bluuebunny/crossref_metadata_2025_split huggingface dataset:
Causal association between insulin sensitivity index and Alzheimer's disease
Authors: Xu Fang , Wu Shiyang , Gao Shan , Li Xuan , Huang Chen , Chen Yan , Zhu Ping , Liu Guiyou 
Published: October 2024

AbstractEvidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD.image
Costs and economic impact of student‐led clinics—A systematic review
Authors: Mitchell Debra , Maloney Stephen , Robinson Luke , Haines Terry , Foo Jonathan 
Published: October 2024

AbstractPurposeStudent‐led clinics generate a range of benefits to multiple stakeholder groups. Students receive important educational opportunities to advance in their training. Patients with limited access to care may access effective care or a higher amount of effective care and so reduce burden on the health care system. The financial viability of student‐led clinics run by universities is uncertain, and establishing this is complicated by the range of stakeholder costs and benefits that may be involved. This systematic review aimed to synthesise evidence related to the costs and benefits of student‐led clinics and report the methods that have been used to measure these costs and benefits.MethodWe conducted a systematic search of MEDLINE All, PsychInfo, CINAHL, A+ Education (Informit), ERIC (ProQuest) and ProQuest Education databases for studies that reported the costs and/or economic benefits of student‐led clinics from inception through August 2023. Studies were screened for eligibility, and data were extracted including study characteristics, student‐led clinic description and economic outcomes. A narrative synthesis was undertaken due to the heterogeneity of studies.ResultsOf 349 potentially eligible studies, 24 were included. Nine studies (38%) used an outcome description‐monetised approach; four used partial economic evaluation (17%); four employed cost description (17%); two used cost approximation (8%); two used cost analyses (8%); and one was a full economic analysis (4%). Studies examined costs or benefits, from the perspective of a range of stakeholders, but few examined both. Only six studies (25%) had established the clinical effectiveness of their service. Student clinics generate costs for universities in supplying supervision, capital and consumables. Benefits are shared by patients, students, universities and the broader health system, however, economic evaluations to date have largely ignored or not monetised/valued these benefits.ConclusionsStudent‐led clinics involve many different stakeholders, each of whom may incur costs and reap benefits. This complicates how we can go about trying to establish the economic efficiency and viability of student‐led clinics. Measurement of both costs and benefits is needed to understand the efficiency of student‐led clinics in comparison to alternatives. Without the full picture, decision‐makers may make decisions that are ill‐informed and lead to a loss of benefit for society.
Methyl jasmonate mitigates Fusarium graminearum infection in wheat by inhibiting deoxynivalenol synthesis
Authors: Gao Jing , Sun Yidan , Jin Weiguo , Zhang Feng , Zhou Mingguo , Song Xiushi 
Published: October 2024

AbstractMethyl jasmonate (MeJA), a plant growth regulator, coordinates a diverse array of physiological responses, including the inhibition of seed germination, modulation of secondary metabolite biosynthesis, and activation of defence responses. The external application of MeJA has been demonstrated to effectively diminish the severity of fungal diseases. Here, we unveil a novel mechanism through which exogenous MeJA alleviates Fusarium head blight (FHB) by inhibiting the synthesis of deoxynivalenol (DON) in Fusarium graminearum, rather than by enhancing the wheat resistance response. MeJA treatment reduced the infection by wild‐type F. graminearum in wheat coleoptiles, but exhibited no significant influence on that of the DON‐deficient mutant strain (∆Tri5). The production of DON in F. graminearum was significantly inhibited both in vitro and in planta. MeJA affected the expression of genes related to DON biosynthesis, without influencing the formation of toxisomes as observed under microscopic analysis. Exogenous MeJA demonstrated a limited impact on the early genes of plant jasmonic acid signalling pathway, in contrast to the wild‐type pathogen strain, which induced the upregulation of these genes. The expression levels of defence marker genes induced by MeJA were notably lower compared to those induced by the pathogen. This study elucidates the molecular mechanisms of MeJA in modulating the wheat‐F. graminearum interaction, providing new insights into the development of environmentally friendly strategies against fungi.
PbRVE6 Promotes Anthocyanins Accumulation in Pear Fruit Peel by Regulating Key Biosynthetic Genes
Authors: Li Xieyu , Du Wei , Cheng Yinsheng , Yang Li , Dong Xiujuan , Hussain Syed Bilal , Xu Lingfei , Liu Zheng , Wu Tao 
Published: October 2024

