bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma
Authors: Wang Qiangsheng , Shi Qiqin , Wang Zhenqian , Lu Jiawen , Hou Jian 
Published: September 2023

Abstract
Background
Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets.

Methods
First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively.

Results
We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): − 0.349), NAMPT (MIP:0.433; MACE: − 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points.

Conclusions
Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.
Effect of fermented dandelion on productive performance, meat quality, immune function, and intestinal microbiota of broiler chickens
Authors: Mao Jinju , Wang Yuan , Duan Ting , Yin Na , Dong Chenlin , Ren Xuerong , Liu Na , An Xiaoping , Qi Jingwei 
Published: September 2023

Abstract
Background
Dandelion has a great potential to be used as feed additive. Using microbial fermentation technology to degrade cell walls is conducive to enable better release of bioactive compounds of dandelion. This study intended to explore the effect of fermented dandelion (FD) on production performance, meat quality, immune function, and intestinal microbiota of broiler chickens. One-hundred and twenty 1-day-old male Arbor Acres broiler chickens were randomly allotted into three treatments: CON (basal diet, control), LFD and HFD (basal diet with 500 and 1000 mg/kg FD, respectively), with five replicates of eight birds each. The experiment lasted for 42 days.

Results
The results showed that birds in HFD group had increased ADG during 1–21 days (P < 0.05). On day 21, the bursa of Fabricius index of birds in LFD group was higher (P < 0.05), while the serum contents of IFN-γ and TNF-ɑ were lower in HFD group (P < 0.05). FD supplementation decreased the observed_species, shannon, chao1 and ace indexes (P < 0.05) as well as the abundance of Bacteroidota, Bacteroides, and Alistipes (P < 0.05). Birds in HFD group had higher abundance of Firmicutes and lower abundance of Verrucomicrobiota (P < 0.05). LFD group had lower abundance of unidentified_bacteria (P < 0.05). On day 42, the abdominal fat yield of HFD group was decreased (P < 0.05). Birds in LFD group had lower L* and b* values of breast muscle (P < 0.05), while higher spleen index. The CAT activities of breast muscle of FD groups were higher (P < 0.05).

Conclusion
In summary, dietary FD supplementation at 1000 mg/kg improved production performance and immune function and modulated microbiota composition in ileum of broiler chickens. FD can be supplemented in the diet to enhance performance and health of broiler chickens, of which 1000 mg/kg FD is more effective.
Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells
Authors: Lin Li-Qin , Zeng Hai-Kang , Luo Yu-Long , Chen Di-Fei , Ma Xiao-Qian , Chen Huan-Jie , Song Xin-Yu , Wu Hong-Kai , Li Shi-Yue 
Published: September 2023

AbstractBackgroundAirway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs.MethodsPrimary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuringMKI67mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface.ResultsCompared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), andMKI67mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression ofNKX2-1was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing thatDDIAS, BIRC5, TGFBI, andNKX2-1may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control.ConclusionsPathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.
Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial
Authors: Martínez-González Miguel A. , Montero Pedro , Ruiz-Canela Miguel , Toledo Estefanía , Estruch Ramón , Gómez-Gracia Enrique , Li Jun , Ros Emilio , Arós Fernando , Hernáez Alvaro , Corella Dolores , Fiol Miquel , Lapetra José , Serra-Majem Lluis , Pintó Xavier , Cofán Montse , Sorlí José V. , Babio Nancy , Márquez-Sandoval Yolanda F. , Castañer Olga , Salas-Salvadó Jordi 
Published: September 2023

Abstract
Background
Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet.

Methods
PREDIMED (‘‘PREvención con DIeta MEDiterránea’’) was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups: < 8, 8–< 10, 10– < 12, and 12–14 points. The outcome was new-onset type 2 diabetes.

Results
Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70–0.92) per + 2 points in Mediterranean Diet Adherence Screener (linear trend p = .001), and 0.46 (0.25–0.83) for the highest (12–14 points) versus the lowest (< 8) adherence. This inverse association was maintained after additionally adjusting for the randomized arm. Age- and sex-adjusted analysis of a validated plasma metabolomic signature of the Mediterranean Diet Adherence Screener (constituted of 67 metabolites) in a subset of 889 participants also supported these results.

