bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance
Authors: Rodriguez B. Leticia , Chen Limo , Li Yanli , Miao Shucheng , Peng David H. , Fradette Jared J. , Diao Lixia , Konen Jessica M. , Alvarez Frank R. Rojas , Solis Luisa M. , Yi Xiaohui , Padhye Aparna , Gibson Laura A. , Ochieng Joshua K. , Zhou Xiaofei , Wang Jing , Gibbons Don L.
Published: June 2023

Introduction

Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy.

Results

Our results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages.

Conclusions

Therapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.
GATA3 induces the pathogenicity of Th17 cells via regulating GM-CSF expression
Authors: Butcher Matthew J. , Gurram Rama Krishna , Zhu Xiaoliang , Chen Xi , Hu Gangqing , Lazarevic Vanja , Zhao Keji , Zhu Jinfang
Published: June 2023

T-bet-expressing Th17 (T-bet+RORγt+) cells are associated with the induction of pathology during experimental autoimmune encephalomyelitis (EAE) and the encephalitic nature of these Th17 cells can be explained by their ability to produce GM-CSF. However, the upstream regulatory mechanisms that control Csf2 (gene encoding GM-CSF) expression are still unclear. In this study, we found that Th17 cells dynamically expressed GATA3, the master transcription factor for Th2 cell differentiation, during their differentiation both in vitro and in vivo. Early deletion of Gata3 in three complimentary conditional knockout models by Cre-ERT2, hCd2Cre and Tbx21Cre, respectively, limited the pathogenicity of Th17 cells during EAE, which was correlated with a defect in generating pathogenic T-bet-expressing Th17 cells. These results indicate that early GATA3-dependent gene regulation is critically required to generate a de novo encephalitogenic Th17 response. Furthermore, a late deletion of Gata3 via Cre-ERT2 in the adoptive transfer EAE model resulted in a cell intrinsic failure to induce EAE symptoms which was correlated with a substantial reduction in GM-CSF production without affecting the generation and/or maintenance of T-bet-expressing Th17 cells. RNA-Seq analysis of Gata3-sufficient and Gata3-deficient CNS-infiltrating CD4+ effector T cells from mixed congenic co-transfer recipient mice revealed an important, cell-intrinsic, function of GATA3 in regulating the expression of Egr2, Bhlhe40, and Csf2. Thus, our data highlights a novel role for GATA3 in promoting and maintaining the pathogenicity of T-bet-expressing Th17 cells in EAE, via putative regulation of Egr2, Bhlhe40, and GM-CSF expression.
A novel DNA damage repair-related gene signature predicting survival, immune infiltration and drug sensitivity in cervical cancer based on single cell sequencing
Authors: Xiang Xiaoqing , Kang Jiawen , Jiang Jingwen , Zhang Yaning , Zhang Yong , Li Lesai , Peng Xiaoning
Published: June 2023

Background

Aberrant DNA damage repair (DDR) is one of the hallmarks of tumors, and therapeutic approaches targeting this feature are gaining increasing attention. This study aims to develop a signature of DDR-related genes to evaluate the prognosis of cervical cancer (CC).

Methods

Differentially expressed genes were identified between high and low DDR groups of cells from the single-cell RNA sequencing dataset GSE168652 based on DDR scores. Using the ssGSEA and WGCNA methods, DDR-related differentially expressed genes were identified from different patients within the TCGA-CESC cohort. Using Cox analysis and LASSO regression analysis, a DDR-related gene signature was constructed based on the intersection of two groups of differentially expressed genes and DDR-related genes from WGCNA, and validated in GSE52903. Immune cell infiltration analysis, mutation analysis, survival analysis, drug sensitivity analysis, etc., were performed in different groups which were established based on the DDR gene signature scoring. A key gene affecting prognosis was selected and validated through biological experiments such as wound healing, migration, invasion, and comet assays.

Results

A novel DDR-related signature was constructed and the nomogram results showed this signature performed better in predicting prognosis than other clinical features for CC. The high DDR group exhibited poorer prognosis, weaker immune cell infiltration in the immune microenvironment, lower expression of immune checkpoint-related genes, lower gene mutation frequencies and more sensitivity to drugs such as BI.2536, Bleomycin and etc. ITGB1, ZC3H13, and TOMM20 were expressed at higher levels in CaSki and HeLa cells compared to ECT1 cells. Compared with the native CaSki and HeLa cells, the proliferation, migration, invasion and DDR capabilities of CaSki and HeLa cell lines with ITGB1 suppressed expression were significantly decreased.