AbstractRed peel color, a desirable trait in pears, is determined by anthocyanin accumulation. While REVEILLE (RVEs) transcription factors regulate anthocyanin biosynthesis in some plant species, their role in pear peel has not been well‐studied. This study investigates the function of RVEs in anthocyanin biosynthesis in ‘Zaosu’ (low anthocyanin content) and its red bud mutant, ‘Red Zaosu’ (high anthocyanin content) fruit peel. Consistent with higher anthocyanin content, ‘Red Zaosu’ pears exhibited increased PbRVE6 expression compared to ‘Zaosu’, while PbRVE3a and PbRVE3b levels remained unchanged. Additionally, PbRVE6 was localized to the nucleus. Overexpression of PbRVE6 in ‘Zaosu’ pear pericarp significantly increased anthocyanin content and upregulated key anthocyanin pathway genes PbANS and PbUFGT. Conversely, VIGS silencing of PbRVE6 in ‘Red Palacer’ pears led to decreased expression of PbANS and PbUFGT and a slight reduction in anthocyanin content. Yeast one‐hybrid and dual‐luciferase assays confirmed that PbRVE6 can bind and activate the promoters of PbANS and PbUFGT. These findings demonstrate that PbRVE6 promotes anthocyanin accumulation in pear peel by directly regulating PbANS and PbUFGT expression. This study provides a valuable foundation for understanding the regulatory network of anthocyanins in pear peels, and offers potential genetic resources for the production of new pear germplasm.
Targeted delivery of flagellin by nebulization offers optimized respiratory immunity and defense against pneumococcal pneumonia
Authors: Baldry Mara , Costa Charlotte , Zeroual Yasmine , Cayet Delphine , Pardessus Jeoffrey , Soulard Daphnée , Wallet Frédéric , Beury Delphine , Hot David , MacLoughlin Ronan , Heuzé-Vourc’h Nathalie , Sirard Jean-Claude , Carnoy Christophe 
Published: October 2024

ABSTRACT

Novel therapeutic strategies are urgently needed to combat pneumonia caused by
Streptococcus pneumoniae
strains resistant to standard-of-care antibiotics. Previous studies have shown that targeted stimulation of lung innate immune defenses through intranasal administration of the Toll-like receptor 5 agonist flagellin improves the treatment of pneumonia when combined with antibiotics. To promote translation to the clinic application, this study assessed the direct delivery of flagellin to the airways through nebulization using a vibrating mesh nebulizer in mice. Intranasal delivery achieved approximately 40% lung deposition of the administered flagellin dose, whereas nebulization yielded less than 1%. Despite these differences, nebulized flagellin induced transient activation of lung innate immunity characterized by cytokine/chemokine production and neutrophil infiltration into airways analogous to intranasal administration. Furthermore, inhalation by nebulization resulted in an accelerated resolution of systemic pro-inflammatory responses. Lastly, adjunct therapy combining nebulized flagellin and amoxicillin proved effective against antibiotic-resistant pneumococcal pneumonia in mice. We posit that flagellin aerosol therapy represents a safe and promising approach to address bacterial pneumonia within the context of antimicrobial resistance.
Development of a
Limosilactobacillus reuteri
therapeutic delivery platform with reduced colonization potential
Authors: Alexander Laura M. , Khalid Saima , Gallego-Lopez Gina M. , Astmann Theresa J. , Oh Jee-Hwan , Heggen Mark , Huss Phil , Fisher Renee , Mukherjee Amitava , Raman Srivatsan , Choi In Young , Smith Morgan N. , Rogers Claude J. , Epperly Michael W. , Knoll Laura J. , Greenberger Joel S. , van Pijkeren Jan-Peter 
Published: October 2024

