bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and genetic risk factors associated with neonatal severe hyperbilirubinemia: a case–control study based on the China Neonatal Genomes Project
Authors: Wang Xiao , Xiao Tiantian , Wang Jin , Wu Bingbing , Wang Huijun , Lu Yulan , Wang Yaqiong , Chen Bin , Hu Liyuan , Cao Yun , Zhang Rong , Cheng Guoqiang , Wang Laishuan , Li Zhihua , Dong Xinran , Yang Lin , Zhou Wenhao
Published: January 2024

Objective: We aimed to investigate the clinical and genetic risk factors associated with neonatal severe unconjugated hyperbilirubinemia.

Methods: This was a retrospective, 1:1 matched, case–control study. We included 614 neonates diagnosed with severe unconjugated hyperbilirubinemia (serum total bilirubin level ≥425 μmol/L or serum total bilirubin concentration that met exchange transfusion criteria) from the China Neonatal Genomes Project in Children’s Hospital of Fudan University. Clinical exome sequencing data were analyzed using a data analysis pipeline of Children’s Hospital of Fudan University. The factors associated with severe unconjugated hyperbilirubinemia were assessed using univariable and multivariable logistic regression analyses. Interaction analyses were examined between clinical and genetic risk factors.

Results: ABO/Rh incompatibility hemolysis (odds ratio [OR] 3.36, 95% confidence interval [CI] 2.32–4.86), extravascular hemorrhage (OR 2.95, 95% CI 2.24–3.89), weight loss (OR 5.46, 95% CI 2.88–10.36), exclusive breastmilk feeding (OR 3.56, 95% CI 2.71–4.68), and the homozygous mutant of UGT1A1 211G>A (OR 2.35, 95% CI 1.54–3.59) were all identified as factors significantly associated with severe unconjugated hyperbilirubinemia. The presence of UGT1A1 211G>A mildly increased the risk of severe unconjugated hyperbilirubinemia caused by ABO/Rh incompatibility hemolysis (OR 3.98, 95% CI 2.19–7.23), although the effect is not statistically significant.

Conclusion: ABO/Rh incompatibility hemolysis, extravascular hemorrhage, weight loss, exclusive breastmilk feeding, and the homozygous mutant of UGT1A1 211G>A were found to be risk factors for severe unconjugated hyperbilirubinemia. Clinical factors remain the most crucial and preventable determinants in managing severe unconjugated hyperbilirubinemia, with a minimal genetic contribution. The establishment of preconception care practices and the reinforcement of screening for the aforementioned risk factors are essential steps for preventing severe unconjugated hyperbilirubinemia.
Genetically predicted circulating levels of cytokines and the risk of oral cavity and pharyngeal cancer: a bidirectional mendelian-randomization study
Authors: Wu Kehan , Sun Qianhui , Liu Dongxu , Lu Jiayi , Wen Deyu , Zang Xiyan , Gao Li
Published: January 2024

Background: Epidemiological research has established associations between various inflammatory cytokines and the occurrence of oral cancer and oropharyngeal cancer (OCPC). We performed a Mendelian randomization (MR) analysis to systematically investigate the causal relationship between inflammatory cytokines and OCPC.

Methods: We performed a bidirectional two-sample MR analysis using OCPC from 12 studies (6,034 cases and 6,585 controls) and genome-wide association study (GWAS) results for 41 serum cytokines from 8,293 Finns, respectively. Inverse variance weighting was used as the primary MR method and four additional MR methods (MR Egger, Weighted median, Simple mode, Weighted mode) were used to examine genetic associations between inflammatory traits and OCPC, and Cochran’s Q test, MR-Egger intercept, leave-one-out analysis, funnel plot, and multivariate MR (MVMR) analysis were used to assess the MR results.

Results: The results suggested a potential association between high gene expression of Macrophage inflammatory protein-1α (MIP1α/CCL3) and an increased risk of OCPC (Odds Ratio (OR): 1.71, 95% Confidence Interval (CI): 1.09–2.68, p = 0.019). Increasing the expression levels of the interleukin-7 (IL-7) gene by 1 standard deviation reduced the risk of OCPC (OR: 0.64, 95%CI: 0.48–0.86, p = 0.003). In addition, multivariate Mendelian randomization analysis also showed the same results (MIP1α/CCL3, OR: 1.002, 95% CI: 0.919–1.092, p = 0.044; IL-7, OR: 0.997, 95% CI: 0.994–0.999, p = 0.011). Conversely, there was a positive correlation between genetic susceptibility to OCPC and an increase in Interleukin-4 (IL-4) (OR: 1.04, 95%CI: 1.00–1.08, p = 0.027).

