bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term trajectories of BMI and cumulative incident metabolic syndrome: A cohort study
Authors: Ying Ming , Hu Xiangming , Li Qiang , Dong Haojian , Zhou Yingling , Chen Zhujun
Published: December 2022

Background

Body mass index (BMI) has been widely recognized as a risk factor for metabolic syndrome (MetS). However, the relationship between the trajectory of BMI and cumulative incident MetS is still unclear. We investigate the associations of long-term measurements of BMI with MetS among young adults in the China Health and Nutrition Survey.

Methods

We enrolled individuals aged 10 to 20 at baseline with recorded BMI at each follow-up interview, and 554 participants were finally included in our study. The assessment and incidence of MetS were evaluated by blood tests and physical examinations in their adulthood. A latent class growth mixed model was used to identify three BMI trajectory patterns: a low baseline BMI with slow development (low-slow, n=438), a low baseline BMI with fast development (low-fast, n=66), and a high baseline BMI with fast development (high-fast, n=50). Logistic regression was used to explore the relationship between different BMI trajectories and the incidence of MetS.

Result

During a follow-up of 16 years, 61 (11.01%) participants developed MetS. The combination of elevated triglycerides and reduced high-density lipoprotein cholesterol was most frequent in diagnosed MetS. In multivariate adjusted models, the low-fast and high-fast BMI trajectories showed a significantly higher risk of MetS than those with the low-slow BMI trajectory (low-high: OR = 3.40, 95% CI: 1.14-10.13, P < 0.05; high-fast: OR = 5.81, 95% CI: 1.63-20.69, P < 0.05).

Conclusion

Our study identified three BMI trajectories in young adults and found that long-term measurements of BMI were also associated with cumulative incident MetS.
“Seminal testosterone”, rising viewpoint of local spermatogenesis in nonobstructive azoospermia: One center long-term bidirectional cohort study
Authors: Liu Huang , Zheng Houbin , Li Yuehua , Tang Yuqian , Peng Hongbo , Li Qianyi , Zhuang Jiaming , Zhou Yingyi , Zhou Yu , Tu Xiang’an , Zhang Xinzong
Published: December 2022

Objective

Reproductive hormones are a traditional good method to evaluate spermatogenesis but might not accurately represent local spermatogenesis. To find a more accurate method, seminal reproductive hormones were studied.

Methods

A bidirectional cohort study was performed. A total of 126 infertile men from 2018 to 2019 were retrospectively analyzed. They were divided into nonobstructive azoospermia (NOA), oligozoospermia (OLZ) and normal (NOR) groups. A prospective study was conducted on patients in the NOA and OLZ groups for 2 years. Microscopic testicular sperm extraction was performed for NOA patients, who were divided into a focal spermatogenesis group (FS) and an idiopathic azoospermia group (IA). Drug treatment was for OLZ patients, who were divided into a valid group (VA) and an invalid group (IN). The differences in sperm parameters and reproductive hormones were compared. ANOSIM analysis was used between and within groups. Pearson correlation analysis, CO inertia analysis and Proctor’s analysis were for relationships. ROC curve for the specificity and sensitivity. Time series analysis was for the trends between hormones and time.

Results

The b-FSH, b-LH, s-T and ΔT in the NOA group were significantly higher than those in the OLZ and NOR groups. However, the s-FSH, s-E2, s-P, ΔFSH, ΔLH, ΔP and ΔE2 were lower. Thirty-one NOA patients underwent MTSE, of whom 12 had sperm (FS) and 19 had no sperm (IA). The s-FSH and s-E2 of the FS group were higher than those of the IA group. Twenty-six OLZ patients completed 30 days of treatment, of which 11 had an improved sperm count (VA) and 15 had no (IN). The ΔT of the VA group was higher than that of the IN group. After follow-up for 2 years, 18 patients’ results showed that b-FSH, b-LH and s-T were different over time, with delays of 19, 3 and -19 days. SC is closely related to pH, s-FSH, s-LH, s-E2, s-P, s-T, b-FSH, b-LH, ΔFSH, ΔLH, ΔP, ΔE2 and ΔT. There were complex common trends and relationships between different kinds of hormones. s-FSH, s-LH, s-E2, s-P, s-T, b-FSH and b-LH were useful to judge spermatogenesis, of which s-T, b-FSH and b-LH were more sensitive. If s-T, b-FSH and b-LH reached 64.4, 9.4 and 4.7, respectively, their prediction performance was the strongest.

Conclusion

Seminal testosterone is sensitive for judging local spermatogenesis in nonobstructive azoospermia patients, which may be the direction of local spermatogenesis in nonobstructive azoospermia.

