bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversified Mammalian Visual Adaptations to Bright- or Dim-Light Environments
Authors: Gai Yulin , Tian Ran , Liu Fangnan , Mu Yuan , Shan Lei , Irwin David M , Liu Yang , Xu Shixia , Yang Guang
Published: March 2023

Photic niche shifts of mammals are associated with changing visual capabilities, primarily mediated by three visual pigments, two (SWS1 and M/LWS) of them for color vision and rhodopsin (RH1) for dim-light vision. To further elucidate molecular mechanisms of mammalian visual adaptations to different light environments, a systematic study incorporating evolutionary analyses across diverse groups and in vitro assays have been carried out. Here, we collected gene sequences for the three opsins from 220 species covering all major mammalian clades. After screening for cone opsin gene losses, we estimated selective pressures on each of the three genes and compared the levels of selection experienced by species living in bright- and dim-light environments. SWS1 pigment is shown to experience accelerated evolution in species living in bright-light environments as has RH1 in aquatic cetaceans, indicating potential shifts for ecological adaptations. To further elucidate the functional mechanisms for these two pigments, we then carried out site-directed mutagenesis in representative taxa. For SWS1, violet and ultraviolet sensitivities in the pika and mouse are mainly affected by substitutions at the critical sites 86 and 93, which have strong epistatic interaction. For RH1, the phenotypic difference between the sperm whale and bovine sequences is largely contributed by a substitution at site 195, which could be critical for dim-light sensation for deep-diving species. Different evolutionary patterns for the visual pigments have been identified in mammals, which correspond to photic niches, although additional phenotypic assays are still required to fully explain the functional mechanisms.
The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis
Authors: Wang Zi , Wang Pan , Zhang Jieying , Gong Han , Zhang Xuchao , Song Jianhui , Nie Ling , Peng Yuanliang , Li Yanan , Peng Hongling , Cui Yajuan , Li Heng , Hu Bin , Mi Jun , Liang Long , Liu Hong , Zhang Ji , Ye Mao , Yazdanbakhsh Karina , Mohandas Narla , An Xiuli , Han Xu , Liu Jing
Published: March 2023

Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis. HES6 physically interacted with GATA1 and influenced the interaction of GATA1 with FOG1. Knockdown of HES6 impaired human erythropoiesis by decreasing GATA1 expression. Chromatin immunoprecipitation and RNA sequencing revealed a rich set of HES6- and GATA1-co-regulated genes involved in erythroid-related pathways. We also discovered a positive feedback loop composed of HES6, GATA1 and STAT1 in the regulation of erythropoiesis. Notably, erythropoietin (EPO) stimulation led to up-regulation of these loop components. Increased expression levels of loop components were observed in CD34+ cells of polycythemia vera patients. Interference by either HES6 knockdown or inhibition of STAT1 activity suppressed proliferation of erythroid cells with the JAK2V617F mutation. We further explored the impact of HES6 on polycythemia vera phenotypes in mice. The identification of the HES6–GATA1 regulatory loop and its regulation by EPO provides novel insights into human erythropoiesis regulated by EPO/EPOR and a potential therapeutic target for the management of polycythemia vera.
Spt6 directly interacts with Cdc73 and is required for Paf1 complex occupancy at active genes in Saccharomyces cerevisiae
Authors: Ellison Mitchell A , Namjilsuren Sanchirmaa , Shirra Margaret K , Blacksmith Matthew S , Schusteff Rachel A , Kerr Eleanor M , Fang Fei , Xiang Yufei , Shi Yi , Arndt Karen M
Published: March 2023

The Paf1 complex (Paf1C) is a conserved transcription elongation factor that regulates transcription elongation efficiency, facilitates co-transcriptional histone modifications, and impacts molecular processes linked to RNA synthesis, such as polyA site selection. Coupling of the activities of Paf1C to transcription elongation requires its association with RNA polymerase II (Pol II). Mutational studies in yeast identified Paf1C subunits Cdc73 and Rtf1 as important mediators of Paf1C association with Pol II on active genes. While the interaction between Rtf1 and the general elongation factor Spt5 is relatively well-understood, the interactions involving Cdc73 have not been fully elucidated. Using a site-specific protein cross-linking strategy in yeast cells, we identified direct interactions between Cdc73 and two components of the Pol II elongation complex, the elongation factor Spt6 and the largest subunit of Pol II. Both of these interactions require the tandem SH2 domain of Spt6. We also show that Cdc73 and Spt6 can interact in vitro and that rapid depletion of Spt6 dissociates Paf1 from chromatin, altering patterns of Paf1C-dependent histone modifications genome-wide. These results reveal interactions between Cdc73 and the Pol II elongation complex and identify Spt6 as a key factor contributing to the occupancy of Paf1C at active genes in Saccharomyces cerevisiae.
Structural basis for the tRNA-dependent activation of the terminal complex of selenocysteine synthesis in humans
Authors: Puppala Anupama K , Castillo Suchkou Jennifer , French Rachel L , Kiernan Kaitlyn A , Simonović Miljan
Published: March 2023