Conclusion: Our study systematically assessed the association between inflammatory cytokines and the risk of OCPC. We identified two upstream regulatory factors (IL-7 and CCL3) and one downstream effector factor (IL-4) that were associated with OCPC, offering potential avenues for the development of novel treatments.
A chimeric antigen receptor-based cellular safeguard mechanism for selective in vivo depletion of engineered T cells
Authors: Svec Mortimer , Dötsch Sarah , Warmuth Linda , Trebo Manuel , Fräßle Simon , Riddell Stanley R. , Jäger Ulrich , D’Ippolito Elvira , Busch Dirk H.
Published: January 2024

Adoptive immunotherapy based on chimeric antigen receptor (CAR)-engineered T cells has exhibited impressive clinical efficacy in treating B-cell malignancies. However, the potency of CAR-T cells carriethe potential for significant on-target/off-tumor toxicities when target antigens are shared with healthy cells, necessitating the development of complementary safety measures. In this context, there is a need to selectively eliminate therapeutically administered CAR-T cells, especially to revert long-term CAR-T cell-related side effects. To address this, we have developed an effective cellular-based safety mechanism to specifically target and eliminate the transferred CAR-T cells. As proof-of-principle, we have designed a secondary CAR (anti-CAR CAR) capable of recognizing a short peptide sequence (Strep-tag II) incorporated into the hinge domain of an anti-CD19 CAR. In in vitro experiments, these anti-CAR CAR-T cells have demonstrated antigen-specific cytokine release and cytotoxicity when co-cultured with anti-CD19 CAR-T cells. Moreover, in both immunocompromised and immunocompetent mice, we observed the successful depletion of anti-CD19 CAR-T cells when administered concurrently with anti-CAR CAR-T cells. We have also demonstrated the efficacy of this safeguard mechanism in a clinically relevant animal model of B-cell aplasia induced by CD19 CAR treatment, where this side effect was reversed upon anti-CAR CAR-T cells infusion. Notably, efficient B-cell recovery occurred even in the absence of any pre-conditioning regimens prior anti-CAR CAR-T cells transfer, thus enhancing its practical applicability. In summary, we developed a robust cellular safeguard system for selective in vivo elimination of engineered T cells, offering a promising solution to address CAR-T cell-related on-target/off-tumor toxicities.
Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action
Authors: Ben Abdallah Hakim , Bregnhøj Anne , Ghatnekar Gautam , Iversen Lars , Johansen Claus
Published: January 2024

Background

Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD).

Objectives

Our study aimed to investigate HSP90 as a novel target to treat AD.

Methods

Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNγ or TNF/IL-4) and a mouse model established by MC903 applications.

Results

In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1- (TNF, IL1B, IL6) and Th2-associated (CCL17, CCL22, TSLP) cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (Il1b, Il4, Il6, Il13), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model.

Conclusion

HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD.
Immunogenicity and protective efficacy of tuzin protein as a vaccine candidate in Leishmania donovani-infected BALB/c mice
Authors: Devender Moodu , Sebastian Prince , Maurya Vijay Kumar , Kumar Krishan , Anand Anjali , Namdeo Madhulika , Maurya Radheshyam
Published: January 2024

Visceral leishmaniasis (VL) is referred to as the most severe and fatal type of leishmaniasis basically caused by Leishmania donovani and L. infantum. The most effective method for preventing the spread of the disease is vaccination. Till today, there is no promising licensed vaccination for human VL. Hence, investigation for vaccines is necessary to enrich the therapeutic repertoire against leishmaniasis. Tuzin is a rare trans-membrane protein that has been reported in Trypanosoma cruzi with unknown function. However, tuzin is not characterized in Leishmania parasites. In this study, we for the first time demonstrated that tuzin protein was expressed in both stages (promastigote and amastigote) of L. donovani parasites. In-silico studies revealed that tuzin has potent antigenic properties. Therefore, we analyzed the immunogenicity of tuzin protein and immune response in BALB/c mice challenged with the L. donovani parasite. We observed that tuzin-vaccinated mice have significantly reduced parasite burden in the spleen and liver compared with the control. The number of granulomas in the liver was also significantly decreased compared with the control groups. We further measured the IgG2a antibody level, a marker of Th1 immune response in VL, which was significantly higher in the serum of immunized mice when compared with the control. Splenocytes stimulated with soluble Leishmania antigen (SLA) displayed a significant increase in NO and ROS levels compared with the control groups. Tuzin-immunized and parasite-challenged mice exhibit a notable rise in the IFN-γ/IL-10 ratio by significantly suppressing IL-10 expression level, an immunosuppressive cytokine that inhibits leishmanicidal immune function and encourages disease progression. In conclusion, tuzin immunizations substantially increase the protective immune response in L. donovani-challenged mice groups compared with control.
A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection
Authors: Pattnaik Aryamav , Dhalech Adeeba H. , Condotta Stephanie A. , Corn Caleb , Richer Martin J. , Snell Laura M. , Robinson Christopher M.
Published: January 2024

Background

Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality.

Methods

We inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection.

Results

We found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model.