Clinical trial registration

http://www.chictr.org.cn/index.aspx, identifier ChiCTR2200060463.
Sublethal and intergenerational effects of fipronil on Binodoxys communis larvae based on transcriptome sequencing
Authors: Du Lingen , Zhao Likang , Zhu Xiangzhen , Wang Li , Zhang Kaixin , Li Dongyang , Ji Jichao , Niu Lin , Luo Junyu , Cui Jinjie , Gao Xueke
Published: December 2022

Fipronil is widely used in the agricultural world as an efficient phenylpyrazole insecticide to control pests. Binodoxys communis is a key parasitic natural enemy of major homopteran pests and can successfully control the population of pests such as cotton aphids. It has not yet been studied what effects would sublethal doses of fipronil have on Binodoxys communis larvae. Here, this study evaluated the effect of fipronil on Binodoxys communis larvae and analyze the transcriptome results. The results showed that LC10 (1.19 mg/L) and LC25 (1.73 mg/L) had significant negative effects on the survival rate and parasitism rate of F0 generation. Moreover, exposure to high concentrations (LC25) of fipronil still had obvious passive effect on the F1 generation of Binodoxys communis. These results indicated that sublethal doses of fipronil have malignant effects on the biological functions of parasitoids and their offspring. The results of transcriptome analysis showed that differentially expressed genes (DEGs) of Binodoxys communis after LC10 treatment are mainly related to immunity and detoxification. LC25 treatment instead resulted in changes in the expression of genes related to nutrition, energy and metabolism reactions. Seven of the identified DEGs were selected for real-time fluorescence quantitative PCR analysis. To the best of our knowledge, this is the first report to evaluate the sublethal, intergenerational, and transcriptomic side effects of fipronil on larvae of parasitic natural pest enemies. Our findings provide data to accurately assess the risk of fipronil usage on Binodoxys communis larvae, and provide important theoretical support for the comprehensive prevention and control of natural enemies and pesticides.
Replenishing the Indus Delta through multi-sector transformation
Authors: Awais Muhammad , Vinca Adriano , Parkinson Simon , McPherson Madeleine , Byers Edwards , Willaarts Barbara , Muhammad Abubakr , Riahi Keywan
Published: December 2022

The Indus River Basin (IRB) is a severely water-stressed and rapidly developing home to an estimated 250 million people in South Asia. An acute deficit of environmental flows (EFs) in the basin’s delta negatively impacts geomorphology and surrounding ecosystems. Here, a sub-national model of the IRB’s integrated water–energy–land systems is applied to quantify multi-sector transformations and system costs for enhancing EFs to the Indus Delta. The results show that increasing the average outflows from the basin relative to historical policy levels by 2.5 and 5 times would increase sectoral costs for upstream water users between 17–32 and 68–72% for low and high ecological potential targets. The enhanced EFs result in more energy for pumping and treating water upstream from the delta and a net increase in irrigation and energy investments. The EF policy costs are minimized by 7–14% through cooperation across countries and 6–9% through the coordinated implementation of water efficiency measures in the irrigation, conveyance, power plant cooling, and water treatment sectors. The results underscore the crucial role of a multi-sector, multi-scale collaboration in achieving EF targets in water-stressed river basins for ecosystem adaptation to climate vulnerability, restoration of the delta, and socio-economic benefits.
Shifts in soil phosphorus fractions during seasonal transitions in a riparian floodplain wetland
Authors: Coppolino Jacob , Munford Kimber E. , Macrae Merrin , Glasauer Susan
Published: December 2022

Losses of phosphorus from soil to surface waters in agricultural areas have been linked to substantial declines in water quality. Riparian wetlands can potentially intercept phosphorus mobilized from upland soils before it reaches connecting waterways, but the capacity of wetlands to buffer against downstream losses of P is poorly understood, especially in northern temperate zones. In these regions, the spring freshet releases large volumes of water from snowmelt and soil pore water during the time when microbial productivity, which transfers available P into biomass, is low. In addition, losses of P in runoff may be exacerbated by freeze-thaw cycling (FTC) in soil during late winter and early spring through the physical degradation of organic matter. We investigated P dynamics from late fall through spring thaw and into summer to assess P transfers between inorganic, organic and microbial biomass pools, as functions of season and distance from a river. The site is located on the Grand River in southern Ontario, which discharges to Lake Erie, and consists of riparian wetland and wooded areas. Reactive P (Olsen P) and microbial biomass P (PMBIO) increased with distance from the river and varied more over time in the wetland soil compared to the adjacent wooded area, reflecting higher variability in vegetation, topography and hydrology. The positive correlation between microbial biomass P and microbes linked to ammonification supports the release of N and P through mineralization pathways as spring progresses, with microbial biomass decreasing in June as plant growth increases. There was evidence for leaching of Fe and Al, and lower concentrations of total P, in the transect proximate to the river. Seasonal flooding during spring thaw contributed to a pulse of dissolved reactive P, but temperature monitoring showed that the wetland soil did not experience freeze-thaw cycling. Investigation of FTC using wetland soil in mesocosms indicated that multiple FTC (>3) were necessary to increase the pool of reactive soil P, with the highest amount of soil reactive P observed after six FTC, when dissolved reactive P also tended to increase.
Differential effects of anthropogenic noise and vegetation cover on the breeding phenology and success of two urban passerines
Authors: Monniez Emmanuelle , Jiguet Frédéric , Vignal Clémentine , Biard Clotilde
Published: December 2022