O-Phosphoseryl-tRNASec selenium transferase (SepSecS) catalyzes the terminal step of selenocysteine (Sec) synthesis in archaea and eukaryotes. How the Sec synthetic machinery recognizes and discriminates tRNASec from the tRNA pool is essential to the integrity of the selenoproteome. Previously, we suggested that SepSecS adopts a competent conformation that is pre-ordered for catalysis. Herein, using high-resolution X-ray crystallography, we visualized tRNA-dependent conformational changes in human SepSecS that may be a prerequisite for achieving catalytic competency. We show that tRNASec binding organizes the active sites of the catalytic protomer, while stabilizing the N- and C-termini of the non-catalytic protomer. Binding of large anions to the catalytic groove may further optimize the catalytic site for substrate binding and catalysis. Our biochemical and mutational analyses demonstrate that productive SepSecS•tRNASec complex formation is enthalpically driven and primarily governed by electrostatic interactions between the acceptor-, TΨC-, and variable arms of tRNASec and helices α1 and α14 of SepSecS. The detailed visualization of the tRNA-dependent activation of SepSecS provides a structural basis for a revised model of the terminal reaction of Sec formation in archaea and eukaryotes.
Survival After Sentinel Lymph Node Biopsy Compared with Axillary Lymph Node Dissection for Female Patients with T3-4c Breast Cancer
Authors: Li Peiyong , Yang Ciqiu , Zhang Junsheng , Chen Yitian , Zhang Xiaoqi , Liang Minting , Huang Na , Chen Yilin , Wang Kun
Published: March 2023

Background

For patients with cN0 and T1-2 breast cancer, sentinel lymph node biopsy (SLNB) can provide survival results equivalent to axillary lymph node dissection (ALND). However, whether it can be performed on T3-4c patients is still controversial.

Materials and Methods

Female patients diagnosed with cN0, T3-4c, and M0 breast cancer from 2004 to 2019 were identified using the surveillance, epidemiology and end results (SEER) database and divided into 2 groups, the SLNB group (1-5 regional lymph nodes examined) and the ALND group (≥10 regional lymph nodes examined). Finally, only those with pN0 disease were included in the SLNB group. The baseline differences in clinicopathological characteristics between groups were eliminated by propensity score matching (PSM). We also conducted subgroup analyses according to age, overall TNM stage, breast cancer subtypes, surgical approaches, radiation therapy, and chemotherapy. The primary endpoint was survival.

Results

With a mean follow-up of 75 months, a total of 186 deaths were reported among 864 patients. The overall survival (OS) and breast cancer-specific survival (BCSS) in the SLNB group were 78.2% and 87.5%, respectively, and that in the ALND group were 78.7% and 87.3%, respectively. The unadjusted hazard ratio (HR) for OS and BCSS in the SLNB group (vs. the ALND group) was 0.922 (95% CI, 0.691-1.230, P = .580) and 0.874 (95% CI, 0.600-1.273, P = .481), respectively. Besides, the OS and BCSS between the 2 groups were also similar in all subgroup analyses.

Conclusions

SLNB may be performed on female patients with cN0, T3-4c, and M0 breast cancer.
The functional evolution of architecturally different plant geranyl diphosphate synthases from geranylgeranyl diphosphate synthase
Authors: Song Shuyan , Jin Ruitao , Chen Yufan , He Sitong , Li Kui , Tang Qian , Wang Qi , Wang Linjuan , Kong Mengjuan , Dudareva Natalia , Smith Brian J , Zhou Fei , Lu Shan
Published: March 2023

Terpenoids constitute the largest class of plant primary and secondary metabolites with a broad range of biological and ecological functions. They are synthesized from isopentenyl diphosphate and dimethylallyl diphosphate, which in plastids are condensed by geranylgeranyl diphosphate synthases (GGPPSs) to produce GGPP (C20) for diterpene biosynthesis and by geranyl diphosphate synthases (GPPSs) to form GPP (C10) for monoterpene production. Depending on the plant species, unlike homomeric GGPPSs, GPPSs exist as homo- and heteromers, the latter of which contain catalytically inactive GGPPS-homologous small subunits (SSUs) that can interact with GGPPSs. By combining phylogenetic analysis with functional characterization of GGPPS homologs from a wide range of photosynthetic organisms, we investigated how different GPPS architectures have evolved within the GGPPS protein family. Our results reveal that GGPPS gene family expansion and functional divergence began early in nonvascular plants, and that independent parallel evolutionary processes gave rise to homomeric and heteromeric GPPSs. By site-directed mutagenesis and molecular dynamics simulations, we also discovered that Leu-Val/Val-Ala pairs of amino acid residues were pivotal in the functional divergence of homomeric GPPSs and GGPPSs. Overall, our study elucidated an evolutionary path for the formation of GPPSs with different architectures from GGPPSs and uncovered the molecular mechanisms involved in this differentiation.
Two B-box proteins, PavBBX6/9, positively regulate light-induced anthocyanin accumulation in sweet cherry
Authors: Wang Yanyan , Xiao Yuqin , Sun Yueting , Zhang Xiang , Du Bingyang , Turupu Maihemuti , Yao Qisheng , Gai Shilin , Tong Shi , Huang Jing , Li Tianhong
Published: March 2023

