulated by adding Zn at concentrations of 500 and 1000 mg/kg or OTC at concentrations of 30 and 100 mg/kg; however, the addition of their combination hindered the expression of MGEs in soil. The abundance of total MGEs and ARGs tended to decrease with increasing concentrations of Zn and OTC and the number of incubation days. Low and high OTC concentrations strongly inhibited sul and tet resistance genes, respectively. Network analysis showed that changes in the population of Firmicutes and Proteobacteria had the greatest impact on ARG abundance. Redundancy analysis revealed that MGEs, particularly intI2, facilitated the transfer and spread of ARGs and had the greatest impact on changes in ARG abundance. These findings provide reference values for the prevention and resolution of ecological and environmental risks posed by the presence of Zn and OTC in organic manure soil.
Subject(s)
Microbiota , Oxytetracycline , Anti-Bacterial Agents/toxicity , Anti-Bacterial Agents/analysis , Oxytetracycline/toxicity , Zinc/toxicity , Zinc/analysis , Soil , Manure/microbiology , Genes, Bacterial , Drug Resistance, Microbial/genetics , Interspersed Repetitive Sequences , Soil MicrobiologyABSTRACT
A novel multi-color emitting Na2 YMg2 V3 O12 :Sm3+ phosphor was synthesized using a solid-state reaction, and its crystal structure, luminescence properties, and thermal stability were studied. Charge transfer within the (VO4 )3- groups in the Na2 YMg2 V3 O12 host led to a broad emission band between 400 and 700 nm, with a maximum at 530 nm. The Na2 Y1-x Mg2 V3 O12 :xSm3+ phosphors exhibited a multi-color emission band under 365 nm near-ultraviolet (near-UV) light, consisting of the green emission of the (VO4 )3- groups and sharp emission peaks at 570 nm (yellow), 618 nm (orange), 657 nm (red), and 714 nm (deep red) of Sm3+ ions. The optimal doping concentration of Sm3+ ions was found to be 0.05 mol%, and the dipole-dipole (d-d) interaction was primarily responsible for the concentration quenching phenomenon. Using the acquired Na2 YMg2 V3 O12 :Sm3+ phosphors, commercial BaMgAl10 O17 :Eu2+ blue phosphor, and a near-UV light-emitting diode (LED) chip, a white-LED lamp was designed and packaged. It produced bright neutral white light, manifesting a CIE coordinate of (0.314, 0.373), a color rendering index (CRI) of 84.9, and a correlated color temperature (CCT) of 6377 K. These findings indicate the potential of Na2 YMg2 V3 O12 :Sm3+ phosphor to be used as a multi-color component for solid-state illumination.
Subject(s)
Lighting , Luminescence , Sodium , Ultraviolet Rays , TemperatureABSTRACT
TRIM33 is a chromatin reader required for mammalian mesendoderm differentiation after activation of Nodal signaling, while its role in mESCs is still elusive. Here, we report that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mESCs, to mediate Nodal signaling-directed transcription of Lefty1/2. We show that TRIM33 puncta formation in mESCs depends on PML and on specific assembly of PML-NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs, with both PML protein and formation of mESCs-specific PML-NBs being required for TRIM33 recruitment to these loci, and PML-NBs directly associating with the Lefty1/2 loci. Finally, a TurboID proximity-labeling experiment confirmed that TRIM33 is highly enriched only in mESCs-specific PML-NBs. Thus, our study supports a model in which TRIM33 condensates regulate Nodal signaling-directed transcription in mESCs and shows that PML-NBs can recruit distinct sets of client proteins in a cell-context-dependent manner.
