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Recent studies focused on exploring phosphodiesterase type 5 inhibitors (PDE5Is)-related hearing impairment. This study aimed to comprehensively explore real-world hearing impairment associated with PDE5Is based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). The characteristics and correlation of PDE5Is-related hearing impairment reported in the FAERS database from the fourth quarter of 2003 to the second quarter of 2023 were analyzed using disproportionality analysis. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) were used to analyze the adverse events (AEs) of hearing impairment. A total of 1,438 reported cases of hearing impairment were associated with four PDE5Is, revealing statistically significant reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) with the SMQ. The average age of all patients was more than 55 years, over 70% of AEs were reported in men. Most of the reported cases were from the United States. Reports for all the drugs indicated an increase since 2008, except for avanafil. This study showed that the disability rates of PDE5Is were 8.14–40%, the rates of initial or prolonged hospitalization were 6.21–10.24%, and the rates of required intervention were 3.31–9.45%. The pharmacovigilance study identified a potential risk of hearing impairment associated with PDE5Is, indicating the need for continuous monitoring and appropriate management. [ABSTRACT FROM AUTHOR]

The chromatin-based rule governing the selection and activation of replication origins in metazoans remains to be investigated. Here we report that NFIB, a member of Nuclear Factor I (NFI) family that was initially purified in host cells to promote adenoviral DNA replication but has since mainly been investigated in transcription regulation, is physically associated with the pre-replication complex (pre-RC) in mammalian cells. Genomic analyses reveal that NFIB facilitates the assembly of the pre-RC by increasing chromatin accessibility. Nucleosome binding and single-molecule magnetic tweezers shows that NFIB binds to and opens up nucleosomes. Transmission electron microscopy indicates that NFIB promotes nucleosome eviction on parental chromatin. NFIB deficiency leads to alterations of chromosome contacts/compartments in both G1 and S phase and affects the firing of a subset of origins at early-replication domains. Significantly, cancer-associated NFIB overexpression provokes gene duplication and genomic alterations recapitulating the genetic aberrance in clinical breast cancer and empowering cancer cells to dynamically evolve growth advantage and drug resistance. Together, these results point a role for NFIB in facilitating replication licensing by acting as a genome organizer, shedding new lights on the biological function of NFIB and on the replication origin selection in eukaryotes. The precise rule of replication origin selection and activation in metazoans remains unclear. Here, the authors identify NFIB as a genome organizer and replication pioneer by facilitating nucleosome remodeling and chromatin assembly of the pre-RC. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy resistance is the major cause of recurrence in patients with colorectal cancer (CRC). A previous study found that Fusobacterium (F.) nucleatum promoted CRC chemoresistance. Additionally, metformin rescued F. nucleatum-induced tumorigenicity of CRC. Here, we aimed to investigate whether metformin could revert F. nucleatum-induced chemoresistance and explore the mechanism.Methods: The role of metformin in F. nucleatum-infected CRC cells was confirmed using cell counting kit 8 assays and CRC xenograft mice. Stemness was identified by tumorsphere formation. Bioinformatic analyses were used to explore the regulatory molecules involved in metformin and F. nucleatum-mediated regulation of the sonic hedgehog pathway.Results: We found that metformin abrogated F. nucleatum-promoted CRC resistance to chemotherapy. Furthermore, metformin attenuated F. nucleatum-stimulated stemness by inhibiting sonic hedgehog signaling. Mechanistically, metformin diminished sonic hedgehog signaling proteins by targeting the MYC/miR-361-5p cascade to reverse F. nucleatum-induced stemness, thereby rescuing F. nucleatum-triggered chemoresistance in CRC.Conclusions: Metformin acts on F. nucleatum-infected CRC via the MYC/miR-361-5p/sonic hedgehog pathway cascade, subsequently reversing stemness and abolishing F. nucleatum-triggered chemoresistance. Our results identified metformin intervention as a potential clinical treatment for patients with chemoresistant CRC with high amounts of F. nucleatum. [ABSTRACT FROM AUTHOR]