Conclusions
Dietary intervention trials should quantify actual dietary adherence throughout the trial period to enhance the benefits and to assist results interpretation. A rapid dietary assessment tool, yearly repeated as a screener, was able to capture a strong inverse linear relationship between Mediterranean diet and type 2 diabetes.
Trial registration ISRCTN35739639
High triglyceride-glucose (TyG) index is associated with poor prognosis of heart failure with preserved ejection fraction
Authors: Zhou Qing , Yang Jie , Tang Hongyi , Guo Zexuan , Dong Wenyue , Wang Yiting , Meng Xiangbin , Zhang Kuo , Wang Wenyao , Shao Chunli , Hua Xinwei , Tang Yi-Da 
Published: September 2023

Abstract
Background
The impact of insulin resistance on the prognosis of heart failure with preserved ejection fraction (HFpEF) remains unknown. This study aimed to investigate the association between the triglyceride-glucose (TyG) index, an easily calculated marker of insulin resistance, and the long-term prognosis of HFpEF.

Methods
A total of 823 patients with HFpEF were enrolled in the study. The TyG index was determined using the formula ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). The primary endpoint was all-cause death. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization. Restricted cubic spline, multivariate Cox proportional hazard models, and competing risk models were used for analyses.

Results
During a median follow-up period of 3.16 years, 147 (17.8%) all-cause deaths, 139 (16.8%) CV deaths, and 222 (27.0%) HF rehospitalizations occurred. Restricted cubic spline analysis revealed a J-shaped association between the TyG index and the mortality and rehospitalization rates. In the multivariate Cox proportional hazard models, compared with those in the lowest TyG index tertile, patients in the highest tertile exhibited the greatest susceptibility to all-cause death (HR 1.53, 95% CI 1.19–1.98) and CV death (HR 1.52, 95% CI 1.19–1.96). In the competing risk model, a significant association between the TyG index and HF rehospitalization was observed (HR 1.31, 95% CI, 1.07–1.61).

Conclusion
A high TyG index is associated with an increased risk of mortality and rehospitalization in patients with HFpEF. The TyG index may serve as a promising prognostic marker for patients with HFpEF.
Refactoring the architecture of a polyketide gene cluster enhances docosahexaenoic acid production in Yarrowia lipolytica through improved expression and genetic stability
Authors: Dietrich Demian , Jovanovic-Gasovic Sofija , Cao Peng , Kohlstedt Michael , Wittmann Christoph 
Published: September 2023

Abstract
Background
Long-chain polyunsaturated fatty acids (LC-PUFAs), such as docosahexaenoic acid (DHA), are essential for human health and have been widely used in the food and pharmaceutical industries. However, the limited availability of natural sources, such as oily fish, has led to the pursuit of microbial production as a promising alternative. Yarrowia lipolytica can produce various PUFAs via genetic modification. A recent study upgraded Y. lipolytica for DHA production by expressing a four-gene cluster encoding a myxobacterial PKS-like PUFA synthase, reducing the demand for redox power. However, the genetic architecture of gene expression in Y. lipolytica is complex and involves various control elements, offering space for additional improvement of DHA production. This study was designed to optimize the expression of the PUFA cluster using a modular cloning approach.

Results
Expression of the monocistronic cluster with each gene under the control of the constitutive TEF promoter led to low-level DHA production. By using the minLEU2 promoter instead and incorporating additional upstream activating UAS1B4 sequences, 5' promoter introns, and intergenic spacers, DHA production was increased by 16-fold. The producers remained stable over 185 h of cultivation. Beneficially, the different genetic control elements acted synergistically: UAS1B elements generally increased expression, while the intron caused gene-specific effects. Mutants with UAS1B16 sequences within 2–8 kb distance, however, were found to be genetically unstable, which limited production performance over time, suggesting the avoidance of long repetitive sequence blocks in synthetic multigene clusters and careful monitoring of genetic stability in producing strains.