ABSTRACT

Bacterial biotherapeutic delivery vehicles have the potential to treat a variety of diseases. This approach obviates the need to purify the recombinant effector molecule, allows delivery of therapeutics
in situ
via oral or intranasal administration, and protects the effector molecule during gastrointestinal transit. Lactic acid bacteria have been broadly developed as therapeutic delivery vehicles though risks associated with the colonization of a genetically modified microorganism have so-far not been addressed. Here, we present an engineered
Limosilactobacillus reuteri
strain with reduced colonization potential. We applied a dual-recombineering scheme for efficient barcoding and generated mutants in genes encoding five previously characterized and four uncharacterized putative adhesins. Compared with the wild type, none of the mutants were reduced in their ability to survive gastrointestinal transit in mice. CmbA was identified as a key protein in
L. reuteri
adhesion to HT-29 and enteroid cells. The nonuple mutant, a single strain with all nine genes encoding adhesins inactivated, had reduced capacity to adhere to enteroid monolayers. The nonuple mutant producing murine IFN-β was equally effective as its wild-type counterpart in mitigating radiation toxicity in mice. Thus, this work established a novel therapeutic delivery platform that lays a foundation for its application in other microbial therapeutic delivery candidates and furthers the progress of the
L. reuteri
delivery system towards human use.

IMPORTANCE

One major advantage to leverage gut microbes that have co-evolved with the vertebrate host is that evolution already has taken care of the difficult task to optimize survival within a complex ecosystem. The availability of the ecological niche will support colonization. However, long-term colonization of a recombinant microbe may not be desirable. Therefore, strategies need to be developed to overcome this potential safety concern. In this work, we developed a single strain in which we inactivated the encoding sortase, and eight genes encoding characterized/putative adhesins. Each individual mutant was characterized for growth and adhesion to epithelial cells. On enteroid cells, the nonuple mutant has a reduced adhesion potential compared with the wild-type strain. In a model of total-body irradiation, the nonuple strain engineered to release murine interferon-β performed comparable to a derivative of the wild-type strain that releases interferon-β. This work is an important step toward the application of recombinant
L. reuteri
in humans.
Corynebacterial membrane vesicles disrupt cariogenic interkingdom assemblages
Authors: Treerat Puthayalai , Rozendal Tanner , de Mattos Camilla , Davis Anli , Helliwell Emily , Merritt Justin , Kreth Jens 
Published: October 2024

ABSTRACT

Polymicrobial diseases such as periodontal disease and caries pose significant treatment challenges due to their resistance to common approaches like antibiotic therapy. These infections exhibit increased resilience, due to microbial interactions that also disrupt host immune responses. Current research focuses on virulence and disease-promoting interactions, but less is known about interactions that could inhibit or prevent disease development. Normally human-associated microbiomes maintain homeostasis, preventing pathobionts from becoming dominant. In conditions like chronic disseminated candidiasis or severe early childhood caries (s-ECC), an overgrowth of microbes such as
Candida albicans
disrupts this balance. Typically,
C. albicans
coexists benignly within the microbial community but can become pathogenic, forming biofilms and interacting with other microbes such as cariogenic
Streptococcus mutans
. This interaction is particularly significant in s-ECC, where it exacerbates the disease’s progression and severity. Here, we present that
Corynebacterium durum
, itself and through its extracellular membrane vesicles disrupts interkingdom assemblages between
C. albicans
and
S. mutans
. Mechanistically the interaction interference occurs at the genetic level with downregulated HWP1 expression, a surface protein specifically induced in the presence of
S. mutans
promoting the interkingdom interaction. Additionally, we show that
C. durum
can impede
C. albican
s systemic virulence in the
Galleria mellonella
infection model. This suggests that oral corynebacteria may act as a beneficial commensal species, exerting antifungal effects within polymicrobial communities and opening new avenues for managing polymicrobial diseases.