The optimal systemic treatment of advanced large cell neuroendocrine carcinoma (LCNEC) is still controversial. We intend to explore advanced LCNEC through SEER database, construct nomogram model of advanced LCNEC, and understand the effect of different treatment regimens on LCNEC. We collected 909 patients, divided them into a training set validation set, constructed nomograms using Cox proportional hazards regression models, and evaluated nomogram discrimination and calibration by C-index and calibration curves. Kaplan–Meier will also be used to compare OS in different groups of patients and to explore the impact of different treatment regimens on advanced LCNEC. On the nomogram plotted, the nomogram predicted AUC values over time were always greater than 0.7, the C-index was 0.681 (95% CI 0.656–0.706) and 0.663 (95% CI 0.628–0.698) in the training and validation sets, respectively, and patients were divided into two groups according to risk, and a significant difference in OS was observed between the high-risk and low-risk groups in the training and validation cohorts. Different treatment analyses showed that chemotherapy is still the best treatment for advanced LCNEC. This nomogram provides a convenient and reliable tool for individual assessment and clinical decision-making of patients with advanced LCNEC. [ABSTRACT FROM AUTHOR]

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Introduction: This phase I clinical trial was conducted to evaluate the safety of RP22 as a skin test reagent for tuberculosis (TB) diagnosis and to explore the appropriate dosage. Methods: We used a randomized, double-blind, placebo-controlled identification allergen (IA) skin test. A total of 72 healthy adult volunteers with negative chest X-ray results were randomized into six groups and given a QuantiFERON-TB Gold (QFT) test. Of the 12 participants in each group, eight received RP22 and four received placebo. The doses of RP22 in the six experimental groups ranged from 0.1 to 4.0 μg in a single intradermal injection of 0.1 ml. Skin reactions and adverse events were recorded at intervals. Results: All doses of RP22 except the highest were well tolerated and safe. No serious adverse events associated with the injection were observed in all groups. There were 11 participants who had positive QFT results, eight had a skin reaction with a redness or induration area diameter of greater than 10 mm at 48–72 h, one had no skin reaction. Among the 60 negative-QFT participants, none had a reaction area diameter of greater than 10 mm. Conclusion: The RP22 skin test was well tolerated and safe, it could play a key role in screening for latent tuberculosis infection (LTBI) by providing a much-wanted alternative to the tuberculin skin test (TST) and interferon-γ release assays (IGRAs). [ABSTRACT FROM AUTHOR]

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development. [ABSTRACT FROM AUTHOR]

LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC50 values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-l-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design. [ABSTRACT FROM AUTHOR]

Iron tailings have few macropores which severely inhibit infiltration and transport of soil water. Polyacrylamide (PAM) can regulate soil water, but it is rarely used when remediating tailings matrix. In this research, PAM of four molecular weights of 300w, 600w, 800w, and 1000w were selected as amendments, and were each applied at five mass concentrations of 0% (CK), 0.01%, 0.04%, 0.08%, and 0.16% to observe their effects on water transport in iron tailings using column simulations in the laboratory. After adding PAM, the water retention and saturated water content of iron tailings increased significantly (P < 0.05). With increases in PAM molecular weight and mass concentration, the saturated hydraulic conductivity showed a downward trend, but the saturated hydraulic conductivity increased after a dry–wet cycle. With the increase of PAM mass concentration, adding PAM of 1000w molecular weight to iron tailing decreased infiltration capacity, but treatments of other molecular weights all initially increased then decreased infiltration capacity. The greatest improvement on infiltration capacity of iron tailings was observed with the addition of PAM of 300w molecular weight and 0.01% mass concentration. Adding PAM increased the vertical depth of the saturation zone of iron tailings (P < 0.05) with a maximum depth of 20.83 cm. The Kostiakov model more accurately simulated water infiltration of iron tailings compared with the Horton and Philip models. On the whole, when PAM of low molecular weight and concentration was added to iron tailings, PAM increased stable infiltration, saturated water content, and water retention. It also inhibited saturated hydraulic conductivity of iron tailings. Therefore, in practice, it is necessary to select the appropriate molecular weight and mass concentration of PAM according to the dominant limiting factors and remediation needs of the matrix. [ABSTRACT FROM AUTHOR]