Anthocyanin production in bicolored sweet cherry (Prunus avium cv. Rainier) fruit is induced by light exposure, leading to red coloration. The phytohormone abscisic acid (ABA) is essential for this process, but the regulatory relationships that link light and ABA with anthocyanin-associated coloration are currently unclear. In this study, we determined that light treatment of bicolored sweet cherry fruit increased anthocyanin accumulation and induced ABA production and that ABA participates in light-modulated anthocyanin accumulation in bicolored sweet cherry. Two B-box (BBX) genes, PavBBX6/9, were highly induced by light and ABA treatments, as was anthocyanin accumulation. The ectopic expression of PavBBX6 or PavBBX9 in Arabidopsis (Arabidopsis thaliana) increased anthocyanin biosynthesis and ABA accumulation. Overexpressing PavBBX6 or PavBBX9 in sweet cherry calli also enhanced light-induced anthocyanin biosynthesis and ABA accumulation. Additionally, transient overexpression of PavBBX6 or PavBBX9 in sweet cherry peel increased anthocyanin and ABA contents, whereas silencing either gene had the opposite effects. PavBBX6 and PavBBX9 directly bound to the G-box elements in the promoter of UDP glucose-flavonoid-3-O-glycosyltransferase (PavUFGT), a key gene for anthocyanin biosynthesis, and 9-cis-epoxycarotenoid dioxygenase 1 (PavNCED1), a key gene for ABA biosynthesis, and enhanced their activities. These results suggest that PavBBX6 and PavBBX9 positively regulate light-induced anthocyanin and ABA biosynthesis by promoting PavUFGT and PavNCED1 expression, respectively. Our study provides insights into the relationship between the light-induced ABA biosynthetic pathway and anthocyanin accumulation in bicolored sweet cherry fruit.
Riboflavin mediates m6A modification targeted by miR408, promoting early somatic embryogenesis in longan
Authors: Xu Xiaoping , Zhang Chunyu , Xu Xiaoqiong , Cai Roudi , Guan Qingxu , Chen Xiaohui , Chen Yukun , Zhang Zihao , XuHan Xu , Lin Yuling , Lai Zhongxiong
Published: March 2023

Plant somatic embryogenesis (SE) is an in vitro biological process wherein bipolar structures are induced to form somatic cells and regenerate into whole plants. MicroRNA (miRNA) is an essential player in plant SE. However, the mechanism of microRNA408 (miR408) in SE remains elusive. Here, we used stable transgenic technology in longan (Dimocarpus longan) embryogenic calli to verify the mechanism by which miR408 promotes cell division and differentiation of longan early SE. dlo-miR408-3p regulated riboflavin biosynthesis by targeting nudix hydrolase 23 (DlNUDT23), a previously unidentified gene mediating N6-methyladenosine (m6A) modification and influencing RNA homeostasis and cell cycle gene expression during longan early SE. We showed that DlMIR408 overexpression (DlMIR408-OE) promoted 21-nt miRNA biosynthesis. In DlMIR408-OE cell lines, dlo-miR408-3p targeted and downregulated DlNUDT23, promoted riboflavin biosynthesis, decreased flavin mononucleotide (FMN) accumulation, promoted m6A level, and influenced miRNA homeostasis. DNA replication, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, the pentose phosphate pathway, and taurine and hypotaurine metabolism were also closely associated with riboflavin metabolism. In a riboflavin feeding assay, dlo-miR408-3p and pre-miR408 were upregulated and DlNUDT23 was downregulated, increasing the m6A level and cell division and differentiation in longan globular embryos. When riboflavin biosynthesis was inhibited, dlo-miR408-3p was downregulated and DlNUDT23 was upregulated, which decreased m6A modification and inhibited cell division but did not inhibit cell differentiation. FMN artificial demethylated m6A modification affected the homeostasis of precursor miRNA and miRNA. Our results revealed a mechanism underlying dlo-miR408-3p-activated riboflavin biosynthesis in which DlNUDT23 is targeted, m6A modification is dynamically mediated, and cell division is affected, promoting early SE in plants.
How the Other Half Died: Immigration and Mortality in U.S. Cities
Authors: Ager Philipp , Feigenbaum James J , Hansen Casper W , Tan Hui Ren
Published: March 2023

Fears of immigrants as a threat to public health have a long and sordid history. At the turn of the 20th century, when immigrants made up one-third of the population in crowded American cities, contemporaries blamed high urban mortality rates on the newest arrivals. We evaluate how the implementation of country-specific immigration quotas in the 1920s affected urban health. Cities with larger quota-induced reductions in immigration experienced a persistent decline in mortality rates, driven by a reduction in deaths from infectious diseases. The unfavourable living conditions immigrants endured explains the majority of the effect as quotas reduced residential crowding and mortality declines were largest in cities where immigrants resided in more crowded conditions and where public health resources were stretched thinnest.
Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus
Authors: Fagni Filippo , Bettiol Alessandra , Silvestri Elena , Fedi Roberto , Palermo Adalgisa , Urban Maria Letizia , Mazzotta Ruggero , Malandrino Danilo , Bello Federica , Mattioli Irene , Simon David , Di Scala Gerardo , Schett Georg , Prisco Domenico , Emmi Giacomo
Published: March 2023

Objectives

To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE.