Subject(s)
Mouse Embryonic Stem Cells , Promyelocytic Leukemia Nuclear Bodies , Animals , Humans , Promyelocytic Leukemia Protein/genetics , Promyelocytic Leukemia Protein/metabolism , Mouse Embryonic Stem Cells/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Signal Transduction , Cell Nucleus/metabolism , Mammals , Transcription Factors/geneticsABSTRACT
Background: An in-silico screen identified mebendazole with potential antiviral activity that could be a repurposed drug against SARS-CoV-2. Mebendazole is a well-tolerated and cheap antihelminthic agent that is readily available worldwide and thus could be a therapeutic tool in the fight against COVID-19. Methods: This is an observational retrospective study of PCR-confirmed COVID-19 patients who received mebendazole with the intention-to-treat. The study included an inpatient cohort (157 inpatients) and an outpatient cohort (185 outpatients). Of the 157 inpatients and 185 outpatients, 68 (43.3%) and 94 (50.8%) received mebendazole, respectively. Patients who presented within the same timeframe but did not receive mebendazole were used as controls. Patients received standard-of-care treatment including remdesivir, dexamethasone, and anticoagulants as deemed necessary by the treating physician. The following clinical outcomes were evaluated: for the inpatient cohort, length of stay (LOS) at the hospital, need for ventilation (combined invasive and noninvasive), and mortality; for the outpatient cohort, time to symptom resolution, need for hospitalization, and mortality. Results: For the inpatient cohort, the median age did not differ between the treatment and control groups; 62 (56, 67) vs. 62 (56, 68), P, and there was a comparable proportion of males in both groups; 43 (63%) vs. 55 (62%), P=0.85. The hospital LOS was 3.5 days shorter in the treatment group compared to the control group (P < 0.001). There were fewer patients who required invasive or noninvasive ventilation in the treatment group, 2 (2.9%) vs. 7 (7.9%), and the mortality rate is lower in the treatment group, 3 (4.4%) vs. 8 (9.0%), though the differences did not reach statistical significance. For the outpatient cohort, the median age was lower in the treatment group compared with the control group; 40 (34, 48) vs. 48 (41, 54), P < 0.001. There was a comparable proportion of males between both groups; 50 (53%) vs. 52 (57%), P=0.59. Patients in the treatment group were 3.3 days closer to symptom resolution (P < 0.001). There were numerically fewer patients requiring hospitalization in the treatment group compared with the control group, 3 (3.2%) vs. 6 (6.6%), though this did not reach statistical significance (P=0.33). Conclusion: In this retrospective observational study, the use of mebendazole in COVID-19 patients was associated with shorter hospitalizations in the inpatient cohort and shorter durations of symptom resolution in the outpatient cohort. The findings from this small observational study are hypothesis-generating and preclude drawing conclusions about clinical efficacy. Further studies are needed to examine the role of mebendazole in the treatment of COVID-19 patients.
ABSTRACT
The application of livestock manure is the leading cause of antibiotic and heavy metal pollution in agricultural soil. However, the effects of oxytetracycline (OTC) and lead (Pb) pollution in the single or combined form on antibiotic resistance genes (ARGs) in the soil need to be further studied. This study was planned to investigate the effects of OTC and Pb application on ARGs, mobile genetic elements (MGEs), and bacterial abundance in the soil. The relative abundance of ARGs and MGEs increased by 0.31-fold and 0.03-fold after the addition of 80 mg kg-1 Pb to the soil, and by 0.49-fold and 0.03-fold after the addition of 160 mg kg-1 Pb. In addition, under the premise of the existence of OTC, the inhibitory effect of a low concentration of Pb on ARG is stronger than that of a high concentration of Pb, resulting in a lower abundance of ARGs. The abundance of ARGs and MGEs increased by 0.11-fold and 0.17-fold after the addition of OTC (30 mg kg-1) to the soil at a Pb concentration of 80 mg kg-1 and by 0.18-fold and 0.04-fold at a Pb concentration of 160 mg kg-1. The addition of OTC and Pb in the soil also decreased the many bacterial communities such as Bacteroidetes, Proteobacteria, Acidobacteria, and Firmicutes. Redundancy analysis (RDA) showed that organic matter content and pH were positively correlated with the abundance of ARGs and MGEs. At the same time, electrical conductivity (EC) had a negative correlation with the abundance of ARGs and MGEs in the soil. Intl1 was significantly associated with tetB, sul1, tetQ, sul2, and sul3. Network analysis illustrated that Actinobacteria, Bacteroidetes, and Proteobacteria were the main host bacteria causing changes in the abundance of ARGs and MGEs, and they were also predominant phylum in the culture environment. This conclusion can provide a reference for the related research of ARGs in soil.