Conclusions

Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.
IgG in the control of FcεRI activation: a battle on multiple fronts
Authors: Storni Federico , Vogel Monique , Bachmann Martin F. , Engeroff Paul
Published: January 2024

The rising global incidence of IgE-mediated allergic reactions poses a significant challenge to the quality of life of affected individuals and to healthcare systems, with current treatments being limited in effectiveness, safety, and disease-modifying capabilities. IgE acts by sensitizing the high-affinity IgE receptor FcεRI expressed by mast cells and basophils, tuning these cells for inflammatory degranulation in response to future allergen encounters. In recent years, IgG has emerged as an essential negative regulator of IgE-dependent allergic inflammation. Mechanistically, studies have proposed different pathways by which IgG can interfere with the activation of IgE-mediated inflammation. Here, we briefly summarize the major proposed mechanisms of action by which IgG controls the IgE-FcεRI inflammatory axis and how those mechanisms are currently applied as therapeutic interventions for IgE-mediated inflammation.
A genomic approach for the identification of population management units for the dolphinfish (Coryphaena hippurus) in the eastern Pacific
Authors: Mar-Silva Adan Fernando , Díaz-Jaimes Píndaro , Ochoa-Zavala Maried , Ortega-Garcia Sofia , Sotil Giovanna , Alegre Ana , Escarabay Teddy , Elias Esteban , Carvajal-Rodríguez Jose Miguel
Published: January 2024

In the Tropical Eastern Pacific dolphinfish (TEP) Corypahena hippurus is part of commercial, recreational, and artisanal fisheries and is also caught incidentally by the tuna purse-seine and longline fisheries. Defining the existence of differenced populations in exploited species for being considered independent management units is crucial for conservation plans. However, there is a great uncertainty about the species population genetic structure across the TEP. To investigate it and to identify possible management units for conservation purposes this study was carried out, based on two SNPs datasets of 3867 and 3220 SNPs for young of the year (YOY) and adult individuals, respectively, obtained through NGS protocols. Sampling covered the species’ range distribution in the Tropical Eastern Pacific and was structured into YOY and adult individuals in order to discard the effects of migrating individuals into sampled locations. Our results revealed slight but significant differences among locations occupying the latitudinal limits of the species distribution at transitional areas between tropical and subtropical waters. These areas are characterized by strong seasonal variations in sea surface temperature and limit the prevalence of populations in these extremes. Genetic differences also seem to be related to spatial separation of locations as the northernmost (Los Cabos) and southernmost (Peru) locations including a set of oceanic samples, showed the highest levels of genetic differentiation. Whereas were detected barriers to gene flow among spatially separated locations for YOY individuals probably related to site fidelity, clear limitations to gene flow between Mexico and Central America locations were observed probably related to oceanic circulation in the area. Design management strategies in countries where the dolphinfish is explored is of primary interest to preserve genetic resources. It is necessary to define the existence of genetic differences of populations for species that are highly dependent on environmental factors limiting its distributional range as is the case of the dolphinfish.
Framing seascape connectivity modeling to prioritize marine conservation effort in China’s coastal sea
Authors: Kang Yiyang , Lin Yuxuan , Chen Zhixue , Zhang Xinyi , Li Yi
Published: January 2024

Anthropogenic disturbances and climate change are projected to become leading drivers of biodiversity loss and ecological connectivity degradation in marine ecosystems. However, the lack of quantitative understanding for seascape connectivity modeling hinders our ability in providing large-scale marine conservation guidance. By applying well-established theories and tools in landscape connectivity study and marine-specific indicators, we proposed a framework to evaluate the resistance-based seascape connectivity among marine habitats and Marine Protected Areas (MPAs) across China’s coastal sea. The spatial vulnerability of marine habitats was further assessed to prioritize conservation effort. Our results showed that 82% of China’s coastal seas were covered with middle to high level of resistance for migratory marine species, mainly due to concentrated inshore anthropogenic disturbances such as ship traffic and ocean pollution. With the modeled migration distances of different species guilds from short-range (25 km) to long-range (100 km), the area percentage of connected corridors increased from 12.02% to 44.68% in the study area. Vulnerable areas were identified as high resistance (high exposure) and abundant threatened species (high sensitivity) but with small number of connected corridors (low adaptive capacity), primarily distributed in offshore regions of Yellow Sea and East China Sea. Collectively, inshore regions with high anthropogenic disturbances warrant regulation and mitigation in major coastal cities and ports. While the lack of interconnected networks for offshore regions prioritized efforts to enhance seascape connectivity through the establishment of MPA network. Sensitive species groups require more attention in future marine conservation, including threatened populations, climate refugees of marine species, and species with limited movement ranges. This study highlights the potential of developing seascape connectivity model based on landscape theories, and the importance of seascape connectivity study in guiding evidence-based marine conservation strategies.
Grain-size, coarse fraction lithology and clay mineral compositions of surface sediments from Ross Sea, Antarctica: implications for their provenance and delivery mode
Authors: Wu Li , Li Longwei , Wang Rujian , Shao Hebin , Chen Yi , Lin Zipei , Liu Yue , Xiao Wenshen , Xu Ran
Published: January 2024