Methods

In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up.

Results

A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3–23.3) years for cases and 12.4 (IQR 7.2–13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%).

Conclusion

In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.
Efficacy and safety outcomes of a compounded testosterone pellet versus a branded testosterone pellet in men with testosterone deficiency: a single-center, open-label, randomized trial
Authors: Kresch Eliyahu , Lima Thiago Fernandes Negris , Molina Manuel , Deebel Nicholas A , Reddy Rohit , Patel Mehul , Loloi Justin , Carto Chase , Nackeeran Sirpi , Gonzalez Daniel C , Ory Jesse , Ramasamy Ranjith
Published: March 2023

Background

Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients.

Aim

To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively.

Methods

This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg).

Outcomes

We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 am): serum testosterone, estradiol, hematocrit, and prostate-specific antigen.

Results

After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study.

Clinical Implications

Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD.

Strengths and Limitations

Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort.

Conclusion

E100 compounded testosterone pellets are a noninferior option of TTh as compared with Testopel for men presenting with TD.
Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome
Authors: Shaz Beth H , Kraft Bryan D , Troy Jesse D , Poehlein Emily , Chen Lingye , Cheatham Lynn , Manyara Raha , Hanafy Khalid , Brown Linda , Scott Margaret , Palumbo Ralph , Vrionis Frank , Kurtzberg Joanne
Published: March 2023

Background

Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking.

Materials and Methods

In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety.

Results

Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs.

Conclusion

We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.
HBx downregulated decorin and decorin‐derived peptides inhibit the proliferation and tumorigenicity of hepatocellular carcinoma cells
Authors: Li Yong , Gan Lipeng , Lu Min , Zhang Xiaodan , Tong Xiaomei , Qi Dandan , Zhao Yan , Ye Xin
Published: March 2023

Hepatitis B virus (HBV) is one of the important risk factors in inducing the occurrence and development of liver cancer, while the mechanism has not been fully clarified. In this study, we found decorin (DCN) was significantly reduced in HBV transgenic cell line HepG2‐4D14 compared to HepG2. The data from hepatocellular carcinoma (HCC) patients indicated that the level of DCN mRNA was significantly lower in tumor tissues than healthy control and positively correlated with the survival of HCC patients. We revealed that HBV HBx can inhibit the transcription of DCN by blocking p53 activity. Functional analysis demonstrated that overexpression of DCN substantially inhibits the proliferation of HCC cells, while knockdown of DCN enhances the proliferation of HCC cells. It is known that DCN could competitively bind to c‐Met to inhibit HGF/c‐Met signaling pathway to inhibit the development of HCC. Therefore, we screened the novel antitumor peptides derived from DCN based on the sequence of DCN and the complex structure of HGF/c‐Met with virtual screening and identified a set of DCN‐derived peptides (DCN‐Ps) which may competitively bind to c‐Met. We found that 5 of peptides can reduce the proliferation and migration of HepG2 cells significantly. Among them, DCN‐P#3 can inhibit the growth of HCC cells both in vitro and in vivo. In conclusion, we discovered that HBV HBx downregulates the expression of DCN, which in turn promotes the proliferation of hepatocytes and the development of HCC. We identified DCN‐derived antitumor peptides which provides the candidates for developing novel drugs against HCC.
Hematopoietic/erythroid enhancers activate nearby target genes by extending histone H3K27ac and transcribing intergenic RNA
Authors: Kim Yea Woon , Kang Jin , Kim AeRi
Published: March 2023

Enhancers activate gene transcription remotely, which requires tissue specific transcription factors binding to them. GATA1 and TAL1 are hematopoietic/erythroid‐specific factors and often bind together to enhancers, activating target genes. Interestingly, we found that some hematopoietic/erythroid genes are transcribed in a GATA1‐dependent but TAL1‐independnet manner. They appear to have enhancers within a relatively short distance. In this study, we paired highly transcribed hematopoietic/erythroid genes with the nearest GATA1/TAL1‐binding enhancers and analyzed these putative enhancer‐gene pairs depending on distance between them. Enhancers located at various distances from genes in the pairs, which was not related to transcription level of the genes. However, genes with enhancers at short distances away tended to be transcriptionally unaffected by TAL1 depletion. Histone H3K27ac extended from the enhancers to target genes. The H3K27ac extension was maintained without TAL1, even though it disappeared owing to the loss of GATA1. Intergenic RNA was highly transcribed from the enhancers to nearby target genes, independent of TAL1. Taken together, TAL1‐independent transcription of hematopoietic/erythroid genes appears to be promoted by enhancers present in a short distance. These enhancers are likely to activate nearby target genes by tracking the intervening regions.
Deficiency of G protein‐coupled receptor Gpr111/Adgrf2 causes enamel hypomineralization in mice by alteration of the expression of kallikrein‐related peptidase 4 (Klk4) during pH cycling process
Authors: Chiba Yuta , Yoshizaki Keigo , Sato Hiroshi , Ikeuchi Tomoko , Rhodes Craig , Chiba Mitsuki , Saito Kan , Nakamura Takashi , Iwamoto Tsutomu , Yamada Aya , Yamada Yoshihiko , Fukumoto Satoshi
Published: March 2023