Background: Cancer poses a huge disease burden, which could be reduced by adopting healthy lifestyles mainly composed of healthy diet, body weight, physical activity, limited alcohol consumption, and avoidance of smoking. However, no systematic review has summarised the relations of combined lifestyle factors with cancer morbidity and mortality.Methods: EMBASE and PubMed were searched up to April 2019. Cohort studies investigating the association of combined lifestyle factors with risks of incident cancer and cancer mortality were selected. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Heterogeneity and publication bias tests were conducted.Results: The HRs (95% CIs) comparing individuals with the healthiest versus the least healthy lifestyles were 0.71 (0.66-0.76; 16 studies with 1.9 million participants) for incident cancer and 0.48 (0.42-0.54; 30 studies with 1.8 million participants) for cancer mortality. Adopting the healthiest lifestyles was also associated with 17 to 58% lower risks of bladder, breast, colon, endometrial, oesophageal, kidney, liver, lung, rectal, and gastric cancer. The relations were largely consistent and significant among participants with different characteristics in the subgroup analyses.Conclusions: Adopting healthy lifestyles is associated with substantial risk reduction in cancer morbidity and mortality, and thus should be given priority for cancer prevention. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: A healthy lifestyle has been widely recommended for the prevention and management of type 2 diabetes. However, no systematic review has summarised the relationship between combined lifestyle factors (including, but not limited to, smoking, alcohol drinking, physical activity, diet and being overweight or obese) and incident type 2 diabetes and risk of health outcomes among diabetic individuals. Methods: EMBASE and PubMed were searched up to April 2019 without language restrictions. References included in articles in relevant publications were also screened. Cohort studies investigating the combined associations of at least three lifestyle factors with incident type 2 diabetes and health outcomes among diabetic individuals were included. Reviewers were paired and independently screened studies, extracted data and evaluated study quality. Random-effects models were used to calculate summary HRs. Heterogeneity and publication bias tests were also conducted. Results: Compared with participants considered to have the least-healthy lifestyle, those with the healthiest lifestyle had a 75% lower risk of incident diabetes (HR 0.25 [95% CI 0.18, 0.35]; 14 studies with approximately 1 million participants). The associations were largely consistent and significant among individuals from different socioeconomic backgrounds and baseline characteristics. Among individuals with type 2 diabetes (10 studies with 34,385 participants), the HRs (95% CIs) were 0.44 (0.33, 0.60) for all-cause death, 0.51 (0.30, 0.86) for cardiovascular death, 0.69 (0.47, 1.00) for cancer death and 0.48 (0.37, 0.63) for incident cardiovascular disease when comparing the healthiest lifestyle with the least-healthy lifestyle. Conclusions/interpretation: Adoption of a healthy lifestyle is associated with substantial risk reduction in type 2 diabetes and long-term adverse outcomes among diabetic individuals. Tackling multiple risk factors, instead of concentrating on one certain lifestyle factor, should be the cornerstone for reducing the global burden of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Exploring how suitable habitat and population size of Red-crowned crane Grus japonensis respond to long-term coastal reclamation plays an important role in species conservation and in related coastal management. Here, we combined field data for suitable habitats and wintering population size of G. japonensis with GIS-based information to elucidate the influence of long-term coastal reclamation on this species and related conservation efforts. During 1975-2013, the intensity and spatial extent of coastal reclamation exhibited a temporal change, increasing dramatically in 1975-2000 and lessening considerably in 2000-2013. Under the pressure of long-term coastal reclamation, the decline of suitable habitat of G. japonensis was affected by increasing levels of human disturbance and decreasing availability of natural habitat. Moreover, the wintering population size of G. japonensis exhibited a decreasing trend during 1975-2013 as a result of the decreasing availability of fish ponds, bare tidal flats, and increasing spatial extent of residential areas and P. australis habitat, which were indirectly affected by long-term reclamation. Our results highlight the importance of considering the long-term effects of coastal reclamation on both populations and suitable habitat of G. japonensis, which should be considered in future plans for coastal management and conservation. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the allelic frequency of 4 short terminal repeats (STRs) in Han and She populations from eastern China. Methods: DNA samples from Han (N = 110) and She (N = 110) healthy subjects were amplified using PCR and primers specific for the STRs. D21S11 and D21S1446 (chromosome 21) and D18S865 and D18S535 (chromosome 18). The frequency and homozygocity of different STRs were evaluated. Results: For both populations, D21S11 and D18S535 were more polymorphic than D21S1446 and D18S865, and the D21S1446 1 allele was very common (48.6% and 55.0% for the Han and She groups, respectively).The Han and She groups significantly differed from one another in respect to the distribution of D21S11, D18S865, and D18S535 allelic frequency (all P -values ≤ 0.48) but had a similar allelic distribution for D21S1446 ( P = 0.106). D21S1446 was found to be homozygous about 50% of the time which was significantly greater compared to the other STRs analyzed. Conclusion: This study found that the Han and She differ genetically at 3 autosomal STRs located on chromosome 18 and 21. The STR D21S1146 was often homozygous within these groups, indicating it would be poor marker for analyzing trisomy within these populations. [ABSTRACT FROM AUTHOR]