IMPORTANCE

Polymicrobial diseases such as severe early childhood caries (s-ECC) lack effective treatment options. Prevention, requiring a deeper understanding of ecological processes before the onset of disease symptoms, could be a potential strategy. In this context, we investigated how relatively abundant oral biofilm
Corynebacterium
species, which are associated with oral health, can interfere with the interkingdom partnership of
Streptococcus mutans
and
Candida albicans
. This partnership is a significant driver of tooth decay in s-ECC due to synergistic activities that increase cariogenicity. Our study reveals that oral corynebacteria, through the production of extracellular membrane vesicles, can disrupt the
S. mutans
and
C. albicans
partnership by inhibiting fungal hyphae formation. Additionally, the fatty acid cargo within these vesicles exhibits antifungal properties, suggesting that corynebacteria play a role in shaping microbial dynamics within the oral biofilm.
Cyclophilin A facilitates HIV-1 integration
Authors: Padron Adrian , Dwivedi Richa , Chakraborty Rajasree , Prakash Prem , Kim Kyusik , Shi Jiong , Ahn Jinwoo , Pandhare Jui , Luban Jeremy , Aiken Christopher , Balasubramaniam Muthukumar , Dash Chandravanu 
Published: October 2024

ABSTRACT

Cyclophilin A (CypA) binds to the HIV-1 capsid to facilitate reverse transcription and nuclear entry and counter the antiviral activity of TRIM5α. Interestingly, recent studies suggest that the capsid enters the nucleus of an infected cell and uncoats prior to integration. We have previously reported that the capsid protein regulates HIV-1 integration. Therefore, we probed whether CypA-capsid interaction also regulates this post-nuclear entry step. First, we challenged CypA-expressing (CypA
+/+
) and CypA-depleted (CypA
-/-
) cells with HIV-1 and quantified the levels of provirus. CypA-depletion significantly reduced integration, an effect that was independent of CypA’s effect on reverse transcription, nuclear entry, and the presence or absence of TRIM5α. In addition, cyclosporin A, an inhibitor that disrupts CypA-capsid binding, inhibited proviral integration in CypA
+/+
cells but not in CypA
-/-
cells. HIV-1 capsid mutants (G89V and P90A) deficient in CypA binding were also blocked at the integration step in CypA
+/+
cells but not in CypA
-/-
cells. Then, to understand the mechanism, we assessed the integration activity of the HIV-1 preintegration complexes (PICs) extracted from acutely infected cells. PICs from CypA
-/-
cells retained lower integration activity
in vitro
compared to those from CypA
+/+
cells. PICs from cells depleted of both CypA and TRIM5α also had lower activity, suggesting that CypA’s effect on PIC was independent of TRIM5α. Finally, CypA protein specifically stimulated PIC activity, as this effect was significantly blocked by CsA. Collectively, these results provide strong evidence that CypA directly promotes HIV-1 integration, a previously unknown role of this host factor in the nucleus of an infected cell.