Subject(s)
Microbiota , Oxytetracycline , Oxytetracycline/pharmacology , Soil/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/analysis , Genes, Bacterial , Lead/analysis , Drug Resistance, Microbial/genetics , Manure/microbiology , Bacteria/genetics , Soil Microbiology , Interspersed Repetitive SequencesABSTRACT
The practical application of nanoscale zero-valent iron (NZVI) is restricted by its easy oxidation and aggregation. Here, sludge biochar (SB) was used as a carrier to stabilize NZVI for Cd2+ and Cu2+ removal. SB supported NZVI (SB-NZVI) was synthesized using the carbothermic method. The superior preparation conditions, structural characteristics, and performance and mechanisms of the SB-NZVI composites for the removal of Cd2+ and Cu2+ were investigated via batch experiments and characterization analysis. The optimal removal capacities of 55.94 mg/g for Cd2+ and 97.68 mg/g for Cu2+ were achieved at a Fe/sludge mass ratio of 1:4 and pyrolysis temperature of 900 °C. Batch experiments showed that the SB-NZVI (1:4-900) composite had an excellent elimination capacity over a broad pH range, and that weakly acidic to neutral solutions were optimal for removal. The XPS results indicated that the Cd2+ removal was mainly dependent on the adsorption and precipitation/coprecipitation, while reduction and adsorption were the mechanisms that play a decisive role in Cu2+ removal. The presence of Cd2+ had an opposite effect on the Cu2+ removal. Moreover, the SB-NZVI composites made of municipal sludge greatly reduces the leaching toxicity and bio-availability of heavy metals in the municipal sludge, which can be identified as an environmentally-friendly material.
Subject(s)
Iron , Water Pollutants, Chemical , Iron/chemistry , Cadmium , Sewage , Water Pollutants, Chemical/analysis , AdsorptionABSTRACT
Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.
Subject(s)
Lipodystrophy , Progeria , Humans , Young Adult , Adult , Progeria/genetics , Proteomics , Lipodystrophy/genetics , Homozygote , Exome , Mutation , Membrane Proteins/genetics , Mitochondrial Proteins/geneticsABSTRACT
The most lethal subtype of diffuse intrinsic pontine glioma (DIPG) is H3K27M. Although ACVR1 mutations have been implicated in the pathogenesis of this currently incurable disease, the impacts of bone morphogenetic protein (BMP) signaling on more than 60% of H3K27M DIPG carrying ACVR1 wild-type remain unknown. Here we show that BMP ligands exert potent tumor-suppressive effects against H3.3K27M and ACVR1 WT DIPG in a SMAD-dependent manner. Specifically, clinical data revealed that many DIPG tumors have exploited the capacity of CHRDL1 to hijack BMP ligands. We discovered that activation of BMP signaling promotes the exit of DIPG tumor cells from 'prolonged stem-cell-like' state to differentiation by epigenetically regulating CXXC5, which acts as a tumor suppressor and positive regulator of BMP signaling. Beyond showing how BMP signaling impacts DIPG, our study also identified the potent antitumor efficacy of Dacinostat for DIPG. Thus, our study delineates context-dependent features of the BMP signaling pathway in a DIPG subtype.
Subject(s)
Astrocytoma , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Astrocytoma/genetics , Bone Morphogenetic Proteins/genetics , Brain Stem Neoplasms/genetics , Cell Line, Tumor , DNA-Binding Proteins/genetics , Diffuse Intrinsic Pontine Glioma/genetics , Epigenesis, Genetic , Humans , Ligands , Signal Transduction/genetics , Transcription Factors/geneticsABSTRACT
With an increase in municipal solid waste incineration (MSWI) fly ash and its dangerous characteristics, the manner of its disposal has caused widespread concerns. In this study, ceramsite was prepared by using MSWI fly ash, civil sludge, and contaminated soil as the main raw materials; then, a certain proportion of clay was added as an additive. The optimum MSWI fly ash content and sintering conditions were investigated, and the immobilization mechanisms of heavy metals were explored. Based on the obtained results, the optimum preparation conditions were a preheating temperature of 400 °C, a preheating time of 10 min, a sintering temperature of 1150 °C, and a sintering time of 20 min. Moreover, the optimal raw material ratio of MSWI fly ash, civil sludge, contaminated soil, and flint clay was 30%:40%:15%:15%. Under these optimum preparation conditions, the obtained ceramsite showed the following excellent performance parameters: a 1-h water absorption of 0.97%, bulk density of 998.7 kg/m3, and cylindrical compressive strength of 37.84 MPa. Furthermore, the leaching of heavy metals was far less than the standard GB5085.3-2007. The immobilization of heavy metals in the ceramsite was mainly caused by the glass phase encapsulation and the formation of new crystal phase with the heavy metals. In addition, the generation of aluminosilicates played a positive role in the immobilization of heavy metals. Thus, the reuse of MSWI fly ash by preparing fly ash-based ceramsite is one of the effective methods for reducing solid wastes.