Conclusion

The 7 DDR-related gene signature was an independent and powerful prognostic biomarker that might effectively evaluate the prognosis of CC and provide supplementary information for a more personalized evaluation and precision therapy. ITGB1 was a potential candidate gene that may affect the DDR capacity of CC cells, and its mechanism of action was worth further in-depth study.
Hypoxia in the Bohai Bay, China: distributions, causes and mechanisms
Authors: Zhang Guodong , Wen Yujian , Ding Changling , Zhang Guicheng , Sun Jun
Published: June 2023

The Haihe River system is a major conduit of land-based pollution into the Bohai Sea in North China, This study presented the first-ever observation of hypoxia in the Haihe River estuary, providing valuable insights into the complex interplay between physical and biochemical factors influencing hypoxia in estuarine systems. The research found seasonal variations in DO distribution in the estuaries of the Haihe and Yongdingxin Rivers. Hypoxia emerged in summer at the bottom of the Haihe River estuary and dissipated in autumn, with the minimum DO concentration of 1.85 mg/L recorded at the bottom of the HH-2 station. Within the hypoxic zone, the average DO concentration was 4.02 mg/L, and the average of DO saturation was less than 0.4. This study also identified the primary drivers of summer hypoxia as a combination of physical and biochemical factors, with water stratification due to hydrodynamic factors limiting exchange and reoxygenation between different water layers. In addition, the decomposition of organic matter in the bottom consumed a significant amount of dissolved oxygen.The significantly higher DO concentration and saturation in autumn compared to summer suggested the possible existence of seasonal hypoxia in the Haihe estuary. This study of hypoxia in the Haihe River estuary contribute to a better understanding of the factors that influence seasonal hypoxia. The findings have important implications for the management and remediation of hypoxia in the Haihe estuary and other estuarine systems.
‘Internet+’ comprehensive nursing training course in the post-epidemic era—an exploration of the mixed teaching mode: a randomized trial
Authors: Wang Qing-Ling , Liu Lan-Lan , Liu Cheng-Rui , Zhu Qing-Shuang , Ren Zhi-Ying , Gang Ting-Ting , Zhou Chun-Yan , Li Qiu-Ping , Chen Xi , Han Bin-Ru
Published: June 2023

Objective

To explore the effect of the application of the ‘Internet+’ nursing teaching mode on the comprehensive teaching ‘Fundamentals of Nursing’.

Trial design

Parallel design and convenient sampling were used to select vocational nursing students from the Nursing College of Capital Medical University.

Methods

Selected students were randomly divided into two groups. The control group consisted of 30 students in Grade 2020 higher vocational nursing education (traditional teaching mode). The observation group consisted of 30 students in Grade 2021 higher vocational nursing education (Internet+ mixed teaching mode). Training assessment results, automatic learning ability, professional identity, and satisfaction were compared between the two groups.

Results

Compared with the control group, the students in the observation group scored higher in the following operation practices: venous blood sampling, intradermal injection, cardiopulmonary resuscitation (CPR), sputum aspiration, and putting on and taking off robes (84.01 ± 0.87 vs. 92.14 ± 1.23; 91.41 ± 0.82 vs. 96.86 ± 0.27; 87.56 ± 0.31 vs. 93.91 ± 2.79; 88.11 ± 0.51 vs. 93.75 ± 0.29; and 82.29 ± 0.29 vs. 90.96 ± 0.34, respectively, with p < 0.05 for all scores). The total scores for autonomous learning ability and subjective satisfaction were also higher in the observation group compared with the control group (82.98 ± 4.72 vs. 93.17 ± 5.01 and 96.67% vs. 90.00%, respectively, with p < 0.05 for all scores).

Conclusion

In the post-epidemic era, the ‘Internet+ hybrid teaching mode’ was applied to comprehensive nursing teaching. This changed the traditional education mode, which focuses only on professional knowledge. The ‘Internet+’ teaching mode results showed that the professional, ideological, and political courses exhibited the same value guidance, which improved students’ independent learning ability, practical operation ability, professional identity, and satisfaction.
Conjunctival infiltrates and cytokines in an experimental immune-mediated blepharoconjunctivitis rat model
Authors: Hou Aihua , Tin Min Qi , Fenner Beau , Liu Yu-Chi , Tong Louis
Published: June 2023

Purpose

To characterize the histopathological and immunological findings of a rat model of allergic blepharoconjunctivitis (BC) and demonstrate its potential utility for the assessment of BC therapies.

Methods

Sprague–Dawley (SD) rats were immunized with ovalbumin (OVA) and topically challenged with OVA (BC group) or PBS (control group), while a corticosteroid group was pre-treated with triamcinolone acetate 24 h before the challenge. Morphological features were evaluated and tissues were harvested for histological, flow cytometry and cytokine analysis.

Results

The BC group rats developed eyelid excoriations, redness, and conjunctival edema 24 h after the OVA challenge, while corticosteroid pre-treated and PBS-challenged rats were unaffected. The BC features were reduced despite repeated challenges for 5 days. Massive immune cell infiltration was observed in conjunctivae of BC rats, while no significant infiltration was seen in the other groups. Populations of T cells, mono-macrophages, neutrophils, and NK cells made up more than 77% of CD45+7AAD− cells in the conjunctival tissues. T cell proportions were increased at 96 h compared to 24 h post-challenge, while macrophages decreased during the same time period. Eosinophils and intraepithelial neutrophils were detected in the BC rats, but not in the PBS and corticosteroid groups. BC eyes had significantly higher levels of IFN-γ and IL-2, while IL-4 and IL-6 levels were similar to controls.