Conclusions
Overall, the results demonstrate the effectiveness of synthetic heterologous gene clusters to drive DHA production in Y. lipolytica. The combinatorial exploration of different genetic control elements allowed the optimization of DHA production. These findings have important implications for developing Y. lipolytica strains for the industrial-scale production of valuable polyunsaturated fatty acids.
Managing high-risk behaviours and challenges to prevent housing loss in permanent supportive housing: a rapid review
Authors: Kerman Nick , Kidd Sean A. , Mutschler Christina , Sylvestre John , Henwood Benjamin F. , Oudshoorn Abe , Marshall Carrie Anne , Aubry Tim , Stergiopoulos Vicky 
Published: September 2023

AbstractPermanent supportive housing is an effective intervention for stably housing most people experiencing homelessness and mental illness who have complex support needs. However, high-risk behaviours and challenges are prevalent among this population and have the potential to seriously harm health and threaten housing tenures. Yet, the research on the relationship between high-risk issues and housing stability in permanent supportive housing has not been previously synthesized. This rapid review aimed to identify the housing-related outcomes of high-risk behaviours and challenges in permanent supportive housing settings, as well as the approaches used by agencies and residents to address them. A range of high-risk behaviours and challenges were examined, including risks to self (overdose, suicide/suicide attempts, non-suicidal self-injury, falls/fall-related injuries), and risks to multiple parties and/or building (fire-setting/arson, hoarding, apartment takeovers, physical/sexual violence, property damage, drug selling, sex trafficking). The search strategy included four components to identify relevant academic and grey literature: (1) searches of MEDLINE, APA PsycINFO, and CINAHL Plus; (2) hand searches of three journals with aims specific to housing and homelessness; (3) website browsing/searching of seven homelessness, supportive housing, and mental health agencies and networks; and (4) Advanced Google searches. A total of 32 articles were eligible and included in the review. Six studies examined the impacts of high-risk behaviours and challenges on housing tenancies, with overdose being identified as a notable cause of death. Twenty-six studies examined approaches and barriers to managing high-risk behaviours and challenges in PSH programs. These were categorized into eight types of approaches: (1) clinical, (2) relational/educational, (3) surveillant, (4) restrictive, (5) strategic, (6) design-based, (7) legal, and (8) self-defence. Consistent across all approaches was a lack of rigorous examination of their effectiveness. Further, some approaches that are legal, restrictive, surveillant, or strategic in nature may be used to promote safety, but may conflict with other program objectives, including housing stability, or resident empowerment and choice. Research priorities were identified to address the key evidence gaps and move toward best practices for preventing and managing high-risk behaviours and challenges in permanent supportive housing.
MicroRNA-125a-5p regulates the effect of Tregs on Th1 and Th17 through targeting ETS-1/STAT3 in psoriasis
Authors: Yan Kexiang , Zhang Fuxin , Ren Jie , Huang Qiong , Yawalkar Nikhil , Han Ling 
Published: September 2023

Abstract
Background
Psoriasis is an inflammatory disease mediated by helper T (Th)17 and Th1 cells. MicroRNA-125a (miR-125a) is reduced in the lesional skin of psoriatic patients. However, the mechanism by which miR-125a participates in psoriasis remains unclear.

Methods
The levels of miR-125a-5p and its downstream targets (ETS-1, IFN-γ, and STAT3) were detected in CD4+ T cells of healthy controls and psoriatic patients by quantitative real-time PCR (qRT-PCR). In vitro, transfection of miR-125a-5p mimics was used to analyze the effect of miR-125a-5p on the differentiation of Th17 cells by flow cytometry. Imiquimod (IMQ)-induced mouse model was used to evaluate the role of upregulating miR-125a-5p by intradermal injection of agomir-125a-5p in vivo.

