bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Case and Comprehensive Review of the Ophthalmic Manifestations of 172 Individuals With Branchio-Oculo-Facial Syndrome
Authors: Lam Kevin , Cassidy Benjamin , Arreola Rolando , Al Saif Hind , King Kayla , Couser Natario L. 
Published: October 2022

Purpose:
To review the literature on branchio-oculo-facial syndrome and describe a new case.

Methods:

A girl presented with a de novo pathogenic mutation in the
TFAP2A
gene consistent with branchio-oculo-facial syndrome. A systematic review was also performed to characterize the eye manifestations associated with the syndrome.

Results:
A total of 172 total patients were identified from the literature. Among these, 102 patients received molecular confirmation. The most common pathogenic variants reported were p.R255G, p.A256V, p.R254W, and p.G251E. Common eye abnormalities associated with the syndrome in total combined cases (represents individuals with a clinical diagnosis only of branchio-oculo-facial syndrome plus those who additionally had molecular confirmation of the syndrome from genetic testing) were nasolacrimal duct stenosis (n = 98, 57%), coloboma (n = 76, 46%), anophthalmia/microphthalmia (n = 64, 37%), and cataracts (n = 27, 16%).

Conclusions:

This analysis provides a comprehensive review of genetic variants and ophthalmic findings to characterize the most common eye manifestations associated with branchio-oculo-facial syndrome. The report provides incentive to further investigate
TFAP2A
variants and identify genotype-phenotype correlations.

[
J Pediatr Ophthalmol Strabismus
. 2023;60(4):295–301.]
T Cell Transcriptome in Chromosome 22q11.2 Deletion Syndrome
Authors: Raje Nikita R , Noel-MacDonnell Janelle R , Shortt Katherine A , Gigliotti Nicole M , Chan Marcia A , Heruth Daniel P 
Published: October 2022

Abstract
Phenotypic variations of chromosome 22q11.2 deletion syndrome (22qDS) have unclear explanations. T cell lymphopenia in 22qDS related to varying degrees of thymic hypoplasia contributes to the phenotypic heterogeneity. No phenotype correlation with genotype or deletion size is known for lymphopenia. We investigated gene expression in human T cells of participants with and without 22qDS and T cells of participants with 22qDS with low or normal T cells. Peripheral blood was collected from participants aged 5–8 y. Immune function was checked. RNA sequencing was completed on isolated T cells, and differential gene expression profiles of T cells between 22qDS and healthy control subjects were established. A total of 360 genes were differentially expressed (q &lt; 0.05) between T cells of patients with 22qDS (n = 13) and healthy control subjects (n = 6) (log2 fold change range, −2.0747, 15.6724). We compared gene expression between participants with 22qDS with low (n = 7) and normal T cell counts (n = 6), finding 94 genes that were differentially expressed (q &lt; 0.05) (log2 fold change range, −4.5445, 5.1297). Twenty-nine genes correlated with T cell counts and markers CD3, CD4, CD8, and CD45RA+CD4 (R ≥ 0.8). We found significantly differentially expressed genes in participants with 22qDS compared with healthy control subjects and in participants with 22qDS with low T cell counts compared with those with normal T cell counts. Several enriched pathways suggest a role of T cells in defective communication between T cells and the innate immune system in 22qDS. Among these, the liver X receptor/retinoid X receptor pathway was noted to show several differentially expressed genes affecting participants with 22qDS compared with healthy control subjects and more so those with low T cell counts than in those with normal T cell counts.
Protein Kinase CK2 Controls CD8+ T Cell Effector and Memory Function during Infection
Authors: Yang Wei , Wei Hairong , Benavides Gloria A , Turbitt William J , Buckley Jessica A , Ouyang Xiaosen , Zhou Lianna , Zhang Jianhua , Harrington Laurie E , Darley-Usmar Victor M , Qin Hongwei , Benveniste Etty N 
Published: October 2022