Abstract  Many bioactive peptides possess specific biological properties that make these potential ingredients of health-promoting foods. Increasing attention is being focused on physiologically active peptides derived from soybean proteins. In this study, soybean peptides were produced by fermentation of defatted soybean meal with Bacillus subtilis SHZ and purified by ultrafiltration and gel chromatogram. Free radical scavenging property and the effect on anti-fatigue of the peptides were evaluated in vitro and in vivo, respectively. Swimming endurance tests of mice were carried out after 20 days of soybean peptides administration (0, 100, 200, 400 mg/kg BW/day for control, low-dose, middle-dose and high-dose group, respectively). And the blood lactate and hepatic glycogen of mice were determined. Results showed that the purified peptides exhibited significant (P P P  [ABSTRACT FROM AUTHOR]

The impacts of coastal reclamation on carbon (C) and nitrogen (N) sinks of coastal wetlands remain unclearly understood. This study was conducted to investigate the alterations of soil organic C and N (SOC and SON) pools following conversion of Phragmites australis salt marsh into fishpond, wheat and rapeseed fields and town construction land through reclamation along Jiangsu coast in eastern China. Coastal reclamation significantly increased stocks of soil total, labile and recalcitrant organic C and N (SLOC, SLON, SROC, and SRON), and concentrations of water-soluble organic C (WSOC), microbial biomass C and N (SMBC and SMBN), cumulative CO2-C mineralization (MINC) following conversion of P. australis salt marsh into fishpond, wheat and rapeseed fields. However, coastal reclamation reduced SOC, SLOC, SROC, SRON, WSOC, SMBC, SMBN, and MINC following conversion of P. australis salt marsh into town construction land. Our results suggest that coastal reclamation affects C and N sinks of coastal wetlands by changing SOC and SON pools size, stability and dynamics changes following conversion of P. australis salt marsh into other land use types. This finding were primarily attributed to alterations in quantity and quality of exogenous materials returning the soil, and soil physiochemical properties as affected by coastal reclamation. [ABSTRACT FROM AUTHOR]