Results
miR-125a-5p was downregulated in peripheral blood CD4+ T cells of psoriatic patients, which was positively associated with the proportion of regulatory T cells (Tregs) and negatively correlated with the Psoriasis Area and Severity Index (PASI) score. Moreover, the miR-125a-5p mimics promoted the differentiation of Tregs and downregulated the messenger RNA (mRNA) levels of ETS-1, IFN-γ, and STAT3 in murine CD4+ T cells. Furthermore, agomir-125a-5p alleviated psoriasis-like inflammation in an IMQ-induced mouse model by downregulating the proportion of Th17 cells.

Conclusions
miR-125a-5p may have therapeutic potential in psoriasis by restoring the suppressive function of Tregs on Th17 cells through targeting STAT3, and on Th1 cells indirectly through targeting ETS-1 and IFN-γ.
Influenza H7N9 virus disrupts the monolayer human brain microvascular endothelial cells barrier in vitro
Authors: Lei Yuxuan , Sun Ying , Wu Weihua , Liu Hui , Wang Xin , Shu Yuelong , Fang Shisong 
Published: September 2023

AbstractInfluenza H7N9 virus causes human infections with about 40% case fatality rate. The severe cases usually present with pneumonia; however, some present with central nervous system complications. Pneumonia syndrome is attributed to the cytokine storm after infection with H7N9, but the pathogenic mechanism of central nervous system complications has not been clarified. This study used immortalized human brain microvascular endothelial cells hCMEC/D3 to simulate the blood-brain barrier. It demonstrated that H7N9 virus could infect brain microvascular endothelial cells and compromise the blood-brain barrier integrity and permeability by down-regulating the expression of cell junction-related proteins, including claudin-5, occludin, and vascular endothelial (VE)-cadherin. These results suggested that H7N9 could infect the blood-brain barrier in vitro and affect its functions, which could be a potential mechanism for the pathogenesis of H7N9 viral encephalopathy.
Use of thyroid hormones in hypothyroid and euthyroid patients: a 2022 THESIS questionnaire survey of members of the Latin American Thyroid Society (LATS)
Authors: Cassemiro Jessica F. , Ilera Veronica , Batalles Stella , Reyes Adriana , Nagy Endre V. , Papini Enrico , Perros Petros , Hegedüs Laszlo , Ramos Helton Estrela 
Published: September 2023

Abstract
Purpose
Inconsistencies in the medical management of hypothyroidism have been reported between endocrinologists in different countries. This study aimed to identify the attitudes of Latin America thyroid specialists towards the use of thyroid hormones.

Methods
Online survey of members of the Latin America Thyroid Society.

Results
81/446 (18.2%) completed the questionnaire. Levothyroxine (LT4) was the initial treatment of choice for all respondents. 56.8% would consider LT4 use in biochemically euthyroid patients: infertile women with elevated anti-thyroid antibodies (46.9%), resistant depression (17.3%) and growing goiter (12%). Most respondents preferred tablets (39.5%) over liquid formulations (21.0%) or soft gel capsules (22.2%) and would not consider switching formulations in patients with persistent symptoms. 39.5% would never use LT4 + liothyronine (LT3) combination therapy in symptomatic euthyroid patients, due to low quality evidence for benefit. 60.5% reported that persistence of symptoms despite normal TSH is rare (below 5% of patients) and its prevalence has been stable over the last five years. Psychosocial factors (84.0%), comorbidities (86.4%) and the patient unrealistic expectation (72.8%) were considered the top three explanations for this phenomenon.

Conclusion
LT4 tablets is the treatment of choice for hypothyroidism. A significant proportion of respondents would use LT4 in some groups of euthyroid individuals, contrasting the recommendations of the major clinical practice guideline indications. LT4 + LT3 combination treatment in euthyroid symptomatic patients was considered by nearly 50%. Practices based on weak or absent evidence included use of thyroid hormones for euthyroid subjects by 56.8% of respondents and use of LT4 + LT3 treatment by 60.5% of respondents for patients with persistent symptoms. In contrast to many European countries, LATS respondents report a low and unchanged proportion of dissatisfied patients over the last five years.