Conclusion

A robust BC response was detected in this rat model which was suppressed by corticosteroid pre-treatment. Immune cell composition and cytokine profiles changed over time.
The effects of early mobilization in mechanically ventilated adult ICU patients: systematic review and meta-analysis
Authors: Wang Lijie , Hua Yusi , Wang Luping , Zou Xia , Zhang Yan , Ou Xiaofeng
Published: June 2023

Background

The effects of early mobilization (EM) on intensive care unit (ICU) patients remain unclear. A meta-analysis of randomized controlled trials was performed to evaluate its effect in mechanically ventilated adult ICU patients.

Methods

We searched randomized controlled trials (RCTs) published in Medline, Embase, and CENTRAL databases (from inception to November 2022). According to the difference in timing and type, the intervention group was defined as a systematic EM group, and comparator groups were divided into the late mobilization group and the standard EM group. The primary outcome was mortality. The secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV), and adverse events. EM had no impact on 180-day mortality and hospital mortality between intervention groups and comparator groups (RR 1.09, 95% CI 0.89–1.33, p = 0.39). Systemic EM reduced the ICU length of stay (LOS) (MD −2.18, 95% CI −4.22–−0.13, p = 0.04) and the duration of MV (MD −2.27, 95% CI −3.99–−0.56, p = 0.009), but it may increase the incidence of adverse events in patients compared with the standard EM group (RR 1.99, 95% CI 1.25–3.16, p = 0.004).

Conclusion

Systematic EM has no significant effect on short- or long-term mortality in mechanically ventilated adult ICU patients, but systematic EM could reduce the ICU LOS and duration of MV.
Vascular risk factors for COVID-19 ARDS: endothelium, contact-kinin system
Authors: Bailey Melanie , Linden Dermot , Guo-Parke Hong , Earley Olivia , Peto Tunde , McAuley Danny F. , Taggart Clifford , Kidney Joseph
Published: June 2023

SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity–conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS.
Epidemiological characteristics of Vibrio parahaemolyticus outbreaks, Zhejiang, China, 2010–2022
Authors: Chen Lili , Wang Jikai , Chen Jiang , Zhang Ronghua , Zhang Hexiang , Qi Xiaojuan , He Yue
Published: June 2023

Background

Vibrio parahaemolyticus is one of the most common foodborne pathogens and poses a significant disease burden. The purpose of the study was to elucidate the epidemiological characteristics of Vibrio parahaemolyticus outbreaks in Zhejiang Province, and provide insights for the targeted prevention and control of foodborne diseases.

Methods

Descriptive statistical methods were utilized to analyze the data on Vibrio parahaemolyticus outbreaks reported by all Centers for Disease Control and Prevention (CDCs) through Foodborne Disease Outbreaks Surveillance System (FDOSS) in Zhejiang Province from 2010 to 2022.

Results

From 2010 to 2022, a total of 383 outbreaks caused by Vibrio parahaemolyticus were reported by 90 CDCs in 11 prefectures of Zhejiang Province, resulting in 4,382 illnesses, 326 hospitalizations and 1 death. The main symptoms of the outbreak-related cases were diarrhea (95.18%), abdominal pain (89.23%), nausea (55.64%), vomiting (50.57%), fever (24.21%), etc. The outbreaks occurring between July and September accounted for 77.54% of all outbreaks (297 out of 383). Outbreaks associated with restaurants accounted for the majority (57.96%, 222/383) of all outbreaks, followed by those linked to staff canteens (15.40%, 59/383) and rural banquets (11.23%, 43/383). 31.85% of all outbreaks were associated with the consumption of aquatic products, while ready-to-eat foods such as Chinese cold dishes and cooked meat products accounted for 12.53% of all outbreaks. Serotype O3:K6 (81.94%, 118/144) was the predominant serotype responsible for outbreaks from 2010 to 2020, while serotype O10:K4 (57.89%, 33/57) was the predominant serotype from 2021 to 2022.