The urban environment is associated with a multitude of challenges and stressors for populations of wild species from the surrounding natural environment. Among those, habitat fragmentation and noise pollution are suspected to have negative effects on the behavior and physiology of free-living birds in urban areas. Exposure in early life and chronic exposure to anthropogenic noise could be particularly deleterious, with short-and long-term consequences. In this study, we investigated if noise levels in city parks affect the distribution and reproductive success of two common bird species in the urban environment, the great tit (Parus major) and the blue tit (Cyanistes caeruleus) and if vegetation cover could mitigate those effects. We predicted that high noise levels might correlate with a decreased nest-box occupancy rate, a delayed laying date or a decreased clutch size, hatching, and fledging success. On the contrary, vegetation cover was expected to correlate positively with nest occupancy rate, advanced laying date, increased clutch size, hatching, and fledging success. We used data from population monitoring collected between 2012 and 2019 in parks and green public spaces in the city center and suburbs of Paris, France, and did not find any correlation between nest occupancy rates and noise levels or vegetation cover for both species. Laying date was not significantly related to anthropogenic noise in any species but was delayed with increasing vegetation cover in the great tit, while we did not find any association with clutch size. Hatching success in blue tits negatively correlated with increasing noise levels, and positively with increasing vegetation coverage. Finally, we did not find any correlation between anthropogenic noise or vegetation cover and the clutch size or fledging success in both species. In this study, two closely related species that share a common environment show a different sensibility to environmental parameters during reproduction, a key period for population maintenance. It also highlights the importance of considering multiple parameters when studying wild populations living in the urban environment.
Host and abiotic constraints on the distribution of the pine fungal pathogen Sphaeropsis sapinea (= Diplodia sapinea)
Authors: Roy Julien , Kyritsi Ioanna , Reinwarth Nadja , Bachelier Julien B. , Rillig Matthias C. , Lücking Robert
Published: December 2022

Plant fungal pathogens are an increasing emerging threat as climate change progresses. Sphaeropsis sapinea (syn. Diplodia sapinea), the causal fungal agent of Diplodia tip blight, is a major pathogen of pines of forestry and ornamental relevance in Europe and worldwide. Here, we combined molecular-based field surveys in a common-garden setting and across an elevation gradient with historical records, cultivation-based growth experiments and microscopy to report on host and abiotic constraints on the distribution of S. sapinea. Using the arboretum at the Botanical Garden Berlin, Germany, to control for environmental variability, S. sapinea was detected on all seven host Pinus species we studied. However, P. sylvestris is the only species in which the fungus was detected in symptomless needles at the arboretum, and the most frequently recorded host for over a century, suggesting that it is the main, and perhaps, potential original host. In addition, sampling symptomatic needles in four out of the seven same species across a gradient from 200 to 2,100 m of elevation in the French Alps, S. sapinea was not detected at elevation higher than 800 m. Abiotic constraints were also supported by reduced growth of isolates of S. sapinea at low temperature under controlled conditions, but a 35°C prior stress exposure increased the subsequent growth of S. sapinea within its optimal temperature range (20-30°C). Altogether, our study thus not only suggests that S. sapinea is more likely to cause tip blight in P. sylvestris compared to the other species we studied, but also that in the current context of global climate change with predicted temperature increases, the fungus could infect a wider range of pine hosts and locations worldwide.
Metabolites of endophytic fungi isolated from leaves of Bauhinia variegata exhibit antioxidant activity and agonist activity on peroxisome proliferator-activated receptors α, β/δ and γ
Authors: Mesquita Pedro Góes , Araujo Laiza Magalhaes de , Neves Francisco de Assis Rocha , Borin Maria de Fátima
Published: December 2022

Diabetes mellitus is a metabolic disorder that affects millions of people worldwide and is linked to oxidative stress and inflammation. Thiazolidinediones (TZD) improve insulin sensitization and glucose homeostasis mediated by the activation of peroxisome proliferator-activated receptors γ (PPARγ) in patients with type 2 diabetes. However, their use is associated with severe adverse effects such as loss of bone mass, retention of body fluids, liver and heart problems, and increased risk of bladder cancer. Partial PPARγ agonists can promote the beneficial effects of thiazolidinediones with fewer adverse effects. Endophytic fungi colonize plant tissues and have a particularly active metabolism caused by the interaction with them, which leads to the production of natural products with significant biological effects that may be like that of the colonized plant. Here, we identify seven endophytic fungi isolated from Bauhinia variegata leaves that have antioxidant activities. Also, one of the extracts presented pan-agonist activity on PPAR, and another showed activity in PPARα and PPARβ/δ. A better understanding of this relationship could help to comprehend the mechanism of action of antioxidants in treating diabetes and its complications. Moreover, compounds with these capabilities to reduce oxidative stress and activate the receptor that promotes glucose homeostasis are promising candidates in treatment of diabetes.
Estimating genetic gains for tolerance to stress combinations in tropical maize hybrids
Authors: Menkir Abebe , Dieng Ibnou , Meseka Silvestro , Bossey Bunmi , Mengesha Wende , Muhyideen Oyekunle , Riberio Priscillia F. , Coulibaly Mmadou , Yacoubou Abdoul-Madjidou , Bankole Folusho A. , Adu Gloria Boakyewaa , Ojo Tayo
Published: December 2022