Enamel is formed by the repetitive secretion of a tooth‐specific extracellular matrix and its decomposition. Calcification of the enamel matrix via hydroxyapatite (HAP) maturation requires pH cycling to be tightly regulated through the neutralization of protons released during HAP synthesis. We found that Gpr115, which responds to changes in extracellular pH, plays an important role in enamel formation. Gpr115‐deficient mice show partial enamel hypomineralization, suggesting that other pH‐responsive molecules may be involved. In this study, we focused on the role of Gpr111/Adgrf2, a duplicate gene of Gpr115, in tooth development. Gpr111 was highly expressed in mature ameloblasts. Gpr111‐KO mice showed enamel hypomineralization. Dysplasia of enamel rods and high carbon content seen in Gpr111‐deficient mice suggested the presence of residual enamel matrices in enamel. Depletion of Gpr111 in dental epithelial cells induced the expression of ameloblast‐specific protease, kallikrein‐related peptidase 4 (Klk4), suggesting that Gpr111 may act as a suppressor of Klk4 expression. Moreover, reduction of extracellular pH to 6.8 suppressed the expression of Gpr111, while the converse increased Klk4 expression. Such induction of Klk4 was synergistically enhanced by Gpr111 knockdown, suggesting that proper enamel mineralization may be linked to the modulation of Klk4 expression by Gpr111. Furthermore, our in vitro suppression of Gpr111 and Gpr115 expression indicated that their suppressive effect on calcification was additive. These results suggest that both Gpr111 and Gpr115 respond to extracellular pH, contribute to the expression of proteolytic enzymes, and regulate the pH cycle, thereby playing important roles in enamel formation.
Immediate treatment for recent hepatitis C infection in people with high-risk behaviors: a systematic review and meta-analysis
Authors: Manoharan Lakshmi , Latham Ned H. , Munari Stephanie C. , Traeger Michael W. , Menon Vinay , Luhmann Niklas , Baggaley Rachel , Macdonald Virginia , Verster Annette , Siegfried Nandi , Matthews Gail V. , Stoové Mark , Hellard Margaret E. , Doyle Joseph S.
Published: March 2023

Background and Aims:

Direct-acting antivirals (DAAs) are almost exclusively approved for the treatment of chronic HCV. This poses a significant barrier to the treatment of recently acquired HCV because of the limited access to DAAs. This review seeks to address this issue by synthesizing evidence of the benefits and harms of immediate treatment after the detection of recently acquired HCV in people at higher risk of infection.

Approach and Results:

A systematic review and meta-analysis were conducted reporting on populations with recently acquired HCV at higher risk of infection. Studies were included if they assessed standard duration DAA treatment regimens and reported on the benefits and harms of immediate treatment (within one year of diagnosis). Outcomes included sustained virological response at 12 weeks post-treatment (SVR12), incidence, treatment initiation and adherence, overtreatment, engagement in care, and adverse events. Eight cohort studies, 3 open-label trials, and 1 case series study were included, reporting on 2085 participants with recently acquired HCV infection. No studies included a comparison group. Eight studies assessed DAA treatment in either men who have sex with men or men who have sex with men with HIV, 2 studies assessed treatment in people who inject drugs, and 2 among people living with HIV. Immediate treatment of HCV was associated with a pooled SVR12 of 95.9% (95% CI, 92.6%–99.3%). Three studies reported on hepatitis C incidence, where most participants were treated in the chronic phase of infection. A treatment completion rate of 100% was reported in 2 studies, and only 1 serious adverse event was described.

Conclusions:

High rates of cure were achieved with the treatment of recently acquired hepatitis C in people at higher risk of infection. Serious adverse events were rare, highlighting individual benefits consistent with the treatment of chronic hepatitis C. The impact of immediate treatment on HCV incidence requires further evaluation.
Humoral and T-cell–mediated immunity to SARS-CoV-2 vaccination in patients with liver disease and transplant recipients
Authors: Willauer Alexandra N. , Rouster Susan D. , Meeds Heidi L. , Jennings Carrie L. , Abdel-Hameed Enass A. , Daria Diane E. , Stambrook Elizabeth P. , Shata Mohamed Tarek M. , Sherman Kenneth E.
Published: March 2023

Background:

SARS-CoV-2 vaccination induces a varied immune response among persons with chronic liver disease (CLD) and solid organ transplant recipients (SOTRs). We aimed to evaluate the humoral and T-cell–mediated immune responses to SARS-CoV-2 vaccination in these groups.