Abstract
Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α′) and two regulatory subunits (CK2β). CK2 promotes cancer progression by activating the NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways, and also is critical for immune cell development and function. The potential involvement of CK2 in CD8+ T cell function has not been explored. We demonstrate that CK2 protein levels and kinase activity are enhanced upon mouse CD8+ T cell activation. CK2α deficiency results in impaired CD8+ T cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T cell metabolic reprogramming through regulating the AKT/mTOR pathway. Lastly, using a mouse Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T cell expansion, maintenance, and effector function in both primary and memory immune responses. Collectively, our study implicates CK2α as an important regulator of mouse CD8+ T cell activation, metabolic reprogramming, and differentiation both in vitro and in vivo.
The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1
Authors: Liu Haiyan , Wang Xin , Ding Renyi , Jiao Anjun , Zheng Huiqiang , Zhang Cangang , Feng Zhao , Su Yanhong , Yang Xiaofeng , Lei Lei , Sun Lina , Zhang Lianjun , Sun Chenming , Zhang Baojun 
Published: October 2022

Abstract
Memory CD8+ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8+ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8+ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8+ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8+ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8+ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8+ T cell memory.
Med1 Controls Effector CD8+ T Cell Differentiation and Survival through C/EBPβ-Mediated Transcriptional Control of T-bet
Authors: Jiao Anjun , Liu Haiyan , Ding Renyi , Zheng Huiqiang , Zhang Cangang , Feng Zhao , Lei Lei , Wang Xin , Su Yanhong , Yang Xiaofeng , Sun Chenming , Zhang Lianjun , Bai Liang , Sun Lina , Zhang Baojun 
Published: October 2022

Abstract
Effector CD8+ T cells are crucial players in adaptive immunity for effective protection against invading pathogens. The regulatory mechanisms underlying CD8+ T cell effector differentiation are incompletely understood. In this study, we defined a critical role of mediator complex subunit 1 (Med1) in controlling effector CD8+ T cell differentiation and survival during acute bacterial infection. Mice with Med1-deficient CD8+ T cells exhibited significantly impaired expansion with evidently reduced killer cell lectin-like receptor G1+ terminally differentiated and Ly6c+ effector cell populations. Moreover, Med1 deficiency led to enhanced cell apoptosis and expression of multiple inhibitory receptors (programmed cell death 1, T cell Ig and mucin domain–containing-3, and T cell immunoreceptor with Ig and ITIM domains). RNA-sequencing analysis revealed that T-bet– and Zeb2-mediated transcriptional programs were impaired in Med1-deficient CD8+ T cells. Overexpression of T-bet could rescue the differentiation and survival of Med1-deficient CD8+ effector T cells. Mechanistically, the transcription factor C/EBPβ promoted T-bet expression through interacting with Med1 in effector T cells. Collectively, our findings revealed a novel role of Med1 in regulating effector CD8+ T cell differentiation and survival in response to bacterial infection.
Contribution of Lipid Mediators in Divergent Outcomes following Acute Bacterial and Viral Lung Infections in the Obese Host
Authors: Schwarz Benjamin , Roberts Lydia M , Bohrnsen Eric , Jessop Forrest , Wehrly Tara D , Shaia Carl , Bosio Catharine M 
Published: October 2022

Abstract
Obesity is considered an important comorbidity for a range of noninfectious and infectious disease states including those that originate in the lung, yet the mechanisms that contribute to this susceptibility are not well defined. In this study, we used the diet-induced obesity (DIO) mouse model and two models of acute pulmonary infection, Francisella tularensis subspecies tularensis strain SchuS4 and SARS-CoV-2, to uncover the contribution of obesity in bacterial and viral disease. Whereas DIO mice were more resistant to infection with SchuS4, DIO animals were more susceptible to SARS-CoV-2 infection compared with regular weight mice. In both models, neither survival nor morbidity correlated with differences in pathogen load, overall cellularity, or influx of inflammatory cells in target organs of DIO and regular weight animals. Increased susceptibility was also not associated with exacerbated production of cytokines and chemokines in either model. Rather, we observed pathogen-specific dysregulation of the host lipidome that was associated with vulnerability to infection. Inhibition of specific pathways required for generation of lipid mediators reversed resistance to both bacterial and viral infection. Taken together, our data demonstrate disparity among obese individuals for control of lethal bacterial and viral infection and suggest that dysregulation of the host lipidome contributes to increased susceptibility to viral infection in the obese host.
Epitope Mapping of Therapeutic Antibodies Targeting Human LAG3
Authors: Agnihotri Pragati , Mishra Arjun K , Agarwal Priyanka , Vignali Kate M , Workman Creg J , Vignali Dario A A , Mariuzza Roy A 
Published: October 2022