Knowledge on spatial distribution, provenance and delivery mode of surface sediment aids in interpretation of nearby sediment records for paleoenvironmental reconstruction. Such knowledge, however, remains largely unknown for the modern Ross Sea, Antarctica: a key region for understanding the dynamical behavior of Antarctic Ice Sheet over geological past. In this study, we address this gap by analyzing the grain-size distribution, coarse fraction (>250 μm) lithology, and clay mineralogy of a set of surface sediment samples covering the whole Ross Sea continental shelf. Our data reveals that the sediments were mostly delivered by icebergs and bottom currents. Iceberg delivery was significantly controlled by factors such as water depth, proximity to the iceberg sources, and invasion of the Modified Circumpolar Deep Water. Bottom current activity was stronger in the Western Ross Sea (WRS) than in the Eastern Ross Sea (ERS), controlled by the formation and transport of Dense Shelf Water. Three major sorts of coarse fraction were identified, including the quartz-rich Iceberg Rafted Detritus (IRD) originating from West Antarctic glaciers and primarily distributed in the ERS, the mafic rocks-rich IRD from the Ferrar Group as well as the McMurdo Volcanic Group and mainly found in the WRS, and deformed silt traced back to the grounding zone of the David Glacier-Dragalski Ice Tongue system. The distribution of clay minerals is dominated by a distinct binary mixing pattern. Smectite and kaolinite are mainly present in the ERS, derived from beneath the West Antarctic Ice Sheet. Higher illite and chlorite contents were found offshore of the Southern Victoria Land, derived from the East Antarctic craton. Overall, these results demonstrate that the glaciers draining into Ross Sea from both the East and West Antarctic Ice Sheets are highly dynamical in the context of modern climate conditions, with implications for potential contribution to future sea level rise.
Research progress of plant medicine and Chinese herbal compounds in the treatment of rheumatoid arthritis combined with osteoporosis
Authors: Gu Zhuoxu , Zhou Guanghui , Zhang Xianquan , Liang Guihong , Xiao Xiao , Dou Yaoxing
Published: January 2024

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. The clinical manifestations of various joint pain and bone destruction are common. RA has a high disability rate and is closely related to local and systemic osteoporosis (OP). RA can occur at any age, however, its incidence increases with age. Most patients are 40 to 50 years old with an incidence among women approximately 3 to 5 times more than among men. Osteoporosis is a kind of metabolic bone disease characterized by bone mass and bone microstructure damage and is one of the common complications of RA. Currently, in the clinic, more patients develop RA with OP symptoms. Therefore, both OP and RA-related factors should be considered in the OP treatment of RA. Currently, there is more and more research on RA combined with OP drugs, including basic drugs, bone resorption inhibitors, bone formation promoters, and anti-rheumatic drugs to improve the condition. The high cost or limited efficacy of certain Western drugs, coupled with their potential for adverse reactions during treatment highlight the pressing need for novel pharmaceuticals in clinical practice. In recent years, traditional Chinese medicine (TCM) can improve the bone formation and bone resorption indexes of patients with RA, regulate the balance of osteoclasts and osteoblasts, and regulate the immune inflammatory response, so as to treat RA combined with OP. This article discusses the advancements in single Chinese medicine and Chinese medicine combination treatments for RA complicated with OP, focusing on the mechanism of action and syndrome differentiation and classification, to offer new ideas for future clinical prevention and treatment.
Low grade of satisfaction related to the use of current systemic therapies among pustular psoriasis patients: a therapeutic unmet need to be fulfilled
Authors: Coscarella Giulia , Falco Gennaro Marco , Palmisano Gerardo , Ippoliti Elena , De Luca Eleonora , Gori Niccolò , Di Nardo Lucia , Caldarola Giacomo , De Simone Clara , Chiricozzi Andrea , Peris Ketty
Published: January 2024

Introduction

Pustular psoriasis is considered a separate entity from plaque psoriasis and can be categorized as generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau, or palmoplantar pustulosis (PPP). Current guidelines mostly include treatment options that have not been specifically developed for the treatment of pustular psoriasis. The majority of them does not have indication for the treatment of pustular psoriasis. Their effectiveness and safeness have been described in small cohort-based studies or case series with a low level of evidence. Previous studies evaluated treatment response through physician-based assessment but none reported patient satisfaction to treatment, quality of life and patient perception of disease severity during systemic therapies, particularly with biologics commonly used in plaque psoriasis. This study aimed to investigate patient satisfaction to treatment and patients’ quality of life during treatment, correlating patient-reported outcomes with residual disease severity.

Methods

A cross-sectional, cohort-based, single center study included patients affected by pustular psoriasis undergoing treatment with systemic agents. Demographic, clinical characteristics were collected. Treatment satisfaction as well as disease severity were assessed through dedicated assessment scores.

Results

A total of 31 patients affected by GPP or PPP were included. Despite biologic treatment, 80.6% of patients continued to experience mild-to-severe disease activity, with discrepancies between patient and physician assessments. Patients reported a substantial impairment in their quality of life, with notable limitations in physical activity and emotional distress. Mental health conditions, such as depression and anxiety disorders, were common. Treatment satisfaction varied, with moderate scores for effectiveness and convenience. Only a small proportion of patients (41.9%) reported complete or high overall treatment satisfaction. GPP and PPP subcohorts exhibited similar quality of life and treatment satisfaction levels.