Methods:

Blood samples were collected following the completion of a standard SARS-CoV-2 vaccination (2 doses of either BNT162b2 or mRNA-12732), and a subset of patients had a blood sample collected after a single mRNA booster vaccine. Three separate methods were utilized to determine immune responses, including an anti-spike protein antibody titer, neutralizing antibody capacity, and T-cell–mediated immunity.

Results:

The cohort included 24 patients with chronic liver disease, 27 SOTRs, and 9 controls. Patients with chronic liver disease had similar immune responses to the wild-type SARS-CoV-2 compared with controls following a standard vaccine regimen and single booster vaccine. SOTRs had significantly lower anti-S1 protein antibodies (p < 0.001), neutralizing capacity (p < 0.001), and T-cell–mediated immunity response (p = 0.021) to the wild-type SARS-CoV-2 compared with controls following a standard vaccine regimen. Following a single booster vaccine, immune responses across groups were not significantly different but numerically lower in SOTRs. The neutralization capacity of the B.1.1.529 Omicron variant was not significantly different between groups after a standard vaccine regimen (p = 0.87) and was significantly lower in the SOTR group when compared with controls after a single booster vaccine (p = 0.048).

Conclusion:

The immunogenicity of the SARS-CoV-2 vaccine is complex and multifactorial. Ongoing and longitudinal evaluation of SARS-CoV-2 humoral and cellular responses is valuable and necessary to allow frequent re-evaluation of these patient populations.
Long noncoding RNAs in cardiovascular disease
Authors: Kohlmaier Alexander , Holdt Lesca M. , Teupser Daniel
Published: March 2023

Purpose of review

Here, we review recent findings on the role of long noncoding RNAs (lncRNAs) in cardiovascular disease (CVD). In addition, we highlight some of the latest findings in lncRNA biology, providing an outlook for future avenues of lncRNA research in CVD.

Recent findings

Recent publications provide translational evidence from patient studies and animal models for the role of specific lncRNAs in CVD. The molecular effector mechanisms of these lncRNAs are diverse. Overall, cell-type selective modulation of gene expression is the largest common denominator. New methods, such as single-cell profiling and CRISPR/Cas9-screening, reveal additional novel mechanistic principles: For example, many lncRNAs establish RNA-based spatial compartments that concentrate effector proteins. Also, RNA modifications and splicing features can be determinants of lncRNA function.

lncRNA research is passing the stage of enumerating lncRNAs or recording simplified on-off expression switches. Mechanistic analyses are starting to reveal overarching principles of how lncRNAs can function. Exploring these principles with decisive genetic testing in vivo remains the ultimate test to discern how lncRNA loci, by RNA motifs or DNA elements, affect CVD pathophysiology.
MACULAR ATROPHY AND PHENOTYPIC VARIABILITY IN AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY DUE TO PROM1 MUTATION
Authors: Ricca Aaron M. , Han Ian C. , HOFFMANN JEREMY , Stone Edwin M. , Sohn Elliott H.
Published: March 2023

Purpose:

To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1-associated macular dystrophy.

Methods:

Patients in this retrospective, longitudinal case series from a tertiary center had clinical examination and multimodal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time by optical coherence tomography were calculated by two independent graders.

Results:

Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. The average age was 39 years, and 80% were women. The visual acuity was 20/40 at presentation and 20/57 at last follow-up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (13%), 2) multifocal geographic atrophy (20%), and 3) bull's eye maculopathy (67%). The overall rate of atrophy progression was 0.36 mm2/year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm2/year for central geographic atrophy, 0.53 mm2/year for multifocal geographic atrophy, and 0.23 mm2/year for bull's eye maculopathy.

Conclusion:

Patients with PROM1-associated macular dystrophy demonstrate distinct phenotypes, with bull's eye maculopathy being the most common. The average rate of atrophy progression may be similar to reported rates for ABCA4-related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem cell–based therapies.
Case Study
Authors: Jellerichs Bradley , Rajendran Arun
Published: March 2023

This is a case study of a 55-year-old woman presenting with dystrophic nails that arose during her teenage years and has worsened over the last few years. The patient reported frequent wet work, exposure to irritants, and cuticle manipulation. The physical examination showed proximal nail fold bolstering, loss of cuticle, and a wavy dorsal nail plate resembling a “washboard.” She was diagnosed with chronic paronychia and onychotillomania. She was prescribed clobetasol ointment and sulfacetamide in ethanol and was counseled on hygiene and at-home care. One month after the regimen was started, there was noticeable reduction of inflammation to the cuticle.
Nevus Simplex
Authors: Gomez Jason , Admani Shehla
Published: March 2023