Abstract
Lymphocyte activation gene 3 protein (LAG3; CD223) is an inhibitory receptor that is highly upregulated on exhausted T cells in tumors and chronic viral infection. Consequently, LAG3 is now a major immunotherapeutic target for the treatment of cancer, and many mAbs against human (h) LAG3 (hLAG3) have been generated to block its inhibitory activity. However, little or no information is available on the epitopes they recognize. We selected a panel of seven therapeutic mAbs from the patent literature for detailed characterization. These mAbs were expressed as Fab or single-chain variable fragments and shown to bind hLAG3 with nanomolar affinities, as measured by biolayer interferometry. Using competitive binding assays, we found that the seven mAbs recognize four distinct epitopes on hLAG3. To localize the epitopes, we carried out epitope mapping using chimeras between hLAG3 and mouse LAG3. All seven mAbs are directed against the first Ig-like domain (D1) of hLAG3, despite their different origins. Three mAbs almost exclusively target a unique 30-residue loop of D1 that forms at least part of the putative binding site for MHC class II, whereas four mainly recognize D1 determinants outside this loop. However, because all the mAbs block binding of hLAG3 to MHC class II, each of the epitopes they recognize must at least partially overlap the MHC class II binding site.
Impact of Estrogen and Progesterone on Immune Cells and Host–Pathogen Interactions in the Lower Female Reproductive Tract
Authors: Collins Morgan K , McCutcheon Cole R , Petroff Margaret G 
Published: October 2022

Abstract
Microbial infections are a threat to women’s reproductive health. Although reproductive cycles and pregnancy are controlled by sex hormones, the impact of hormones on host–pathogen interactions and immune function in the female reproductive tract are understudied. Furthermore, the changing endocrine environment throughout pregnancy may influence how and when women are susceptible to ascending infection. Because most intrauterine microbial infections originate in the lower reproductive tract, it is vital that future studies determine how different hormonal conditions influence the lower reproductive tract’s susceptibility to infection to understand temporal components of infection susceptibilities across pregnancy. These studies should also extend to nonpregnant women, as it is critical to establish how hormonal fluctuations across the menstrual cycle and hormonal contraceptives may influence disease susceptibility. This review summarizes current knowledge of how estrogen and progesterone impact vaginal and cervical mucosal immunity, barrier function, and interactions with microbial communities.
Pre–Germinal Center Interactions with T Cells Are Natural Checkpoints to Limit Autoimmune B Cell Responses
Authors: Parham Kate A , Tan Xiu Xia Sherry , Morelli Daniel M , Chowdhury Lika , Craig Heather C , Kerfoot Steven M 
Published: October 2022