IMPORTANCE
Interaction between the HIV-1 capsid and host cellular factors is essential for infection. However, the molecular details and functional consequences of viral-host factor interactions during HIV-1 infection are not fully understood. Over 30 years ago, Cyclophilin A (CypA) was identified as the first host protein to bind to the HIV-1 capsid. Now it is established that CypA-capsid interaction promotes reverse transcription and nuclear entry of HIV-1. In addition, CypA blocks TRIM5α-mediated restriction of HIV-1. In this report, we show that CypA promotes the post-nuclear entry step of HIV-1 integration by binding to the viral capsid. Notably, we show that CypA stimulates the viral DNA integration activity of the HIV-1 preintegration complex. Collectively, our studies identify a novel role of CypA during the early steps of HIV-1 infection. This new knowledge is important because recent reports suggest that an operationally intact HIV-1 capsid enters the nucleus of an infected cell.
Identification of critical residues for RNA binding of nairovirus nucleoprotein
Authors: Ohta Keisuke , Saka Naoki , Nishio Machiko 
Published: October 2024

ABSTRACT

Orthonairovirus haemorrhagiae (CCHFV) is a tick-borne virus of the
Orthonairovirus
genus. CCHFV nucleoprotein binds to the viral genomic RNA, which is essential for transcription and replication. Based on structural analyses, several residues located in positively-charged regions of CCHFV nucleoprotein have been indicated to be important for RNA binding. We investigated the effects of each residue on RNA binding using Orthonairovirus hazaraense (HAZV), a surrogate model for CCHFV, to address the lack of detailed investigations. RNA immunoprecipitation assay revealed that the four basic amino acid residues (R59, R178, K414, and K465) are critical for RNA binding. All of these residues are located within the same positively-charged region. Basicity of these residues was also found to be necessary for RNA binding. Recombinant HAZVs carrying RNA binding-defective mutants of nucleoprotein could not be rescued. We identified the critical residues for RNA binding of nairovirus nucleoprotein. This study provides new insights into a detailed binding model between nairovirus nucleoprotein and its genomic RNA.

IMPORTANCE
We sought to identify the important residues for RNA binding of nairovirus nucleoprotein using Orthonairovirus hazaraense, a surrogate model for Orthonairovirus haemorrhagiae. The four basic amino acid residues of Orthonairovirus hazaraense nucleoprotein were critical for RNA binding. Sufficient RNA-binding capacity of nucleoprotein was essential for successful virus replication. This study provides new insights into a detailed binding model between nairovirus nucleoprotein and its genomic RNA.
Effect of a microencapsulated complex of biofactors and antioxidants on the growth performance, plasma biochemistry, intestinal health, and immune and antioxidant status of broiler chickens challenged with cold stress
Authors: Oretomiloye Fisayo , Lahaye Ludovic , Adewole Deborah 
Published: October 2024

The study examined the effects of a microencapsulated complex of biofactors and antioxidants (P(BF + AOx)) on growth and health status of broiler chickens challenged with cold stress. Day-old broilers were allotted to four treatments in a 2 × 2 factorial design with two dietary treatments: (1) Control (CON; corn–wheat–soybean-based) and (2) CON + 0.015% P(BF + AOx), and two thermal treatments: (1) Thermoneutral (TN; 29 °C ± 1 on days 8–10, 54 h) and (2) Cold stress (CS; 20 °C on days 8–10, 54 h). Treatments were allocated to six replicates, with eight chicks/replicate. Growth performance was measured weekly from days 0–21. On day 14, two birds/cage were euthanized. Cold stress reduced ( P < 0.05) total antioxidant capacity (TAC), serum IgM, jejunal villus height (VH), villus width (VW), and VH:crypt depth (VH:CD). Irrespective of CS, P(BF + AOx) improved ( P < 0.05) feed intake (631 vs. 592 g/bird), body weight (BW) (383 vs. 349 g/bird), BW gain (337 vs. 301 g/bird) up to day 14, and plasma TAC. Regardless of the challenge model, P(BF + AOx) increased ( P < 0.05) duodenal VW, VH:CD, jejunal, and ileal VH:CD, and the relative abundance of cecal Intestinimonas and Colidextribacteria, compared to the CON. In conclusion, CS altered broiler blood parameters and gut morphology, but 0.015% P(BF + AOx) improved early life growth performance, TAC, and gut health, irrespective of CS, suggesting that it could be an effective strategy to support overall health and performance.