Maize is a strategic food crop in sub-Saharan Africa. However, most maize growing tropical savannas particularly in West and Central African experience the occurrence of frequent droughts and Striga infestation, resulting in 30–100% yield losses. This production zones need maize cultivars that combine tolerance to the two stresses. IITA in collaboration with national partners has thus employed a sequential selection scheme to incorporate both drought tolerance and Striga resistance in topical maize hybrids using reliable screening protocols. The main objective of the present study was therefore to use grain yield and other agronomic traits recorded in regional collaborative hybrid trials conducted for 8 years under manged stressful and non-stressful conditions and across rainfed field environments to estimate genetic gains in grain yields using mixed model analyses. The results showed significant (p < 0.05) annual yield gains of 11.89 kg ha−1 under manged drought stress (MDS) and 86.60 kg ha−1 under Striga infestation (STRIN) with concomitant yield increases of 62.65 kg ha−1 under full irrigation (WW), 102.44 kg ha−1 under Striga non-infested (STRNO) conditions and 53.11 kg ha−1 across rainfed field environments. Grain yield displayed significant but not strong genetic correlation of 0.41 ± 0.07 between MDS and STRIN, indicating that gene expression was not consistent across the two stress conditions. Furthermore, grain yield recorded in MET had significant moderate genetic correlations of 0.58 ± 0.06 and 0.44 ± 0.07It with MDS and STRIN, respectively. These results emphasize the need to screen inbred linens under both stress conditions to further enhance the rate of genetic gain in grain yield in hybrids for areas where the two stresses co-occur. Nonetheless, this study demonstrated that the sequential selection scheme has been successful in generating hybrids with dependable yields that can reduce chronic food deficits in rural communities experiencing simultaneous presence of drought and S. hermonthica infestation in their production fields.
Integrated single-cell and bulk RNA sequencing analyses reveal a prognostic signature of cancer-associated fibroblasts in head and neck squamous cell carcinoma
Authors: Yang Yichen , Ma Ben , Han Litao , Xu Weibo , Du Xiaoxue , Wei Wenjun , Liao Tian , Ji Qinghai , Qu Ning , Wang Yu
Published: December 2022

Objectives: To identify a prognosis-related subtype of cancer-associated fibroblasts (CAFs) in head and neck squamous cell carcinoma (HNSCC) and comprehend its contributions to molecular characteristics, immune characteristics, and their potential benefits in immunotherapy and chemotherapy for HNSCC.

Materials and Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of CAFs from the samples of HNSCC patients derived from Gene Expression Omnibus (GEO), to identify the prognosis-related subtype of CAFs. CAFs were clustered into five subtypes, and a prognosis-related subtype was identified. Univariate and multivariate cox regression analyses were performed on the cohort selected from The Cancer Genome Atlas (TCGA) to determine signature construction, which was validated in GSE65858 and GSE42743. A prognostic signature based on 4 genes was constructed, which were derived from prognosis-related CAFs. The molecular characteristics, immune characteristics as well as the predicted chemosensitivity and immunotherapeutic response in the signature-defined subgroups were analyzed subsequently.

Results: The patients with higher CAF scores correlated with poor survival outcomes. Additionally, a high CAF score correlated with lower infiltration levels of many immune cells including M1 macrophages, CD8+ T cells, follicular T helper cells, monocytes, and naïve B cells. High CAF score also demonstrated different enrichment pathways, mutation genes and copy number variated genes. Furthermore, patients with high CAF scores showed lower sensitivity for chemotherapy and immunotherapy than those with low CAF scores.

Conclusion: The results of our study indicate the potential of the CAF signature as a biomarker for the prognosis of HNSCC patients. Furthermore, the signature could be a prospective therapeutic target in HNSCC.
Pan-cancer analysis reveals NAA50 as a cancer prognosis and immune infiltration-related biomarker
Authors: Fang Tao , Wang Dingxin , Li Rongyang , Yu Wenhao , Tian Hui
Published: December 2022

Background: N-Alpha-Acetyltransferase 50 (NAA50) has acetyltransferase activity and is important for chromosome segregation. However, the function and mechanism of NAA50 expression in cancer development was still unclear. Here, we systematically researched the function and mechanism of NAA50 in pan-cancer, and further verified the results of NAA50 in lung adenocarcinoma (LUAD).