Abstract
Interactions with Ag-specific T cells drive B cell activation and fate choices that ultimately determine the quality of high-affinity Ab responses. As such, these interactions, and especially the long-lived interactions that occur before germinal center formation, may be important checkpoints to regulate undesirable responses. Using mouse model Ag systems, we directly observed interactions between T and B cells responding to the self-antigen myelin oligodendrocyte glycoprotein (MOG) and found that they are of lower quality compared with interactions between cells responding to the model foreign Ag nitrophenyl-haptenated OVA. This was associated with reduced expression of molecules that facilitate these interactions on the B cells, but not on T cells. B cell expression of these molecules was not dictated by the T cell partner, nor could the relative lack of expression on MOG-specific (MOG-sp.) B cells be reversed by a multivalent Ag. Instead, MOG-sp. B cells were inherently less responsive to BCR stimulation than MOG-non-sp. cells. However, the phenotype of MOG-sp. B cells was not consistent with previous descriptions of autoimmune B cells that had been tolerized via regular exposure to systemically expressed self-antigen. This suggests that alternate anergy pathways may exist to limit B cell responses to tissue-restricted self-antigens.
Anti-arthritic effect of Distemonanthus benthamianus extracts against rheumatoid arthritis in rats
Authors: William Yousseu Nana , Hoki Kwenteh Ernest Allah , Gilbert Ateufack , Gonzal Tsafack Eric , Flore Djuichou Nguemnang Stephanie , Linda Fagni Njoya Zenab , Donatien Atsamo Albert , Mba Matah Marthe Vanessa , Flore Adjouzem Carine , Karelle Madjo Kouam Yacine , Elvira Ngoufack Azanze , Marius Mbiantcha 
Published: October 2022

Objective:
To evaluate the anti-arthritic effect of aqueous and methanolic extracts of Distemonanthus benthamianus.

Methods:
Monoarthritis was induced by an injection of 0.3 mL zymosan A (0.9% NaCl, v/v) in the right posterior knee joints of rats. Then, joint diameter and pain threshold were determined. Polyarthritis was induced by an intracaudal injection of complete Freund’s adjuvant and rats were treated from day 14 post 1st complete Freund’s adjuvant injection until 28 day. The clinical, hematological, biochemical and oxidative stress parameters were evaluated. In addition, histological analysis of the knee joint was perfomed in both tests.

Results:
The aqueous and methanolic extracts of Distemonanthus benthamianus at a dose of 500 mg/kg ameliorated zymosan A-induced monoarthritis, as evidenced by reduced joint diameter, increased pain threshold, as well as improved joint architecture. In addition, both extracts of Distemonanthus benthamianus markedly increased body weight and pain threshold, while reducing paw edema in polyarthritic rats. They also led to a marked decrease in platelets and white blood cells (P<0.05), as well as a significant increase in red blood cells, hemoglobin and hematocrit (P<0.05). The aqueous and methanolic extracts of Distemonanthus benthamianus significantly reduced alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activities, while increasing serum protein levels (P<0.05) with no significant variation in creatinine level. Moreover, both extracts increased catalase and glutathione activities (P<0.05), and inhibited malondialdehyde and nitric oxide production (P<0.01 and P<0.001) in the liver and kidneys. Histological analysis of the joints showed that both extracts triggered tissue reparation.

Conclusions:

Distemonanthus benthamianus could be used as a potential candidate in the treatment of rheumatoid arthritis.
Rhamnus crenata leaf extracts exhibit anti-inflammatory activity via modulating the Nrf2/HO-1 and NF-κB/MAPK signaling pathways
Authors: Eo Hyun Ji , Kim Da Som , Park Gwang Hun 
Published: October 2022

Objective:
To elucidate the potential anti-inflammatory mechanisms of Rhamnus crenata leaf extracts using RAW264.7 cells.

Methods:
We used 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay to measure cell viability. Nitric oxide (NO) production was measured using Griess reagent. Western blotting and RT-PCR assays were carried out for analyzing the protein and gene expressions of pro-inflammatory mediators, respectively. Moreover, PD98059 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), and BAY11-7082 (NF-κB inhibitor) were used to evaluate the anti-inflammatory mechanism of Rhamnus crenata leaf extract.

Results:

Rhamnus crenata leaf extracts significantly inhibited the production of the pro-inflammatory mediators such as NO, iNOS, COX-2, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Rhamnus crenata leaf extracts also suppressed LPS-induced degradation of IκB-α and nuclear accumulation of p65, which resulted in the inhibition of NF-κB activation in RAW264.7 cells. Additionally, the extracts attenuated the phosphorylation of p38, ERK1/2, and JNK in LPS-stimulated RAW264.7 cells. Moreover, HO-1 expression induced by Rhamnus crenata leaf extracts was significantly downregulated by SB230580, PD98059, SP600125 and BAY11-7082.