Conclusion

In-depth and comprehensive analysis of long-term surveillance data on Vibrio parahaemolyticus outbreaks is essential to gain insight into the epidemiological characteristics, identify long-term patterns and recent trends, and enable governments to prioritize interventions and develop targeted policies to mitigate such outbreaks.
Variation in epibiotic bacteria on two squat lobster species of Munidopsidae
Authors: Feng Wenze , Wang Minxiao , Dong Dong , Hui Min , Zhang Huan , Fu Lulu , Zhong Zhaoshan , Xu Zheng , Li Chaolun
Published: June 2023

The relationships between epibiotic bacteria on deep-sea hosts and host lifestyle factors are of particular interest in the field of deep-sea chemoautotrophic environmental adaptations. The squat lobstersShinkaia crosnieriandMunidopsis verrilliare both dominant species in cold-seep ecosystems, and they have different distributions and feeding behaviors. These species may have evolved to have distinct epibiotic microbiota. Here, we compared the epibiotic bacterial communities on theM. verrillicarapace (MVcarapace),S. crosniericarapace (SCcarapace), andS. crosnieriventral plumose setae (SCsetae). The epibiotic bacteria on SCsetaewere dense and diverse and had a multi-layer configuration, while those on MVcarapaceand SCcarapacewere sparse and had a monolayer configuration. Chemoautotrophic bacteria had the highest relative abundance in all epibiotic bacterial communities. The relative abundance of amplicon sequence variant 3 (ASV3; unknown species in orderThiotrichales), which is associated with sulfide oxidation, was significantly higher in SCsetaethan MVcarapaceand SCcarapace. Thiotrichalesspecies seemed to be specifically enriched on SCsetae, potentially due to the synthetic substrate supply, adhesion preference, and host behaviors. We hypothesize that theS. crosnieriepisymbionts use chemical fluxes near cold seeps more efficiently, thereby supporting the host’s nutrient strategies, resulting in a different distribution of the two species of squat lobster.
Gut microbiota influences feeding behavior via changes in olfactory receptor gene expression in Colorado potato beetles
Authors: Li Hongwei , Yu Yanxue , Zhang Jian , Wang Yuhan , Zhang Liu , Zhai Junfeng , Zhang Yongjiang
Published: June 2023

The Colorado potato beetle (CPB) is an internationally recognized plant quarantine pest that causes serious losses to potato agricultural production. The gut microbiota plays an important role in its growth and development, and the olfactory system plays an important role in insect feeding behavior. The gut microbiota is known to be capable of inducing changes in the olfactory systems of insects. However, the way these associated gut microbes influence the feeding-related behaviors of CPBs remains unclear. To explore the relationship between them, fresh potato leaves immersed in a mixture of five antibiotics (tetracycline, penicillin, ofloxacin, ciprofloxacin, and ampicillin) at specific concentrations for 1 h were fed to adult CPBs to reduce the abundance of gut microbes. We found that the feeding behavior of CPBs was significantly affected by the gut microbiota and that Pseudomonas was significantly higher in abundance in the control group than in the antibiotic group. We then used transcriptome sequencing to explore the differences in olfactory receptor genes in the heads of non-treatment and antibiotic-fed CPBs. Through Illumina Hiseq™ sequencing and screening of differential genes, we found that the olfactory receptor gene LdecOR9 was significantly upregulated and LdecOR17 was significantly downregulated after antibiotic feeding. A real-time polymerase chain reaction was used to verify the changes in olfactory receptor gene expression in the non-treatment groups and antibiotic-treated groups. The feeding behavior was partially rescued after CPBs were re-fed with intestinal bacteria. These results indicate that a certain amount of gut microbiota can result in the loss of the olfactory discrimination ability of CPBs to host plants. In summary, this study investigated the relationship between gut microbiota and olfactory genes, providing a reference for research on microbial control.
Moonlight functions of glycolytic enzymes in cancer
Authors: Shegay Petr V. , Shatova Olga P. , Zabolotneva Anastasia A. , Shestopalov Aleksandr V. , Kaprin Andrei D.
Published: June 2023

Since an extensive genome research has started, basic principle “one gene—one protein—one function” was significantly revised. Many proteins with more than one function were identified and characterized as “moonlighting” proteins, which activity depend not only on structural peculiarities but also on compartmentation and metabolic environment. It turned out that “housekeeping” glycolytic enzymes show important moonlight functions such as control of development, proliferation, apoptosis, migration, regulation of transcription and cell signaling. Glycolytic enzymes emerged very early in evolution and because of the limited content of genomes, they could be used as ancient regulators for intercellular and intracellular communication. The multifunctionality of the constitutively expressed enzymes began to serve cancer cell survival and growth. In the present review we discuss some moonlight functions of glycolytic enzymes that important for malignant transformation and tumor growth.
Collapsin response mediator protein 5-associated optic neuropathy: clinical characteristics, radiologic clues, and outcomes
Authors: Yan Rong , Mao Yu , Zeng Huiyang , Liu Qian , Jiang Hanqiu , Peng Jingting , Yang Qingling , Cui Shilei , Liu Lei , Guo Yanjun , Wang Jiawei
Published: June 2023

Objective

Collapsin response mediator protein 5-associated optic neuropathy (CRMP5-ON) is a rare entity of autoimmune optic neuropathy. This study aimed to review the neuro-ophthalmic findings and outcomes in a series of patients with CRMP5-ON to further characterize its clinical phenotype, radiologic clues, and outcomes.