Discussion

This study highlights the suboptimal control of PP despite biologic therapies, resulting in a significant impact on patients’ quality of life and treatment satisfaction. The findings highlight the need for specific therapies and standardized guidelines for managing PP. New targeted therapies, such as spesolimab, hold promise for optimizing treatment satisfaction and improving patients’ quality of life in this challenging condition. Future research should focus on refining treatment strategies to address the unmet needs of PP patients comprehensively.
Implementing Horizon Scanning as a tool for the strategic development of regulatory guidelines for nanotechnology-enabled health products
Authors: Rodríguez-Gómez Francisco D. , Monferrer Dominique , Penon Oriol , Rivera-Gil Pilar
Published: January 2024

Strategic regulatory development is essential to ensure that new innovations in nanotechnology-enabled health products (NHPs) successfully reach the market and benefit patients. Currently, the lack of specific regulatory guidelines for NHPs is considered one of the primary causes of the so-called “valley of death” in these products, impacting both current and future advancements. In this study, we have implemented a methodology to anticipate key trends in NHP development and compare them with the current regulatory landscape applicable to NHPs. This methodology relies on Horizon Scanning, a tool commonly used by policymakers to foresee future needs and proactively shape a regulatory framework tailored to those needs. Through the application of this methodology, different trends in NHP have been identified, notably NHPs for drug delivery and dental applications. Furthermore, the most disruptive elements involve NHPs that are multicomposite and multifunctional, harnessing nano-scale properties to combine therapeutic and diagnostic purposes within a single product. When compared with the regulatory landscape, current regulations are gradually adapting to accommodate emerging trends, with specific guidelines being developed. However, for the most disruptive elements, multicomposite and multifunctional NHPs, their novelty still poses significant regulatory challenges, requiring a strategic development of guidelines by regulatory agencies to ensure their safe and effective integration into healthcare practices. This study underscores the importance of proactive regulatory planning to bridge the gap between NHP innovation and market implementation.
Case report: tracheobronchial diverticulum, a potential risk for diving?
Authors: Qing Long , Wang Yan , Zhang Meng , Pu Qinqin , Cai Wanwan , Pan Yaping , Xia Delin
Published: January 2024

Tracheobronchial diverticulum (TBD) is an asymptomatic, benign cystic lesion outside the lumen of the trachea and bronchus. This is the first report case of a SCUBA (self contained underwater breathing apparatus) diver diagnosed with TBD, which is a potential risk to diving. No literature or guideline is available so far on the diving fitness for patients with congenital or acquired TBD condition. A healthy 26-year-old male professional diver has records of SCUBA diving up to a depth of 40 meters sea water. He did not have any diving-related injuries or symptoms during his career and had no history of smoking, drinking, or other special illnesses except for a COVID-19 infection. A tracheal diverticulum was found accidentally by computed tomography (CT), but its communication with the trachea was not clear initially. Therefore, high-resolution CT and electronic bronchoscopy were done to clarify the situation of the diverticulum and identify the diving risk. High-resolution CT showed a possible opening in the diverticulum, but this was not seen under electronic bronchoscopy. Although a potential opening was shown in high-resolution CT, the lack of visual bronchoscopic evidence made it likely to be a dead cavity. As there is a higher theoretical risk of barotrauma during decompression, leading to pneumomediastinum, hemorrhage, or arterial gas embolism, the current clinical consensus is that air-containing tissue should be regarded as a relative contraindication for diving. Overall, it is recommended that the diver should dive carefully and avoid ascending too rapidly.
Caryophyllene-type sesquiterpenes from the endophytic fungus Pestalotiopsis lespedezae through an OSMAC approach
Authors: Yu Xiaoqin , Müller Werner E. G. , Frank Marian , Gao Ying , Guo Zhiyong , Zou Kun , Proksch Peter , Liu Zhen
Published: January 2024

Two new caryophyllene-type sesquiterpenes pestalotiopsins U and V (1 and 2) and three known compounds pestalotiopsin B (7), pestaloporinate B (8), and pestalotiopsin C (9) were isolated by the cultivation of the endophytic fungus Pestalotiopsis lespedezae on solid rice medium, while four additional new caryophyllene pestalotiopsins W–Z (3–6) were obtained when 3.5% NaI was added to the fungal culture medium. The structures of the new compounds were determined by HRESIMS and 1D/2D nuclear magnetic resonance data. Compounds 1–9 were tested for cytotoxicity against the mouse lymphoma cell line L5178Y, but only 6 displayed significant activity with an IC50 value of 2.4 μM.
Association between gut microbiota and peptic ulcer disease, particularly gastric ulcer and duodenal ulcer: a two-sample Mendelian randomization study
Authors: Dong Zhenhua , Yu Kai , Xin Yuchao , Gao Xulei , Bu Fan , Zhao Dingliang , Ren Donghui , Lu Ji , Wang Daguang
Published: January 2024

Background

Recent an observational study has suggested a potential connection between gut microbiota (GM) and peptic ulcer diseases (PUDs), particularly gastric ulcer (GU) and duodenal ulcer (DU). However, the causal connection remains unsure.