Methods: In this study, using the online databases TIMER2.0, SangerBox3.0, HPA, UCSC, GEPIA, cBioPortal, UALCAN, TISIDB, CancerSEA and LinkedOmics, we focused on the relevance between NAA50 and oncogenesis, progression, methylation, immune infiltration, function and prognosis. In addition, the proliferation of cells was detected by CCK-8 and Edu assay. Finally, we analyzed the relationship between the expression of NAA50 and cell cycle related proteins.

Results: Pan-cancer analysis indicated that NAA50 was overexpressed in most cancers. And there was a significant correlation between NAA50 expression and the prognosis of cancer patients. In the meantime, NAA50 gene changes occur in a variety of tumors. Compared with normal tissues, the methylation level of NAA50 promoter increased in most cancer tissues. In addition, the results exhibited that in most cancers, NAA50 was significantly positively correlated with bone myeloid-derived suppressor cell (MDSC) infiltration and negatively correlated with T cell NK infiltration. Moreover, functional enrichment indicated that NAA50 regulates cell cycle and proliferation in LUAD. In vitro experiments testified that knockout of NAA50 could significantly inhibit the proliferation of LUAD.

Conclusion: NAA50 may be a potential biomarker and oncogene of pan-cancer, especially LUAD, which may promote the occurrence and development of tumors through different mechanisms. Furthermore, NAA50 was bound up with to immune cell infiltration in pan-cancer, meaning NAA50 may be an important therapeutic target for human cancers.
Marker-assisted backcross breeding for heat tolerance in bread wheat (Triticum aestivum L.)
Authors: Bellundagi Amasiddha , Ramya K. T. , Krishna Hari , Jain Neelu , Shashikumara P. , Singh Pradeep Kumar , Singh Gyanendra Pratap , Prabhu Kumble Vinod
Published: December 2022

Manipulation of flowering time for adaptation through natural or genetic approaches may combat heat-stress damage that occurs at the reproductive stages in production conditions. HD2733, a popular wheat variety of the eastern plains of India, is largely sensitive to heat stress. Therefore, the current study aims to improve heat tolerance of HD2733 by introgression of QTLs associated with early anthesis and high kernel weight linked to markers Xbarc186 and Xgwm190, respectively, through marker-assisted backcross breeding (MABB) from a tolerant donor, WH730. A total of 124 simple sequence repeat (SSR) markers distributed evenly across the genome were used for the background selection. The alleles of Xbarc186 and Xgwm190 were fixed in BC2F1 and BC1F2 generations by selecting individual plants heterozygous for both marker loci and backcrossed with HD2733 and simultaneously selfed to generate BC2F1 and BC1F2 populations, respectively. Furthermore, the selected BC1F2 were selfed to generate the BC1F4 population. By background screening, a total of 39 BC2F3 and 21 BC1F4 families homozygous for the targeted QTLs with 90.9–97.9% and 86.8–88.3% RPG recoveries were selected. The best performing 17 BC2F3 and 10 BC1F4 lines were evaluated for various morpho-physiological traits. Phenotypic evaluation and multi-location trials of the introgressed lines under late sown conditions led to the selection of three promising lines with early anthesis and higher grain yield. The improved lines will serve as an excellent genetic material for functional genomics and expression studies to understand the molecular mechanisms and pathways underlying the stress tolerance.
Clinical, biochemical, and molecular genetic characteristics of patients with primary carnitine deficiency identified by newborn screening in Shanghai, China
Authors: Chang Siyu , Yang Yi , Xu Feng , Ji Wenjun , Zhan Xia , Gao Xiaolan , Chen Ting , Qiu Wenjuan , Zhang Huiwen , Liang Lili , Lu Deyun , Zhang Kaichuang , Gu Xuefan , Han Lianshu
Published: December 2022

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disease caused by mutations in the SLC22A5 gene, which encodes the organic cation transporter 2 (OCTN2). Patients with PCD may be at risk of skeletal or cardiac myopathy, metabolic decompensation, and even sudden death. This study aimed to analyze the biochemical, clinical, and genetic characteristics of PCD patients identified by newborn screening (NBS) in Shanghai.

Methods: Dried blood spot (DBS) samples of newborns were analyzed through tandem mass spectrometry (MS/MS) from January 2003 to December 2021. Newborns with low free carnitine (C0) levels were recalled. Mutation in the SLC22A5 gene was analyzed on suspected positive newborns with low C0 levels after recall.

Results: 1,247,274 newborns were screened by MS/MS and 40 newborns were diagnosed with PCD, therefore the incidence of PCD in Shanghai was approximately 1:31,200. The mean C0 level in newborns with PCD was 5.37 ± 1.79 μmol/L before treatment and increased to 24.45 ± 10.87 μmol/L after treatment with L-carnitine. Twenty-three different variants were identified in the SLC22A5 gene, including 8 novel variants, of which c.51C>G (p.F17L) was the most frequent (27.27%, 18/66), followed by c.1400C>G (p.S467C) (25.76%, 17/66). Almost all the screened PCD patients were asymptomatic.