Conclusions:

Rhamnus crenata leaf extract may upregulate HO-1 expression through inhibition of p38, ERK1/2, and NF-κB activation, which may contribute to the anti-inflammatory activity of the extracts. Rhamnus crenata leaf extracts may have great potential for the development of anti-inflammatory drugs to treat acute and chronic inflammatory diseases.
Erianin inhibits oral cancer cell growth, migration, and invasion via the Nrf2/HO-1/ GPX4 pathway
Authors: Tian Xiu-Yun , Han Rui , Huang Qing-Yang , Zhou Mei-Yun , Luo Bin , Chen Xin-Ru , Xu Jin-Cheng 
Published: October 2022

Objective:
To evaluate the effect of erianin on the viability, migration, and invasion of KB cells and elucidate its underlying mechanisms.

Methods:
Cell Counting Kit-8, colony formation, wound healing, and Transwell assays were used to determine the proliferation, migration, and invasion of oral cancer KB cells. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels were determined. Fluorescent probes were used to detect changes in intracellular reactive oxygen species and iron ions. Additionally, the expressions of ferroptosis-related proteins, NF-E2-related factor 2 (Nrf2), ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and glutathione peroxidase 4 (GPX4) were analyzed by Western blotting assays.

Results:
Erianin induced ferroptosis and inhibited the proliferation, migration, and invasion of KB cells. Moreover, erianin decreased GSH level, increased MDA level, elevated intracellular ROS and Fe2+ contents, and downregulated the expression of the ferroptosis-related proteins Nrf2, HO-1, GPX4, and FTH1 in KB cells. These effects of erianin were effectively reversed by a ferroptosis inhibitor, ferrostatin-1.

Conclusions:
Erianin inhibits the proliferation, migration, and invasion of oral cancer cells and induces ferroptosis via the Nrf2/HO-1/GPX4 signaling pathway. Therefore, erianin may be a potential candidate for the treatment of oral cancer.
Association of methylenetetrahydrofolate reductase polymorphism and male infertility in type 2 diabetes mellitus patients
Authors: Babu K. Ranjith , Vijayaraman Manibalan , Shastri Deepti , Manivannan E. 
Published: October 2022

INTRODUCTION:
As per World Health Organization, Infertility is a condition which is characterized by not getting conceived with more than 1-year of unprotected sexual intercourse without usage of any contraceptive aids. Folate has a significant role in the metabolism of the cells, like nucleic acids synthesis, gene expression by means of remethylation of the homocysteine into methionine. In the males, deficiency of folate leads to reduced proliferation of the sperm cells. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase genes result in alterations of the methylations resulting pathological conditions being a potential risk factor for male infertility.

MATERIALS AND METHODS:
A total of 100 diabetic infertile males were selected as the study group and 100 nondiabetic fertile males were included as the control group. Blood samples were analyzed for the MTHFR polymorphisms. DNA extraction was done and the extract is subjected to polymerase chain reaction amplification. The resultant is subjected to electrophoresis for MTHFR gene allele confirmation. Statistical analysis was done using IBM SPSS Statistics 20 package. Chi-square test, odds ratio has been done and P < 0.05 is considered statistically significant.

RESULTS:
Genotype frequencies of MTHFR C677T, A1298C in all the subjects were analyzed for the Hardy–Weinberg law of genetic equilibrium. Mutant polymorphisms of MTHFR C677T, i.e., thymine-thymine and cytosine-thymine were increased significantly. Similarly, MTHFR A1298C mutant polymorphisms, i.e. adenine-cytosine, cytosine-cytosine were increased significantly in the infertile group than in the fertile group.

DISCUSSION:
Mutations of both MTHFR C677T, A1298C are found to be linked with lowered enzyme activity. We found that the occurrence of mutant homozygous and mutant heterozygous genotypes was increased in a diabetic male infertile group when compared to nondiabetic fertile group. Hence, it can be concluded that presence of single-nucleotide polymorphisms of MTHFR will increase the risk of infertility in diabetic male population.