Nevus simplex, or salmon patch, is a benign vascular malformation seen in 30%–40% of infants. Most lesions are self-limiting, resolving spontaneously between the ages of 1 and 2 years. The most affected areas of the skin are the occiput and posterior neck; however, facial, scalp, and sacral involvement can also be seen. A nevus simplex must be differentiated from a port wine stain, as port wine stains are persistent and can be associated with genetic syndromes. Although sacral lesions can be common in nevus simplex complex, when associated with a second lumbosacral anomaly, further evaluation for underlying spinal dysraphism should be considered.
Characterization of social determinants of health of a liver transplant referral population
Authors: Henson Jacqueline B. , Chan Norine W. , Wilder Julius M. , Muir Andrew J. , McElroy Lisa M.
Published: March 2023

Disparities exist in referral and access to the liver transplant (LT) waitlist, and social determinants of health (SDOH) are increasingly recognized as important factors driving health inequities, including in LT. The SDOH of potential transplant candidates is therefore important to characterize when designing targeted interventions to promote equity in access to LT. Yet, it is uncertain how a transplant center should approach this issue, characterize SDOH, identify disparities, and use these data to inform interventions. We performed a retrospective study of referrals for first-time, single-organ LT to our center from 2016 to 2020. Addresses were geoprocessed and mapped to the corresponding county, census tract, and census block group to assess their geospatial distribution, identify potential disparities in referrals, and characterize their communities across multiple domains of SDOH to identify potential barriers to evaluation and selection. We identified variability in referral patterns and areas with disproportionately low referrals, including counties in the highest quartile of liver disease mortality (9%) and neighborhoods in the highest quintile of socioeconomic deprivation (17%) and quartile of poverty (21%). Black individuals were also under-represented compared with expected state demographics (12% vs. 18%). Among the referral population, several potential barriers to evaluation and selection for LT were identified, including poverty, educational attainment, access to healthy food, and access to technology. This approach to the characterization of a transplant center’s referral population by geographic location and associated SDOH demonstrates a model for identifying disparities in a referral population and potential barriers to evaluation that can be used to inform targeted interventions for disparities in LT access.
WeChat app combined CBL in oral medicine clinical training: A review
Authors: He Hong , Xu Jingyi , Sun Mingjie , Shao Jing , Deng Xiaotong , Zeng Li
Published: March 2023

Hotly used in student-centered medical education worldwide, case based learning (CBL) is worthen with WeChat, the most popular communication app and is widely used in all walks of life. We have practiced several years combining WeChat and CBL in the clinical training of oral medicine for young doctors, promoting outcomes over traditional bedside training. This article’s objective is demonstrating the acceptability and merits of WeChat CBL in the clinical training of oral medicine for young doctor. A total of eighty young doctors and 2 tutors participated in this study for interns of a every 2-month training during January 2018 to 2020. The control group used clinical bedside mode; the experimental group used bedside plus WeChat CBL mode. The evaluations included participation passion, daily routine and final test. Ten clerkships and thirty residents were in same number respectively of experiment and control groups. The participants in the experimental group produced a higher degree of participation in discussions. The twice and above Q&A action percentage is 40% in experimental group rather than 25% in control group. Daily assessment and final examination scores in the experimental group were significantly higher than those in the control group (P < .001). WeChat CBL mode has a positive effect on students’ learning enthusiasm, assessments and evaluations in clinical training of oral medicine.
Efficacy and safety of Shugan Jieyu Decoction in the treatment of coronary heart disease complicated with depression
Authors: Li Zhenzhen , Zhang Jianying , Qiao Mingqi , Wang Xiaojin , Guo Yinghui , Wang Haijun
Published: March 2023

Background:

Coronary heart disease combined with depression is 1 of the 2 major diseases affecting physical and mental health. It has become a hot spot at the intersection of psychiatry and internal medicine. Most doctors call double heart medicine, which has a high incidence rate and a low diagnostic rate. Clinical research shows that Shugan Jieyu Decoction (SJD) has a better curative effect, increased safety, and fewer adverse reactions, but it lacks systematic evaluation. This study aims to integrate clinical data through network meta-analysis and provide more evidence-based medical evidence for clinical medication.

Methods:

We searched 8 electronic databases: China knowledge network database, Wanfang, VIP, SinoMed, PubMed, Embase, WebofScience, Cochrane Library, and selected 22 randomized controlled trials from January 2012 to January 2022. The common primary endpoint was the relief of angina pectoris and the improvement of depression. Two researchers used Endnote9.1 software to conduct literature screening and information extraction according to the developed nano-passage standard, used Cochrane collaborative tool to evaluate the bias risk in the experiment, and then used RevMan5.3 software to assess the literature and data analysis synthesis.

Results:

In 1908 patients with coronary heart disease and depression, the total effective rate of SJD in the treatment of angina pectoris was 3.49 (95% confidence interval, 1.93–6.29), as well as the network meta-analysis of improving depressive symptoms, anxiety, depression scores (SAS, SDS) and quality of life scores (HAMD), and reducing the indicators related to CPR and homocysteine.