Methods

A two-sample Mendelian randomization (MR) is carried out to explore the connection between the GM and DU or GU. Data on the GM comes from the MiBioGend database, and GU or DU data are based on the FinnGen database. One group of single nucleotide polymorphisms (SNPs) (P < 5 × 10−8) are served as instrumental variables (IVs). To obtain a more comprehensive conclusion, the other SNPs (P < 1 × 10−5) are selected as IVs. Inverse variance weighting (IVW) is used to determine the causal relationship.

Results

At the level of P < 1 × 10−5, the IVW analysis suggests that Clostridiaceae1, Butyriccoccus, and Peptcoccus have harmful effects on GU, while LachnospiraceaeUCG004 and MollicutesRF9 have beneficial effects on GU. Then, in the case of DU, the IVW analysis suggested that Lentisphaeria, Negativicutes, Clostridiaceae1, ClostridiumseMnsustricto1, ErysipelotrichaceaeUCG003, LachnospiraceaeNC2004group, Selenomonadale, Victivallales, and Lentisphaerae have harmful effects, while Catenibacterium, Escherichia.Shigella, LachnospiraceaeUCG008, and Sutterella have beneficial effects. When P < 5 × 10−8, IVW analysis suggests that GM has no significant influence on GU or DU.

Conclusion

This two-sample MR indicates a causal relationship between GM and GU or DU.
Understanding Phakopsora pachyrhizi in soybean: comprehensive insights, threats, and interventions from the Asian perspective
Authors: Hossain Md. Motaher , Sultana Farjana , Yesmin Laboni , Rubayet Md. Tanbir , Abdullah Hasan M. , Siddique Shaikh Sharmin , Bhuiyan Md. Abdullahil Baki , Yamanaka Naoki
Published: January 2024

Soybean (Glycine max L.) is an important crop in Asia, accounting for 17% of global soybean cultivation. However, this crop faces formidable challenges from the devastating foliar disease, Asian Soybean Rust (ASR), caused by Phakopsora pachyrhizi, a biotrophic fungus with a broad host range, causing substantial yield losses (10–100%) in Asia. This comprehensive review consolidates knowledge on ASR, encompassing its impact, historical perspectives, genetic diversity, epidemic drivers, early detection, risk assessment, and sustainable management strategies of ASR in the region. ASR has expanded globally from Asia, reaching Africa and Americas, driven by wind-dispersed urediniospores. Genetic diversity studies reveal the complexity of P. pachyrhizi, with distinct populations exhibiting varying virulence patterns. Factors affecting ASR epidemics in Asia include host susceptibility, landscape connectivity, climate, and environmental conditions. Understanding the interplay of these factors is essential for early intervention and control of ASR in soybean fields. Effectively managing ASR can exploit the utilization of diverse intervention strategies, encompassing disease forecasting, automated early detection, disease resistance, fungicide application, and biological control. A pivotal aspect of successful, sustainable disease management lies in reducing the ASR pathogen virulence and preventing it from developing fungicide resistance, while the highpoint of effectiveness in disease control is attained through a synergistic approach, integrating various strategies. In summary, this comprehensive review provides insights into multifaceted approaches that contribute to the development of sustainable and economically impactful soybean production in the face of the persistent threat of ASR in Asia.
Unlocking the potential of Rosa roxburghii Tratt polyphenol: a novel approach to treating acute lung injury from a perspective of the lung-gut axis
Authors: Tang Li , Zhang Shuo , Zhang Min , Wang Pengjiao , Liang Guiyou , Gan Zhitong , Gao Xiuli
Published: January 2024

Introduction

Acute lung injury (ALI) is a serious respiratory disease characterized by progressive respiratory failure with high morbidity and mortality. It is becoming increasingly important to develop functional foods from polyphenol-rich medicinal and dietary plants in order to prevent or alleviate ALI by regulating intestinal microflora. Rosa roxburghii Tratt polyphenol (RRTP) has significant preventive and therapeutic effects on lipopolysaccharide-induced ALI mice, but its regulatory effects on gut homeostasis in ALI mice remains unclear.

Methods

This study aims to systematically evaluate the ameliorative effects of RRTP from the perspective of “lung-gut axis” on ALI mice by intestine histopathological assessment, oxidative stress indicators detection and short-chain fatty acids (SCFAs) production, and then explore the modulatory mechanisms of RRTP on intestinal homeostasis by metabolomics and gut microbiomics of cecal contents.

Results

The results showed that RRTP can synergistically exert anti-ALI efficacy by significantly ameliorating intestinal tissue damage, inhibiting oxidative stress, increasing SCFAs in cecal contents, regulating the composition and structure of intestinal flora, increasing Akkermansia muciniphila and modulating disordered intestinal endogenous metabolites.