Methods

This was a retrospective case series and a single-center medical chart review of all patients with CRPM5-seropositive ON at the Department of Neurology, Beijing Tongren Hospital, from December 1, 2020, to March 31, 2023. The main outcome measures were neuro-ophthalmic manifestations, radiologic characteristics, and clinical outcomes of CRMP5-ON; coexisting neural autoantibody, paraneoplastic associations, and the impact of immunosuppressant therapy.

Results

Five patients were identified. Four (80%) were female, and the average age at onset was 59.4 years (range 53–69 years), with an average follow-up of 15.3 months (range 1.4–28.7 months). The average best-corrected visual acuity (BCVA) at nadir was 20/120 (range 20/20 to count fingers). Seven of ten affected eyes (70%) showed diffuse defects of the central field. Painless bilateral involvement and optic disk edema occurred in 100% of patients, combined with vitritis, uveitis, or retinitis in four (80%). Four patients (80%) had MRI abnormalities along the optic nerve (one patient with optic nerve enhancement and three patients had optic nerve sheath enhancement or peribulbar fat enhancement). Three patients (60%) had optic neuropathy with other neurologic symptoms. Four patients (80%) had confirmed cancer (two were small-cell lung carcinoma, one was papillary thyroid carcinoma and another was thymoma and invasive pulmonary adenocarcinoma). All cancers were identified after the presentation of the optic neuropathy. The intervention included IVIG, IVMP, surgery and chemotherapy. The average BCVA at the last follow-up was 20/50 (range 20/20 to count fingers). Three patients had surgery during the initial hospitalization, and were stable during the follow-up. Among two patients who received IVMP, both had improvement after treatment, although one patient had worsening non-ocular neurologic symptoms during the steroid taper.

Conclusion

CRMP5-ON presented with optic disc edema, often bilateral involved and combined with vitreitis, retinitis, or uveitis. CRMP5-ON can present with MRI optic nerve or perineural optic nerve enhancement, especially in the optic nerve sheath. CRMP5-ON is closely related to paraneoplastic neurologic syndrome. Cancer screening and intervention are crucial to prognosis.
The continuous performance test aids the diagnosis of post-stroke cognitive impairment in patients with right hemisphere damage
Authors: Li XiuLi , Huang FuBiao , Guo TieJun , Feng MengChen , Li Shan
Published: June 2023

Purpose

The purpose of the study was to investigate the time course difference of relative changes in oxygenated hemoglobin (Oxy-Hb) concentration in the prefrontal cortex (PFC) between controls and patients with post-stroke cognitive impairment (PSCI) who had right hemisphere damage (RHD) using the continuous performance test (CPT) and functional near-infrared spectroscopy (fNIRS) technology. The study aimed to evaluate the feasibility of CPT in the diagnosis and evaluation of PSCI with RHD.

Methods

A total of 16 patients with RHD (RHD group) and 32 normal subjects (control group) were recruited. The Montreal Cognitive Assessment Scale was used to assess post-stroke cognitive impairment. The CPT and fNIRS were employed to investigate task-related changes in Oxy-Hb levels.

Results

The RHD group showed significantly lower accuracy and hit rates than the control group; however, the average reaction time was significantly longer in the former. Although the two groups showed no statistically significant difference in terms of left and right PFC integral values, the mean values were greater in the RHD group. The centroid value of the right PFC was significantly higher in the RHD group than in the control group. The time course of Oxy-Hb concentrations in the PFC differed between the two groups. In the RHD group, neural compensation was observed in both prefrontal lobes; however, the rate of compensation was slower on the affected side.

Conclusion

The CPT may be helpful in the clinical diagnosis of PSCI with RHD. It may therefore be used to evaluate the effectiveness of cognitive interventions.
Effect of moderate prenatal ethanol exposure on the differential expression of two histamine H3 receptor isoforms in different brain regions of adult rat offspring
Authors: Davies Suzy , Lujan Kiana S. , Rappaport Ella J. , Valenzuela Carlos F. , Savage Daniel D.
Published: June 2023