Subject(s)
Metals, Heavy , Refuse Disposal , Carbon/chemistry , Coal Ash/chemistry , Complex Mixtures , Incineration , Metals, Heavy/analysis , Particulate Matter , Refuse Disposal/methods , Solid Waste/analysisABSTRACT
Sewage treatment plants are known as repositories of antibiotic resistance genes (ARGs). Adding biochar and inoculating with exogenous microbial agents are common ways to improve the quality of compost. However, little is known about the effects of these exogenous additives on the fate of ARGs during composting and the related mechanisms. In this study, municipal sludge was taken as the research object to study the ARG-removal effects of four composting methods: ordinary compost (CT), compost with hyperthermophiles (HT), compost with hyperthermophiles and 2.0% biochar (HT2C) and compost with hyperthermophiles and 5.0% biochar (HT5C). Real-time quantitative PCR (qPCR) and 16S rRNA high-throughput sequencing were conducted to analyze the ARGs, MGEs and bacterial community. After composting, the abundance of ARGs in CT was reduced by 72.7%, while HT, HT2C and HT5C were reduced by 80.7%, 84.3% and 84.8%, respectively. Treatments with different proportions of biochar added (HT2C, HT5C) had no significant effect on the abundance of ARGs. Network analysis showed that Firmicutes and Nitrospirae were positively associated with most ARGs and may be potential hosts for them. In addition, redundancy analysis further showed that the class 1 integrase gene (intI1), pH and organic carbon had a greater effect on ARGs. Our findings suggested that the combination of hyperthermophiles and biochar during the composting process was an effective way to control ARGs and mobile genetic elements (MGEs), thus inhibiting the spread and diffusion of ARGs in the environment and improving the efficiency of treating human and animal diseases.
ABSTRACT
BACKGROUND: In clinical setting, current standard-of-care does not include genetic testing for patients with low (<50 mg/dL) and extremely low (<20 mg/dL) levels of serum low-density lipoprotein-cholesterol (LDL-C). OBJECTIVE: We aimed identify the underlying molecular cause - both monogenic and polygenic - of low and extremely low LDL-C levels in a cohort of patients presenting to specialty lipid clinics. METHODS: Whole exome sequencing was done in patients with low or extremely low LDL-C not due to any secondary causes. RESULTS: Nine patients (4 women), ranging in age from 25 to 63 years old, with low or extremely low LDL-C levels were evaluated. Median LDL-C was 16 mg/dL (range undetectable - 43), total cholesterol 82 mg/dL (42 - 101), triglycerides 35 mg/dL (19-239), and high-density lipoprotein-cholesterol 45 mg/dL (24-81). Of nine patients, two carried known pathogenic variants in APOB (one stop-gain, one deletion; LDL-C range undetectable -10 mg/dL); three patients had novel APOB heterozygous mutations (two frameshift deletions and one splice site; LDL-C range undectable-13 mg/dL); two had heterozygous APOB frameshift deletions previously reported as variants of unknown significance (LDL-C 18 mg/dL in both patients); one (LDL-C 43 mg/dL) had two heterozygous mutations in PCSK9, both previously reported to be benign; and one patient (LDL-C 16 mg/dL) had the APO E2/E2 genotype along with several variants of unknown significance in genes associated with triglycerides. No patients had an LDL-C polygenic risk score below the 5th percentile (range 26th percentile to 93rd percentile). CONCLUSION: We found APOB mutations to be the most common molecular defect in patients presenting to lipid clinics with low or extremely low LDL-C . Whether clinical genetic testing and LDL-C polygenic risk scores have any utility - other than diagnostic purposes - for such patients remains unclear. In addition, further efforts may be needed to better reclassify pathogenicity of variants of unknown significance.