Conclusion:

The analysis of this study shows that SJD can reduce the frequency of angina pectoris in patients with coronary heart disease and depression, alleviate anxiety and depression, provide a reference basis for clinical treatment, and select more effective intervention therapy.
Rectum adenocarcinoma metabolic subtypes analysis and a risk prognostic model construction based on fatty acid metabolism genes
Authors: Wang Jian , Dong Yi , Shang Dong
Published: March 2023

Fatty acid metabolism is an essential part of cancer research due to its role in cancer initiation and progression. However, its characteristics and prognostic value in rectum adenocarcinoma have not been systematically evaluated. We collected fatty acid metabolism gene expression profiles and clinical information from the cancer genome atlas and gene expression omnibus databases. After excluding individuals lacking clinical information and the presence of genetic mutations, we performed consistent clustering of the remaining patients and selected stable clustering results to group patients. Differentially expressed genes and gene set enrichment analysis were compared between subgroups, while metabolic signature identification and decoding the tumor microenvironment were performed. In addition, we explored the survival status of patients among different subgroups and identified signature genes affecting survival by least absolute shrinkage and selection operator regression. Finally, we selected signature genes to construct a risk prognostic model by multivariate Cox regression and evaluated model efficacy by univariate Cox regression and the receiver operating characteristic curve. By consensus clustering, patients were distinguished into 2 stable subpopulations, gene set enrichment analysis and metabolic signature identification effectively defined 2 completely different subtypes of fatty acid metabolism: fatty acid catabolic subtype and fatty acid anabolic subtype. Among them, patients with the fatty acid catabolic subtype had a poorer prognosis, with a significantly lower proportion of myeloid dendritic cells infiltration within the tumor microenvironment. Aquaporin 7 (hazard ratio, HR = 2.064 (1.4408–4.5038); P < .01), X inactive specific transcript (HR = (0.3758–0.7564), P = .045) and interleukin 4 induced 1 (HR = 1.34 (1.13–1.59); P = .034), were selected by multivariate Cox regression, which constructed a risk prognostic model. The independent hazard ratio of the model was 2.72 and the area under curve was higher than age, gender and tumor stage, showing better predictive efficacy. Our study revealed the heterogeneity of fatty acid metabolism in rectum adenocarcinoma, defined 2 completely distinct subtypes of fatty acid metabolism, and finally established a novel fatty acid metabolism-related risk prognostic model. The study contributes to the early risk assessment and monitoring of individual prognosis and provides data to support individualized patient treatment.
Assessment of glucose and lipid metabolism in patients with polycystic ovary syndrome with and without Hashimoto’s thyroiditis
Authors: Jia Cenlin , Zhang Lin , Liu Wenhua , Zhang Xiangyan , Wu Hongyan
Published: March 2023

To investigate glucose and lipid metabolism in patients with polycystic ovary syndrome (PCOS) with and without Hashimoto’s thyroiditis (HT). In the present study, 103 women were included as controls and a total of 213 patients (49 patients with HT and 164 patients without HT) diagnosed with PCOS. The oral glucose tolerance, insulin release, thyroid function, and lipid levels were measured. PCOS patients had significantly higher levels of fasting insulin (FINS), hemostasis of model assessment-insulin resistance, low-lipoprotein cholesterol, triglyceride, apolipoprotein B, apolipoprotein B/apolipoprotein A1, and homocysteine than the controls. PCOS Patients with HT + had higher FINS, 60FINS, 120FINS, and insulin resistance levels than those without Hashimoto’s thyroiditis group. HT + group had higher total cholesterol, and thyroid-stimulating hormone levels, while free triiodothyronine, and free thyroxine levels were significantly lower. PCOS can lead to disorders of glucolipid metabolism, PCOS with Hashimoto’s thyroiditis may further exacerbate disorders of glucose and lipid metabolism, and therefore thyroid function assessment in patients with PCOS needs to be emphasized.
The pathogenesis hypothesis and research progress of CLIPPERS: A literature review
Authors: Cao Long , Liu Meiping , Guo Li , Li Mingyan , Xu Min , Wang Rui
Published: March 2023

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is still a rare autoimmune disease in the world. In recent years, there are more and more reports about the clinical manifestations of CLIPPERS, but the specific etiology and pathogenesis are not clear. In this paper, by collating the literature reported in recent years, in the reported effective treatment cases, we found the current hypothesis about the pathogenesis of CLIPPERS. Three pathogenesis hypotheses: organ-specific autoimmunity; virus infection affects autoimmunity; and helper T lymphocyte 17 mediates autoimmunity. Although it is hypothetical, it is expected to further clarify the pathogenesis, evolution characteristics, and treatment of CLIPPERS, so as to provide a reference for further understanding of the disease. In the future, more observations and studies are needed to further verify the feasibility of the hypothesis. This article expands on atypical clinical manifestations and summarizes treatment options. Hope to provide a reference for clinical diagnosis and treatment of CLIPPERS.