Discussion

This study demonstrated that RRTP has significant advantages in adjuvant therapy of ALI, and systematically clarified its comprehensive improvement mechanism from a new perspective of “lung-gut axis”, which provides a breakthrough for the food and healthcare industries to develop products from botanical functional herbs and foods to prevent or alleviate ALI by regulating intestinal flora.
Pan-cancer analysis of SERPINE family genes as biomarkers of cancer prognosis and response to therapy
Authors: Liu Yating , Li Xinyu , Chen Shanshan , Zhu Changyu , Shi Yijun , Dang Shoutao , Zhang Weitao , Li Wei
Published: January 2024

Background: Serine protease inhibitor E (SERPINE) family genes participate in the tumor growth, cancer cell survival and metastasis. However, the SERPINE family members role in the prognosis and their clinical therapeutic potentials in various human cancer types have not been elaborately explored.

Methods: We preliminarily analyzed expression levels and prognostic values of SERPINE family genes, and investigated the correlation between SERPINEs expression and tumor microenvironment (TME), Stemness score, clinical characteristic, immune infiltration, tumor mutational burden (TMB), immune subtype, and drug sensitivity in pan-cancer, which based on updated public databases and integrated some bioinformatics analysis methods. In addition, we conducted the enrichment analysis of SERPINEs from DAVID and KOBAS databases.

Results: SERPINE1, SERPINE2, and SERPINE3 expression were upregulated in nine cancers, twelve cancers, and six cancers, respectively. The expression of SERPINE family genes was associated with the prognosis in several cancers from The Cancer Genome Atlas (TCGA). Furthermore, SERPINE family genes expression also had a significant relation to stromal and immune scores, and RNA stemness score and DNA stemness score in pan-cancer. SERPINE1 and SERPINE2 expression significantly increased in tumor advanced stage in colon adenocarcinoma (COAD). Results showed that SERPINE1 and SERPINE2 expression were negatively related with B cells and Monocytes, respectively. SERPINE2 expression had a significantly positive relation with B cells and Macrophages. In terms of TMB, SERPINE1, SERPINE2, and SERPINE3 were found to associated with TMB in seven cancers, fourteen cancers, and four cancers, respectively. Moreover, all SERPINE gene family members were significantly correlated with immune subtypes. SERPINE1 expression had a significantly positive or negative correlation with drug sensitivity.

Conclusion: The study indicated the great potential of SERPINE family genes as biomarkers for prognosis and provided valuable strategies for further investigation of SERPINE family genes as potential targets in cancer.
Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in frataxin-deficient human brain microvascular endothelial cells—implications for blood-brain barrier physiology in Friedreich’s ataxia
Authors: Smith Frances M. , Kosman Daniel J.
Published: January 2024

Introduction: Friedreich’s Ataxia (FRDA) is the most prevalent inherited ataxia. FRDA results from loss of Frataxin (FXN), an essential mitochondrial iron trafficking protein. FRDA starts with an early burst of neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by progressive brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both brain and heart homeostasis, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Previous reports have identified cytoskeletal alterations in non-barrier forming FRDA cell models, but physiological consequences are limited.

Methods: We investigated brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). We have knocked down FXN in immortalized human brain microvascular endothelial cells (hBMVEC), which compose the microcapillaries of the BBB, by using shRNA. We confirmed known cellular pathophysiologies of FXN-knockdown including decreased energy metabolism, markers of oxidative stress, and increased cell size.

Results: We investigated cytoskeletal architecture, identifying decreased filamentous actin and Occludin and Claudin-5 tight junction protein expression in shFXN hBMVECs. This was consistent with decreased transendothelial electrical resistance (TEER) and increased paracellular tracer flux during early barrier formation. shFXN hBMVEC start with only 67% barrier integrity of the controls, and flux a paracellular tracer at 800% of physiological levels.

Discussion: We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, co-incident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g., the cardiac microvasculature, loci of disease pathology in FRDA.
Exploring the inhibitory potential of in silico-designed small peptides on Helicobacter pylori Hp0231 (DsbK), a periplasmic oxidoreductase involved in disulfide bond formation
Authors: Roszczenko-Jasińska Paula , Giełdoń Artur , Mazur Dominika , Spodzieja Marta , Plichta Maciej , Czaplewski Cezary , Bal Wojciech , Jagusztyn-Krynicka Elzbieta K. , Bartosik Dariusz
Published: January 2024

Introduction:Helicobacter pylori is a bacterium that colonizes the gastric epithelium, which affects millions of people worldwide. H. pylori infection can lead to various gastrointestinal diseases, including gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Conventional antibiotic therapies face challenges due to increasing antibiotic resistance and patient non-compliance, necessitating the exploration of alternative treatment approaches. In this study, we focused on Hp0231 (DsbK), an essential component of the H. pylori Dsb (disulfide bond) oxidative pathway, and investigated peptide-based inhibition as a potential therapeutic strategy.

Methods: Three inhibitory peptides designed by computational modeling were evaluated for their effectiveness using a time-resolved fluorescence assay. We also examined the binding affinity between Hp0231 and the peptides using microscale thermophoresis.