A definitive diagnosis of tuberculosis serositis (TS) is still challenging. Our preliminary practice found that Serous Fluid Drainage Flocky Precipitate (SFDFP) was a useful testing sample to diagnose TS. We designed this study to assess the diagnostic performance of SFDPF for TS compared with conventional bacteriology methods on serous fluid (SF). A cohort study was conducted from July 2014 to April 2016. Patients with suspected TS were consecutively screened. SF and SFDFP were collected and tested by Ziehl-Neelsen stain, MTB culture, and Xpert/RIF assay. We compared the diagnostic performance of SF and SFDFP in several test settings. Through this study, 85 patients were enrolled, of whom 70 (82.4%) were confirmed TS or highly probable TS, 13 (15.3%) were none-TS and 2 (2.4%) indeterminate results were ruled out. The overall sensitivity using both SFDFP and SF was significantly higher than each (60% vs. 48% and 41%, p < 0.05). SFDFP and SF samples had similar diagnostic performance (p < 0.05). No false positive was detected in this study. We concluded that SFDFP is a reliable testing sample for diagnosing tuberculous serositis. SFDFP may significantly improve the diagnostic yield as a supplement to conventional tests. [ABSTRACT FROM AUTHOR]

Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion by the parasite and/or immune inhibition in response to infection. To identify pathways commonly inhibited after malaria infection, we infected C57BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and host genes playing an important role in malaria infection. Strong interferon responses were observed after infection with the N67 strain, whereas initial inhibition and later activation of hematopoietic pathways were found after infection with 17XNL parasite, showing unique responses to individual parasite strains. Inhibitions of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. As a proof of principle, treatment of N67-infected mice with antibodies against T cell receptors OX40 or CD28 to activate the inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine. [ABSTRACT FROM AUTHOR]

Recent advances in upconversion nanophotosensitizers (UCNPs-PS) excited by near-infrared (NIR) light have led to substantial progress in improving photodynamic therapy (PDT) of cancer. For a successful PDT, subcellular organelles are promising therapeutic targets for reaching a satisfactory efficacy. It is of vital importance for these nanophotosensitizers to reach specifically the organelles and to perform PDT with precise time control. To do so, we have in this work traced the dynamic subcellular distribution, especially in organelles such as lysosomes and mitochondria, of the poly(allylamine)-modified and dual-loaded nanophotosensitizers. The apoptosis of the cancer cells induced by PDT with the dependence of the distribution status of the nanophotosensitizers in organelles was obtained, which has provided an in-depth picture of intracellular trafficking of organelle-targeted nanophotosensitizers. Our results shall facilitate the improvement of nanotechnology assisted photodynamic therapy of cancers. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with high heritability, although the underlying genetic determinants of ASDs remain largely unknown. Large-scale whole-genome studies of copy number variation in Han Chinese samples are still lacking. We performed a genome-wide copy number variation analysis of 343 ASD trios, 203 patients with sporadic cases and 988 controls in a Chinese population using Illumina genotyping platforms to identify CNVs and related genes that may contribute to ASD risk. We identified 32 rare CNVs larger than 1 Mb in 31 patients. ASD patients were found to carry a higher global burden of rare, large CNVs than controls. Recurrent de novo or case-private CNVs were found at 15q11-13, Xp22.3, 15q13.1-13.2, 3p26.3 and 2p12. The de novo 15q11-13 duplication was more prevalent in this Chinese population than in those with European ancestry. Several genes, including GRAMD2 and STAM, were implicated as novel ASD risk genes when integrating whole-genome CNVs and whole-exome sequencing data. We also identified several CNVs that include known ASD genes (SHANK3, CDH10, CSMD1) or genes involved in nervous system development (NYAP2, ST6GAL2, GRM6). Besides, our study also implicated Contactins-NYAPs-WAVE1 pathway in ASD pathogenesis. Our findings identify ASD-related CNVs in a Chinese population and implicate novel ASD risk genes and related pathway for further study. [ABSTRACT FROM AUTHOR]