Conclusion: NBS via MS/MS was a quick and efficient method for the early diagnosis of PCD. The incidence of PCD in Shanghai was 1:31,200. Eight novel variants were identified, which greatly expanded the variant spectrum of SLC22A5. MS/MS combined with genetic testing could effectively improve the diagnostic accuracy of PCD.
Trickle infection with Heligmosomoides polygyrus results in decreased worm burdens but increased intestinal inflammation and scarring
Authors: Ariyaratne Anupama , Kim Sang Yong , Pollo Stephen M. J. , Perera Shashini , Liu Hongrui , Nguyen William N. T. , Coria Aralia Leon , Luzzi Mayara de Cassia , Bowron Joel , Szabo Edina K. , Patel Kamala D. , Wasmuth James D. , Nair Meera G. , Finney Constance A. M.
Published: December 2022

Introduction

Intestinal roundworms cause chronic debilitating disease in animals, including humans. Traditional experimental models of these types of infection use a large single-dose infection. However, in natural settings, hosts are exposed to parasites on a regular basis and when mice are exposed to frequent, smaller doses of Heligmosomoides polygyrus, the parasites are cleared more quickly. Whether this more effective host response has any negative consequences for the host is not known.

Results

Using a trickle model of infection, we found that worm clearance was associated with known resistance-related host responses: increased granuloma and tuft cell numbers, increased levels of granuloma IgG and decreased intestinal transit time, as well as higher serum IgE levels. However, we found that the improved worm clearance was also associated with an inflammatory phenotype in and around the granuloma, increased smooth muscle hypertrophy/hyperplasia, and elevated levels of Adamts gene expression.

Discussion

To our knowledge, we are the first to identify the involvement of this protein family of matrix metalloproteinases (MMPs) in host responses to helminth infections. Our results highlight the delicate balance between parasite clearance and host tissue damage, which both contribute to host pathology. When continually exposed to parasitic worms, improved clearance comes at a cost.
Assessment and impact of dose escalation on anti-drug antibodies in Fabry disease
Authors: Lenders Malte , Brand Eva
Published: December 2022

Enzyme replacement therapy (ERT) with recombinant α-galactosidase A (AGAL) can lead to the formation of neutralizing anti-drug antibodies (ADA), which significantly limit treatment efficacy in patients with Fabry disease (FD). The effects of dose escalation on ADA titer and plasma globotriaosylsphingosine (lyso-Gb3) level are unknown. We screened 250 FD patients (200 males, 50 females) under ERT for ADAs and assessed the impact of an approved dose escalation in affected patients, focusing on ADA titers and plasma lyso-Gb3. ADA-positive patients were identified by serum-mediated inhibition assays, followed by titration assays to determine the individual inhibitory capacities of ADAs against agalsidase-alfa and agalsidase-beta. 70 (35%) of the male patients were ADA-positive, with a mean inhibitory capacity of 83.5 ± 113.7mg AGAL. Although patients receiving agalsidase-beta showed higher inhibitory capacities (84.7 ± 34.7mg) than patients under agalsidase-alfa (60.3 ± 126.7mg, p<0.001), the “theoretical deficit” to the infused dose was lower in patients receiving agalsidase-beta. In seven patients receiving agalsidase-alfa (0.2 mg/kg) ADAs were saturable by switching patients to agalsidase-beta (1.0 mg/kg). The switch resulted in increasing ADA titers within the first months. In 2 out of 7 (28.6%) therapy switchers, dose escalation could lead to durable ADA saturation. Independent of an increase in ADA titers, lyso-Gb3 levels decrease and cardiac and renal parameters remained stable after dose escalation. Dose escalation results in a heterogeneous, unpredictable ADA response, with more than a quarter of all treatment switchers succeeding in ADA saturation. Longitudinal ADA measurements are required to assess the individual risk of affected patients.
Upregulated antimicrobial immune response mediated by neutrophils in the development from allergic rhinitis to asthma
Authors: Li Lisha , Zhang Hao , Wang Xiujie , Wang Zixi , Cui Le , Xu Yingyang , Guan Kai
Published: December 2022

Background

Allergic rhinitis (AR) and asthma are closely related, and AR is regarded as an important risk factor for the onset of asthma. However, the pathogenesis of the development of asthma from AR is still undefined.

Objective

The aim of this study was to investigate the mechanisms underlying the development of asthma from AR by comparing the transcriptome features of patients with AR with and without asthma.

Methods

Patients with AR with or without asthma caused by weed pollen who presented to the Allergy Clinic of Peking Union Medical College Hospital were recruited for this study. Peripheral blood samples of all the patients were collected during the weed pollen season (September) when the patients had allergic symptoms and outside the pollen season (November) when the patients had no symptoms. Transcriptomic analysis was conducted, and the differentially expressed genes (DEGs) and enriched immune pathways between the patients with AR with asthma (AR-asthma group) and those without asthma (AR group) were identified. In addition, the expression levels of some pivotal differentially expressed RNAs were quantified using quantitative polymerase chain reaction (PCR).