Subject(s)
Apolipoprotein B-100/genetics , Cholesterol, LDL/blood , Cholesterol, LDL/genetics , Dyslipidemias/blood , Dyslipidemias/genetics , Multifactorial Inheritance , Mutation , Referral and Consultation , Adult , Cohort Studies , Female , Genetic Testing , Heterozygote , Humans , Male , Middle Aged , Exome SequencingABSTRACT
Medulloblastoma is a common pediatric malignant brain tumor. There were four consensus molecular subgroups (WNT, SHH, Group3 and Group4). Group 3 and Group 4 tumors exhibited a great degree of transcriptional overlap, and were neither derived from exact pathway aberration. We investigated transcriptional and chromatin accessibility of medulloblastoma by multi-omics single-cell analysis. Our work identified inter- and intra-tumoral heterogeneity within the Group 3, Group 4 and Group 3/4 intermediate subgroups. Unsupervised cluster of each tumor identified 9 cell clusters with transcriptional profiles and 6 cell clusters with chromatin accessibility profiles. OTX2 had the highest activity and expression level across the clusters in a special cluster based on open chromatin single-cell profilings. We identified multiple genes as a significant targeted gene within the OTX2 target genes, which made sense in prognosis. We analyzed the copy-number-variations which presented with expected subgroup distribution from transcriptional and chromatin accessibility profiles. Collectively, these data provide novel insights into Group 3 and Group 4 medulloblastoma and provide a potential therapeutic target.
Subject(s)
Brain Neoplasms/genetics , Medulloblastoma/genetics , Brain Neoplasms/classification , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Child , Chromatin/genetics , DNA Copy Number Variations/genetics , Female , Gene Expression Profiling , Humans , Male , Medulloblastoma/classification , Medulloblastoma/pathology , Medulloblastoma/therapy , Molecular Targeted Therapy , Otx Transcription Factors/genetics , Prognosis , Transcription, GeneticABSTRACT
PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation. METHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. RESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding. CONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.
Subject(s)
Epilepsy , Neurodevelopmental Disorders , Osteochondrodysplasias , Child , Epilepsy/genetics , Homozygote , Humans , Neurodevelopmental Disorders/genetics , Exome SequencingABSTRACT
BACKGROUND: Autoimmune disease (AID) patients always present with increased risk of psychiatric disorders, and thyroid function or thyroid hormone may play a critical role in the development of anxiety and depression. Thus, this study aimed to assess the free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroid-stimulating hormone (TSH) levels, and their correlations with anxiety/depression in patients with AID. METHODS: Ninety-eight AID patients and 100 health controls (HCs) were recruited. Serum samples were obtained from all the participants to detect FT3, FT4, and TSH levels. Anxiety and depression were determined using the HADS assessment. RESULTS: HADS-Anxiety score, anxiety subject percentage, HADS-Depression score, and depression subject proportion were elevated in AID patients compared with HCs. FT3 and FT4 were downregulated while TSH was upregulated in AID patients compared with HCs. In AID patients, FT3 and FT4 negatively correlated with HADS-Anxiety score, and they were downregulated in patients with anxiety compared to patients without anxiety. Meanwhile, FT3 and FT4 were negatively associated while TSH level positively associated with HADS-Depression score. Besides, FT3 and FT4 reduced, but TSH level was of no difference in patients with depression compared to patients without depression. Additionally, increased FT4 independently correlated with both reduced anxiety risk and depression risk. CONCLUSIONS: FT3, FT4, and TSH are dysregulated, and FT4 has the potential to serve as an independent biomarker related to anxiety as well as depression in AID patients. These findings may provide some information on the values of thyroid hormones in facilitating the management of AID patients with anxiety/depression.