We have reported that prenatal alcohol exposure (PAE) elevates histamine H3 receptor (H3R) agonist-mediated inhibition of glutamatergic neurotransmission in the dentate gyrus. Here, we hypothesized that PAE alters the expression of two prominent H3R isoforms namely, the rH3A and rH3C isoforms, which have differing intrinsic activities for H3R agonists, in a manner that may contribute to heightened H3R function in PAE rats. In contrast to our predictions, we found different effects of sex and PAE in various brain regions with significant interactions between sex and PAE in dentate gyrus and entorhinal cortex for both isoforms. Subsequently, to confirm the PAE-and sex-induced differences on H3R isoform mRNA expression, we developed a polyclonal antibody selective for the rH3A inform. Western blots of rH3A mRNA-transfected HEK-293 cells identified a  ~ 48 kDa band of binding consistent with the molecular weight of rH3A, thus confirming antibody sensitivity for rH3A protein. In parallel, we also established a pan-H3R knockout mice line to confirm antibody specificity in rodent brain membranes. Both qRT-PCR and H3R agonist-stimulated [35S]-GTPγS binding confirmed the absence of mH3A mRNA and H3 receptor-effector coupling in H3R knockout (KO) mice. Subsequent western blotting studies in both rat and mouse brain membranes were unable to detect rH3A antibody binding at ~48 kDa. Rather, the H3RA antibody bound to a  ~ 55 kDa band in both rat and mouse membranes, including H3R KO mice, suggesting H3RA binding was not specific for H3Rs in rodent membranes. Subsequent LC/MS analysis of the ~55 kDa band in frontal cortical membranes identified the highly abundant beta subunit of ATPase in both WT and KO mice. Finally, LC/MS analysis of the ~48 kDa band from rH3A mRNA-transfected HEK-293 cell membranes was able to detect rH3A protein, but its presence was below the limits of quantitative reliability. We conclude that PAE alters rH3A and rH3C mRNA expression in some of the same brain regions where we have previously reported PAE-induced alterations in H3R-effector coupling. However, interpreting the functional consequences of altered H3R isoform expression was limited given the technical challenges of measuring the relatively low abundance of rH3A protein in native membrane preparations.
The impact of TP53 activation and apoptosis in primary hereditary microcephaly
Authors: Iegiani Giorgia , Ferraro Alessia , Pallavicini Gianmarco , Di Cunto Ferdinando
Published: June 2023

Autosomal recessive primary microcephaly (MCPH) is a constellation of disorders that share significant brain size reduction and mild to moderate intellectual disability, which may be accompanied by a large variety of more invalidating clinical signs. Extensive neural progenitor cells (NPC) proliferation and differentiation are essential to determine brain final size. Accordingly, the 30 MCPH loci mapped so far (MCPH1-MCPH30) encode for proteins involved in microtubule and spindle organization, centriole biogenesis, nuclear envelope, DNA replication and repair, underscoring that a wide variety of cellular processes is required for sustaining NPC expansion during development. Current models propose that altered balance between symmetric and asymmetric division, as well as premature differentiation, are the main mechanisms leading to MCPH. Although studies of cellular alterations in microcephaly models have constantly shown the co-existence of high DNA damage and apoptosis levels, these mechanisms are less considered as primary factors. In this review we highlight how the molecular and cellular events produced by mutation of the majority of MCPH genes may converge on apoptotic death of NPCs and neurons, via TP53 activation. We propose that these mechanisms should be more carefully considered in the alterations of the sophisticated equilibrium between proliferation, differentiation and death produced by MCPH gene mutations. In consideration of the potential druggability of cell apoptotic pathways, a better understanding of their role in MCPH may significantly facilitate the development of translational approaches.
Urinary TNF-α as a potential biomarker for chronic primary low back pain
Authors: Gevers-Montoro Carlos , Puente-Tobares Mariana , Monréal Aléxiane , Conesa-Buendía Francisco Miguel , Piché Mathieu , Ortega-De Mues Arantxa
Published: June 2023

Introduction

Over two thirds of individuals with low back pain (LBP) may experience recurrent or persistent symptoms in the long term. Yet, current data do not allow to predict who will develop chronic low back pain and who will recover from an acute episode. Elevated serum levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) have been associated with poor recovery and persistent pain following an acute episode of LBP. Inflammatory cytokines may also mediate mechanisms involved in nociplastic pain, and thus, have significant implications in chronic primary low back pain (CPLBP).

Methods

This study aimed to investigate the potential of urinary TNF-α levels for predicting outcomes and characterizing clinical features of CPLBP patients. Twenty-four patients with CPLBP and 24 sex- and age-matched asymptomatic controls were recruited. Urinary TNF-α concentrations were measured at baseline and after 4 weeks, during which CPLBP patients underwent spinal manipulative therapy (SMT).

Results

Concentrations of TNF-α were found to be elevated in baseline urine samples of CPLBP patients compared to asymptomatic controls. Moreover, these values differed among patients depending on their pain trajectory. Patients with persistent pain showed higher levels of TNF-α, when compared to those with episodic CPLBP. Furthermore, baseline TNF-α concentrations and their changes after 4 weeks predicted alterations in pain intensity and disability following SMT in patients with CPLBP.