Results

During the weed pollen season, the immune-related Gene Ontology (GO) terms with P value < 0.05, enriched by the upregulated genes in the AR-asthma group compared to the AR group included antifungal humoral response, neutrophil-mediated killing of bacterium, antibacterial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptides, and regulation of the T cell receptor signaling pathway. The immune-related GO terms with P values <0.05 enriched by downregulated genes were positive regulation of natural killer cell-mediated cytotoxicity, microglial cell activation, natural killer cell activation, and leukocyte-mediated cytotoxicity. The GO term of antimicrobial humoral immune response mediated by antimicrobial peptides was upregulated both during and outside the pollen season, and the upregulated expression of three DEGs (LTF, PF4, and ELANE) included in this term was verified through quantitative PCR.

Conclusions

The activation of the antimicrobial immune response mediated by neutrophils and the depression of cytotoxicity mediated by natural killer cells may play roles in the progression from AR to asthma.
Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer
Authors: Peng Hui , Li Lijin , Zuo Chong , Chen Michael Y. , Zhang Xiuli , Myers Nancy B. , Hogg Graham D. , DeNardo David G. , Goedegebuure S. Peter , Hawkins William G. , Gillanders William E.
Published: December 2022

Background

Cancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines.

Methods

We used KPC4580P, an established model of PDAC, to test whether neoantigen vaccines can generate therapeutic efficacy against PDAC. We focused on two immunogenic neoantigens associated with genetic alterations in the CAR12 and CDK12 genes. We tested a neoantigen vaccine comprised of two 20-mer synthetic long peptides and poly IC, a Toll-like receptor (TLR) agonist. We investigated the ability of neoantigen vaccine alone, or in combination with PD-1 and TIGIT signaling blockade to impact tumor growth. We also assessed the impact of TIGIT signaling on T cell responses in human PDAC.

Results

Neoantigen vaccines induce neoantigen-specific T cell responses in tumor-bearing mice and slow KPC4580P tumor growth. However, KPC4580P tumors express high levels of PD-L1 and the TIGIT ligand, CD155. A subset of neoantigen-specific T cells in KPC4580P tumors are dysfunctional, and express high levels of TIGIT. PD-1 and TIGIT signaling blockade in vivo reverses T cell dysfunction and enhances neoantigen vaccine-induced T cell responses and tumor regression. In human translational studies, TIGIT signaling blockade in vitro enhances neoantigen-specific T cell function following vaccination.

Conclusions

Taken together, preclinical and human translational studies support testing neoantigen vaccines in combination with therapies targeting the PD-1 and TIGIT signaling pathways in patients with PDAC.
Pathogen spectrum and immunotherapy in patients with anti-IFN-γ autoantibodies: A multicenter retrospective study and systematic review
Authors: Qiu Ye , Fang Gaoneng , Ye Feng , Zeng Wen , Tang Mengxin , Wei Xuan , Yang Jinglu , Li Zhengtu , Zhang Jianquan
Published: December 2022

Background

Anti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data.

Methods

This systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity.

Results

We included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%).

Conclusions

Intracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicella-zoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases.
Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance
Authors: Qin Yue , Xu Guotai
Published: December 2022

Chimeric antigen receptor (CAR) T-cell therapy, belonging to adoptive immune cells therapy, utilizes engineered immunoreceptors to enhance tumor-specific killing. By now new generations of CAR T-cell therapies dramatically promote the effectiveness and robustness in leukemia cases. However, only a few CAR T-cell therapies gain FDA approval till now, which are applied to hematologic cancers. Targeting solid tumors through CAR T-cell therapies still faces many problems, such as tumor heterogeneity, antigen loss, infiltration inability and immunosuppressive micro-environment. Recent advances provide new insights about the mechanisms of CAR T-cell therapy resistance and give rise to potential reversal therapies. In this review, we mainly introduce existing barriers when treating solid tumors with CAR T-cells and discuss the methods to overcome these challenges.
Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation
Authors: Yan Shi , Wu Xuege , Jiang Jinqiu , Yu Shijuan , Fang Xiao , Yang Huan , Bai Xiaoming , Wang Hua , Luo Xiaoyan
Published: December 2022

Background

Netherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by SPINK5 gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets.

Objective

To evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment.

Methods

Four children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis.

Results

All four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0–83.9%) and NRS (by 87.5–90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6–86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment (P = 0.029). The baseline percentage of Th2 cells (among total CD3+CD4+ T cells) was significantly higher in patients than that in healthy controls (HC) (P < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events.