Results and discussion: Our findings demonstrate that in silico-designed synthetic peptides can effectively inhibit Hp0231-mediated peptide oxidation. Targeting Hp0231 oxidase activity could attenuate H. pylori virulence without compromising bacterial viability. Therefore, peptide-based inhibitors of Hp0231 could be candidates for the development of new targeted strategy, which does not influence the composition of the natural human microbiome, but deprive the bacterium of its pathogenic properties.
Prediction of fatigue life of geometrically deviated steam turbine blades under thermo-mechanical conditions
Authors: Mashiachidi Makgwantsha Hermelton , Desai Dawood A.
Published: January 2024

This study explores the intricate factors affecting the fatigue life of steam turbine blades, encompassing steam flow-induced bending, centrifugal loading, vibration response, structural mistuning, and temperature-dependent influences. By focusing on the significance of mistuned steam turbine blades with varying blade geometries due to manufacturing tolerances, this research has paramount relevance for the power generation industries. By employing finite element analysis (FEA) software, a simplified, mistuned, scaled-down steam turbine bladed disk model was developed, considering temperature-dependent material properties. Initial FEA provided insights into the vibration characteristics and steady-state stress responses, with numerical stress distributions evaluated, which were subsequently exported to Fe-Safe software for fatigue life calculations based on centrifugal and harmonic sinusoidal pressure loadings. By investigating the vibration characteristics and response to geometric blade variations, this study affirmed the reliability of the developed FEA model, with findings highlighting the pronounced sensitivity of fatigue life to blade length, width, and thickness variations, in this order. However, in order to validate the developed numerical models, analytical life cycle assessments were calculated, which exhibited a discrepancy of under 3.37%, reinforcing the applicability of the developed numerical methodology to real-world scenarios involving mistuned steam turbine blades experiencing manufacturing deviations in blade geometry.
Transcutaneous electrical acupoint stimulation alleviates cerebral ischemic injury through the TLR4/MyD88/NF-κ B pathway
Authors: Wu Linyu , Tan Zixuan , Su Lei , Dong Fang , Xu Guangyu , Zhang Feng
Published: January 2024

This study was to explore whether transcutaneous electrical acupoint stimulation (TEAS) treatment could mediate inflammation, apoptosis, and pyroptosis of neuronal cells and microglia activation through the TLR4/MyD88/NF-κB pathway in the early stage of ischemic stroke. TEAS treatment at Baihui (GV20) and Hegu (LI4) acupoints of the affected limb was administered at 24, 48, and 72 h following middle cerebral artery occlusion/reperfusion (MCAO/R), with lasting for 30 min each time. Neurological impairment scores were assessed 2 h and 72 h after ischemia/reperfusion (I/R). TTC staining was used to evaluate the volume of brain infarction. The histopathologic changes of hippocampus were detected by H&E staining. WB analysis was performed to assess the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, and inflammation, apoptosis, pyroptosis-related proteins. TLR4 expression was measured using immunohistochemistry. The expression of inflammation-related proteins was also measured using ELISA. Immunofluorescence was used to detect the expression level of Iba1. Our findings demonstrated that TEAS intervention after I/R improved neurological function, reduced the volume of brain infarction, and mitigated pathological damage. Moreover, TEAS reduced the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, TNF-α, IL-6, Bax, NLRP3, cleaved caspase-1/pro caspase-1, IL-1β, IL-18, GSDMD, and Iba1 while enhancing Bcl-2 expression. Moreover, the protective effects of TEAS could be counteracted by lipopolysaccharide (LPS, a TLR4 agonist). In conclusion, TEAS can reduce cerebral damage and suppress inflammation, cell death, and microglia activation after ischemic stroke via inhibiting the TLR4/MyD88/NF-κB pathway.
One-year retention of gait speed improvement in stroke survivors after treatment with a wearable home-use gait device
Authors: Darcy Brianne , Rashford Lauren , Tsai Nancey T. , Huizenga David , Reed Kyle B. , Bamberg Stacy J. M.
Published: January 2024

Background

Gait impairments after stroke are associated with numerous physical and psychological consequences. Treatment with the iStride® gait device has been shown to facilitate improvements to gait function, including gait speed, for chronic stroke survivors with hemiparesis. This study examines the long-term gait speed changes up to 12 months after treatment with the gait device.

Methods

Eighteen individuals at least one-year post-stroke completed a target of 12, 30-minute treatment sessions with the gait device in their home environment. Gait speed was measured at baseline and five follow-up sessions after the treatment period: one  week, one  month, three months, six months, and 12 months. Gait speed changes were analyzed using repeated-measures ANOVA from baseline to each follow-up time frame. Additional analysis included comparison to the minimal clinically important difference (MCID), evaluation of gait speed classification changes, and review of subjective questionnaires.

Results

Participants retained an average gait speed improvement >0.21 m/s compared to baseline at all post-treatment time frames. Additionally, 94% of participants improved their gait speed beyond the MCID during one or more post-treatment measurements, and 88% subjectively reported a gait speed improvement.

Conclusion

Treatment with the gait device may result in meaningful, long-term gait speed improvement for chronic stroke survivors with hemiparetic gait impairments.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT03649217, identifier NCT03649217.