Subject(s)
Anxiety , Autoimmune Diseases , Depression , Thyroid Hormones/blood , Adult , Anxiety/complications , Anxiety/epidemiology , Autoimmune Diseases/blood , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Depression/complications , Depression/epidemiology , Female , Humans , Male , Middle Aged , Risk FactorsABSTRACT
In this study, a type of alkaline solid polyelectrolyte (ASPE) membrane was developed via the introduction of microcrystalline cellulose (MCC) and its modified product (QMCC) into the polyvinyl alcohol (PVA) matrix. In this process, green NaOH/urea-based solvent was used to achieve a good dispersion of MCC in the PVA matrix; meanwhile, the OH- groups in the NaOH/urea-based solvent provided an alkaline environment for good ion conductivity. Compared to the MCC-incorporated ASPE, further improved conductivity was achieved when the MCC was modified with quantitative quaternary ammonium salt. TGA showed that the addition of QMCC improved the water retention of the matrix, which was beneficial to the OH- conduction in the system. Compared to the control (50 mS cm-1), a maximum conductivity of 238 mS cm-1 was obtained after the incorporation of QMCC in the PVA matrix. Moreover, the tensile strength of the polymer electrolyte were also significantly increased with the addition of QMCC. Finally, this developed ASPE membrane was used in assembling a flexible Zn-air battery and showed a promising potential in the development of flexible electronic devices.
ABSTRACT
Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.
Subject(s)
Cardiomyopathies , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , Muscular Dystrophy, Duchenne , Ventricular Dysfunction, Left , Adult , Cardiomyopathies/diagnosis , Cardiomyopathies/etiology , Cardiomyopathies/physiopathology , Dystrophin/genetics , Female , Genetic Predisposition to Disease , Heart Function Tests/methods , Humans , Magnetic Resonance Imaging, Cine/methods , Male , Muscular Dystrophy, Duchenne/blood , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/physiopathology , Mutation, Missense , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Stroke Volume , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/etiology , Exome Sequencing/methodsABSTRACT
RNA is crucial for gene expression and regulation. Recent advances in understanding of RNA biochemistry, structure and molecular biology have revealed the importance of RNA structure in cellular processes and diseases. Various approaches to discovering drug-like small molecules that target RNA structure have been developed. This review provides a brief introduction to RNA structural biology and how RNA structures function as disease regulators. We summarize approaches to targeting RNA with small molecules and highlight their advantages, shortcomings and therapeutic potential.
Subject(s)
Drug Discovery/methods , Molecular Targeted Therapy/methods , RNA/chemistry , RNA/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Disease , Drug Design , Drug Evaluation, Preclinical/methods , High-Throughput Screening Assays/methods , Humans , Molecular Docking SimulationABSTRACT
[This corrects the article DOI: 10.3389/fchem.2020.00144.].
ABSTRACT
Incorporating fluorine (-F) substituents along the main-chains of polymer donors and acceptors is an effective strategy toward efficient bulk-heterojunction (BHJ) solar cells. Specifically, F-substituted polymers often exhibit planar conformations, leading to favorable packing, and electronic coupling. However, the effects of fluorine substituents on the charge generation and recombination characteristics that determine the overall efficiency of BHJ active layers remain critically important issues to examine. In this report, two PBDT[2X]T polymer analogs -poly[4,8-bis((2-ethylhexyl)oxy)benzo[1,2-b:4, 5-b']dithiophene-thiophene] [PBDT[2H]T] and its F-substituted counterpart poly[4,8-bis((2-ethylhexyl)oxy)benzo[1,2-b:4,5-b']dithiophene-3,4-difluoro-thiophene] [PBDT[2F]T]-are studied to systematically examine how -F substituents impact the blend morphology, charge generation, carrier recombination and extraction in BHJ solar cells. Considering the large efficiency differences between PBDT[2H]T- and PBDT[2F]T-based BHJ devices, significant emphasis is given to characterizing the out-of-plane morphology of the blend films as vertical phase-separation characteristics are known to have dramatic effects on charge transport and carrier extraction in polymer-fullerene BHJ solar cells. Herein, we use electron energy loss spectroscopy (EELS) in tandem with charge transport characterization to examine PBDT[2X]T-fullerene blend films. Our analyses show that PBDT[2H]T and PBDT[2F]T possess very different charge generation, recombination and extraction characteristics, resulting from distinct aggregation, and phase-distribution within the BHJ blend films.