Conclusion

Dupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.
Time-restricted feeding reduces monocyte production by controlling hematopoietic stem and progenitor cells in the bone marrow during obesity
Authors: Kim Yelim , Lee Youngyoon , Lee Mi Nam , Nah Jiyeon , Yun Narae , Wu Dayong , Pae Munkyong
Published: December 2022

Time-restricted feeding (TRF) has emerged as a promising dietary approach in improving metabolic parameters associated with obesity, but its effect on immune cells under obesogenic condition is poorly understood. We conducted this study to determine whether TRF exerts its therapeutic benefit over obesity-induced myeloid cell production by analyzing hematopoietic stem and progenitor cells in bone marrow (BM) and immune cell profile in circulation. Male C57BL/6 mice were fed a low-fat diet (LFD) or high-fat diet (HFD) ad libitum for 6 weeks and later a subgroup of HFD mice was switched to a daily 10 h-TRF schedule for another 6 weeks. Mice on HFD ad libitum for 12 weeks had prominent monocytosis and neutrophilia, associated with expansion of BM myeloid progenitors, such as multipotent progenitors, pre-granulocyte/macrophage progenitors, and granulocyte/macrophage progenitors. TRF intervention in overweight and obese mice diminished these changes to a level similar to those seen in mice fed LFD. While having no effect on BM progenitor cell proliferation, TRF reduced expression of Cebpa, a transcription factor required for myeloid differentiation. These results indicate that TRF intervention may help maintain immune cell homeostasis in BM and circulation during obesity, which may in part contribute to health benefits associated with TRF.
Gut microbiome in multiple myeloma: Mechanisms of progression and clinical applications
Authors: Zhang Liuyun , Xiang Yunhui , Li Yanying , Zhang Juan
Published: December 2022

The gut commensal microbes modulate human immunity and metabolism through the production of a large number of metabolites, which act as signaling molecules and substrates of metabolic reactions in a diverse range of biological processes. There is a growing appreciation for the importance of immunometabolic mechanisms of the host-gut microbiota interactions in various malignant tumors. Emerging studies have suggested intestinal microbiota contributes to the progression of multiple myeloma. In this review, we summarized the current understanding of the gut microbiome in MM progression and treatment, and the influence of alterations in gut microbiota on treatment response and treatment-related toxicity and complications in MM patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, we discussed the impact of gut microbiota-immune system interactions in tumor immunotherapy, focusing on tumor vaccine immunotherapy, which may be an effective approach to improve anti-myeloma efficacy.
Immunoglobulin VDJ repertoires reveal hallmarks of germinal centers in unique cell clusters isolated from zebrafish (Danio rerio) lymphoid tissues
Authors: Waly Doaa , Muthupandian Aradana , Fan Chia-Wei , Anzinger Harrison , Magor Brad G.
Published: December 2022

DNA mutagenesis during antibody affinity maturation has potentially oncogenic or autoimmune outcomes if not tightly controlled as it is in mammalian germinal centers. Cold blooded vertebrates lack germinal centers, yet have a functional Ig gene mutator enzyme, Aicda. In fish there are clusters of Aicda+ cells encircled by pigmented ‘melano-macrophages’ and we test the hypothesis that these clusters are functionally analogous to germinal centers. Sequenced IgH VDJ repertoire libraries from individual isolated clusters showed evidence of B-cell clonal expansion and VDJ somatic hypermutation. Construction of Ig clonal lineage trees revealed that unlike surrounding lymphoid tissue, each cluster is dominated by a few B-cell VDJ clonotypes having hundreds of mutated variants. Recruitment of B-cells to the clusters appears to be ongoing, as there are additional Ig clones having smaller lineages. Finally, we show evidence for positive selection for replacement mutations in regions encoding the antigen contact loops, but not in the framework regions, consistent with functional antibody modification. Melano-macrophages appear to trap the Ag used for post-mutation B-cell selection, performing a role analogous to the follicular dendritic cells of mammalian germinal centers. These findings provide insights into the evolution of the affinity maturation process, the improvement of fish vaccines and possibly also the workings of atypical ectopic germinal centers generated in several human diseases.
Causal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study
Authors: Jin Tianyu , Huang Wei , Cao Fangzheng , Yu Xinyue , Guo Shunyuan , Ying Zhenhua , Xu Chao
Published: December 2022

Introduction

It is well-documented that systemic lupus erythematosus (SLE) is associated with dementia. However, the genetic causality of this association remains unclear. Mendelian randomization (MR) was used to investigate the potential causal relationship between SLE and dementia risk in the current study.

Methods

We selected 45 single nucleotide polymorphisms (SNPs) associated with SLE from publicly available genome-wide association studies (GWAS). Summary level statistics were obtained from the dementia GWAS database. MR estimates were performed using the inverse variance weighted (IVW) method, MR-Egger method and weighted median (WM) method. Cochran’s Q test, the intercept of MR-Egger, MR-Pleiotropy Residual Sum and Outlier method, leave-one-out analysis and funnel plot were applied for sensitivity analyses.

Results

No significant causal association was found between SLE and any type of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. These findings were robust across several sensitivity analyses.

Conclusion

Overall, our findings do not support a causal association between SLE and dementia risk.