Discussion

These findings warrant further research on the potential use of urinary TNF-α concentrations as a prognostic biomarker for CPLBP.
Remyelination in animal models of multiple sclerosis: finding the elusive grail of regeneration
Authors: Packer Davin , Fresenko Emily E. , Harrington Em P.
Published: June 2023

Remyelination biology and the therapeutic potential of restoring myelin sheaths to prevent neurodegeneration and disability in multiple sclerosis (MS) has made considerable gains over the past decade with many regeneration strategies undergoing tested in MS clinical trials. Animal models used to investigate oligodendroglial responses and regeneration of myelin vary considerably in the mechanism of demyelination, involvement of inflammatory cells, neurodegeneration and capacity for remyelination. The investigation of remyelination in the context of aging and an inflammatory environment are of considerable interest for the potential translation to progressive multiple sclerosis. Here we review how remyelination is assessed in mouse models of demyelination, differences and advantages of these models, therapeutic strategies that have emerged and current pro-remyelination clinical trials.
LC–MS-based serum metabolomics analysis for the screening and monitoring of colorectal cancer
Authors: Yi Yanan , Wang Jianjian , Liang Chengtong , Ren Chuanli , Lian Xu , Han Chongxu , Sun Wei
Published: June 2023

Background

Colorectal Cancer (CRC) is a prevalent digestive system tumour with significant mortality and recurrence rates. Serum metabolomics, with its high sensitivity and high throughput, has shown potential as a tool to discover biomarkers for clinical screening and monitoring of the CRC patients.

Methods

Serum metabolites of 61 sex and age-matched healthy controls and 62 CRC patients (before and after surgical intervention) were analyzed using a ultra-performance liquid chromatography-high resolution mass spectrometer (UPLC-MS). Statistical methods and pathway enrichment analysis were used to identify potential biomarkers and altered metabolic pathways.

Results

Our analysis revealed a clear distinction in the serum metabolic profile between CRC patients and healthy controls (HCs). Pathway analysis indicated a significant association with arginine biosynthesis, pyrimidine metabolism, pantothenate, and CoA biosynthesis. Univariate and multivariate statistical analysis showed that 9 metabolites had significant diagnostic value for CRC, among them, Guanosine with Area Under the Curve (AUC) values of 0.951 for the training group and0.998 for the validation group. Furthermore, analysis of four specific metabolites (N-Phenylacetylasparticacid, Tyrosyl-Gamma-glutamate, Tyr-Ser and Sphingosine) in serum samples of CRC patients before and after surgery indicated a return to healthy levels after an intervention.

Conclusion

Our results suggest that serum metabolomics may be a valuable tool for the screening and monitoring of CRC patients.
Case report: long-term sustained remission in a case of metastatic colon cancer with high microsatellite instability and KRAS exon 2 p.G12D mutation treated with fruquintinib after local radiotherapy: a case report and literature review
Authors: Wang Ruiqi , Cong Dan , Bai Yuansong , Zhang Wenlong
Published: June 2023

To demonstrate the efficacy of fruquintinib administration after local radiotherapy in a patient with metastatic colon cancer with high microsatellite instability and the KRAS exon 2 p. G12D mutation. The patient was administered four cycles of pembrolizumab intravenous infusion and achieved stable disease as the best outcome. He was then underwent follow-up concurrent radiochemical therapy (local DT4600cGy/23f/32d radiotherapy, and S-1 to increase sensitivity to radiotherapy), but this had little efficacy. Following this, he was administered fruquintinib and achieved sustained partial remission. At the time of last follow-up, the patient was in continuous remission for 30 months. Administration of fruquintinib after local radiotherapy may be an effective treatment for specific populations with metastatic colorectal cancer.
Human induced pluripotent stem cell–derived liver-on-a-chip for studying drug metabolism: the challenge of the cytochrome P450 family
Authors: Tamargo-Rubio Isabel , Simpson Anna Bella , Hoogerland Joanne A. , Fu Jingyuan
Published: June 2023

The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.
A systematic review and meta-regression of exogenous ketone infusion rates and resulting ketosis—A tool for clinicians and researchers
Authors: Storoschuk Kristi L. , Wood Thomas R. , Stubbs Brianna J.
Published: June 2023

Introduction:Ketone bodies such as beta-hydroxybutyrate (BHB) have pleiotropic functional benefits as fuel and signaling metabolites and may have multiple clinical applications. An alternative to inducing ketosis by dietary modification is intravenous delivery of exogenous sources of ketones. It is unknown whether there is a strong relationship between BHB infusion rate and blood BHB concentrations in the published literature; this information is vital for clinical studies investigating therapeutic effects of ketosis. This systematic review aimed to aggregate available data and address this gap.

Methods:The PubMed and EMBASE databases were searched, and data were extracted from 23 manuscripts where BHB was infused and maximum and/or steady state BHB levels assessed. Infusion rate was adjusted when racemic BHB was infused but onlyD-BHB was measured.

Results:Using a random effects meta-regression, strong linear relationships between BHB infusion rate and maximal (y = 0.060 + 0.870x,R2= 87.2%,p< 0.0001) and steady state (y = −0.022 + 0.849x,R2= 86.9%,p< 0.0001) blood BHB concentrations were found. Sensitivity analysis found this relationship was stronger when studies in non-healthy populations were excluded (y = 0.059 + 0.831x,R2= 96.3%,p< 0.0001).

Conclusion:There is a strong relationship between BHB infusion rate and blood BHB concentrations; the regressions described here can be used by clinicians or researchers to determine ketone delivery required for a target blood concentration.
Association mapping reveals novel genes and genomic regions controlling grain size architecture in mini core accessions of Indian National Genebank wheat germplasm collection
Authors: Kumari Jyoti , Lakhwani Deepika , Jakhar Preeti , Sharma Shivani , Tiwari Shailesh , Mittal Shikha , Avashthi Himanshu , Shekhawat Neelam , Singh Kartar , Mishra Kaushlesh Kumar , Singh Rakesh , Yadav Mahesh C. , Singh Gyanendra Pratap , Singh Amit Kumar
Published: June 2023

Wheat (Triticum aestivum L.) is a staple food crop for the global human population, and thus wheat breeders are consistently working to enhance its yield worldwide. In this study, we utilized a sub-set of Indian wheat mini core germplasm to underpin the genetic architecture for seed shape-associated traits. The wheat mini core subset (125 accessions) was genotyped using 35K SNP array and evaluated for grain shape traits such as grain length (GL), grain width (GW), grain length, width ratio (GLWR), and thousand grain weight (TGW) across the seven different environments (E1, E2, E3, E4, E5, E5, E6, and E7). Marker-trait associations were determined using a multi-locus random-SNP-effect Mixed Linear Model (mrMLM) program. A total of 160 non-redundant quantitative trait nucleotides (QTNs) were identified for four grain shape traits using two or more GWAS models. Among these 160 QTNs, 27, 36, 38, and 35 QTNs were associated for GL, GW, GLWR, and TGW respectively while 24 QTNs were associated with more than one trait. Of these 160 QTNs, 73 were detected in two or more environments and were considered reliable QTLs for the respective traits. A total of 135 associated QTNs were annotated and located within the genes, including ABC transporter, Cytochrome450, Thioredoxin_M-type, and hypothetical proteins. Furthermore, the expression pattern of annotated QTNs demonstrated that only 122 were differentially expressed, suggesting these could potentially be related to seed development. The genomic regions/candidate genes for grain size traits identified in the present study represent valuable genomic resources that can potentially be utilized in the markers-assisted breeding programs to develop high-yielding varieties.
Research progress in physiological effects of resistant substances of Urtica dioica L. on animal performance and feed conversion
Authors: Zhang Yifan , Zhang Xin , Zafar Muhammad Hammad , Zhang Jinying , Wang Jiasheng , Yu Xiang , Liu Wujun , Wang Mengzhi
Published: June 2023

Several members of family Urticaceae are mainly found in the temperate and subtropical zones of the Northern Hemisphere and are important medicinal plants. Among them,Urtica dioicaL. (Urticaceae) is an annual or perennial herb that has been used for feeding and medicinal purposes since long time and is the most exploited species of Urticaceae. Recently, it has received attention to be used as animal feed, as its fresh leaves fed to animals in moderate, dried, and other forms. This review details the advantages ofU. dioicaas an alternative feed in terms of germplasm specificity, nutritional composition, and feed application status. Its roots, stems, leaves, and seeds are rich in active ingredients. It has also been found to have anticancer effects through antioxidant action and promotion of apoptosis of cancer cells. In shady conditions,U. dioicais highly adaptable while under stressful conditions of drought; it also reduces light absorption and ensures carbon assimilation through light energy conversion efficiency. Therefore, it can be added to animal diets as a suitable feed to reduce costs and improve economic efficiency. This paper investigates the feasibility of usingU. dioicaas a feed and systematically presents the progress of research and exploitation ofU. dioica.
Biological and genomic analysis of a symbiotic nitrogen fixation defective mutant in Medicago truncatula
Authors: Shen Yitong , Ma Yelin , Li Dengyao , Kang Mingming , Pei Yue , Zhang Rui , Tao Weiyu , Huang Shenxi , Song Wenjie , Li Yuecheng , Huang Wanqi , Wang Duanyang , Chen Yuhui
Published: June 2023

Medicago truncatula has been selected as one of the model legume species for gene functional studies. To elucidate the functions of the very large number of genes present in plant genomes, genetic mutant resources are very useful and necessary tools. Fast Neutron (FN) mutagenesis is effective in inducing deletion mutations in genomes of diverse species. Through this method, we have generated a large mutant resource in M. truncatula. This mutant resources have been used to screen for different mutant using a forward genetics methods. We have isolated and identified a large amount of symbiotic nitrogen fixation (SNF) deficiency mutants. Here, we describe the detail procedures that are being used to characterize symbiotic mutants in M. truncatula. In recent years, whole genome sequencing has been used to speed up and scale up the deletion identification in the mutant. Using this method, we have successfully isolated a SNF defective mutant FN007 and identified that it has a large segment deletion on chromosome 3. The causal deletion in the mutant was confirmed by tail PCR amplication and sequencing. Our results illustrate the utility of whole genome sequencing analysis in the characterization of FN induced deletion mutants for gene discovery and functional studies in the M. truncatula. It is expected to improve our understanding of molecular mechanisms underlying symbiotic nitrogen fixation in legume plants to a great extent.