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Simple Summary: This study utilized small RNA sequencing to explore how the expression of miRNAs differs in milk-derived exosomes from yaks living at different altitudes. The analysis revealed distinct miRNAs associated with yak adaptations to environmental pressures such as mastitis, viral infections, and heat stress. These findings suggest that miRNAs carried by yak milk-derived exosomes play a crucial role in yak resilience, disease resistance, and immune regulation, offering valuable insights for a deeper understanding of yak adaptation. Yaks are a rare and unique animal species inhabiting the Qinghai–Tibet Plateau; they are renowned for their remarkable ability to thrive in harsh environments. Milk-derived exosomes, tiny vesicles containing various biological molecules, play crucial roles in numerous pathological and physiological processes, including cell growth, development, and immune regulation. This study delved into the microRNA expression profiles of yak milk-derived exosomes collected from both high- and low-altitude populations using small RNA sequencing. These miRNAs were found to be implicated in pathways associated with mammary gland inflammation, virus infection regulation, and heat stress response. Functional enrichment analyses, utilizing GO and KEGG databases, revealed that the target genes of these differentially expressed miRNAs are enriched in signaling pathways crucial for Th17 cell differentiation and the Ras-MAPK signaling pathway. In conclusion, this research illuminates the adaptive mechanisms of yaks through the differential expression of miRNAs in their milk-derived exosomes across varying environmental conditions. These findings provide a valuable foundation for future investigations into yak resilience and the potential of milk-derived exosomes as tools for disease management and immune modulation. [ABSTRACT FROM AUTHOR]

Yaks are crucial to local herders' economy and agriculture. However, several diseases pose a significant threat to the health of yaks and cause substantial economic losses for herders. Therefore, studying the immune indicators and breeding of yaks has become an important task. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of the G protein-activated inwardly rectifying K+ channel 2 (KCNJ6, GIRK2) gene and yak immune indicators, with the goal of identifying potential candidate molecular markers for yak breeding. In this study, we genotyped 192 healthy adult yaks and detected three SNPs (g163684421 C > T, g163688148 C > T, and g163690745 T > C) in the yak KCNJ6 gene. These SNPs were found to be distributed in the yak population. Subsequently, we performed a linkage disequilibrium analysis and found that the linkage disequilibrium levels of g163684421 C > T and g163690745 T > C were relatively high. Through a correlation analysis of yak KCNJ6 gene SNPs and immune indicators, we found that g163684421 C > T and g163690745 T > C were significantly associated with IgA, IgG, IgM, CRP, HP, IL-2, IL-4, IFN-γ, and TNF-α (p < 0.05), and the mutation of these SNPs leads to a decrease in yak immune indicators. On the other hand, g163688148 C > T was significantly associated with IgG, IL-4, IFN-γ, TNF-α, IgA, CRP, and HP (p < 0.05), and the mutation of this SNP leads to an increase in yak immune indicators. In conclusion, we identified SNPs associated with yak immune indicators and found that KCNJ6 gene polymorphisms can serve as candidate molecular markers for yak immune indicators. This study provides valuable genetic resources for marker-assisted selection in yak breeding. The results of this study are of great importance for the research on yak immune indicators and marker-assisted selection in yak breeding. [ABSTRACT FROM AUTHOR]

Taste perception is one of the important senses in mammals. Taste dysfunction causes significant inconvenience in daily life, leading to subhealth and even life‐threatening condition. Aging is a major cause to taste dysfunction, while the underlying feature related to gustatory aging is still not known. Using single‐cell RNA Sequencing, differentially expressed genes between aged and young taste papillae are identified, including upregulated mt‐Nd4l and Xist, as well as downregulated Hsp90ab1 and Tmem59. In the Tmem59−/− circumvallate papillae (CVP), taste mature cell generation is impaired by reduction in the numbers of PLCβ2+ and Car4+ cells, as well as decreases in expression levels of taste transduction genes. Tmem59−/− mice showed deficits in sensitivities to tastants. Through screening by GenAge and DisGeNET databases, aging‐dependent genes and oral disease‐associated genes are identified in taste papillae. In the CVP, aging promotes intercellular communication reciprocally between (cycling) basal cell and mature taste cell by upregulated Crlf1/Lifr and Adam15/Itga5 signaling. By transcriptional network analysis, ribosome proteins, Anxa1, Prdx5, and Hmgb1/2 are identified as transcriptional hubs in the aged taste papillae. Chronological aging‐associated transcriptional changes throughout taste cell maturation are revealed. Aged taste papillae contain more Muc5b+ cells that are not localized in gustatory gland. Collectively, this study shows molecular and cellular features associated with taste papilla aging. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the nutritional properties of yak milk in various areas of Gannan. The milk composition analyzer, automatic amino acid analyzer, and flavor analyzer were used to detect the conventional nutrients, amino acids, and volatile flavor substances of 249 yak milks in Meiren grassland, Xiahe grassland, and Maqu grassland (hereinafter referred to as Meiren yak, Xiahe yak, and Maqu yak) in the Gannan area. The results showed that the fat content of Meiren yak milk was significantly higher than that of Maqu yak and Xiahe yak (p < 0.05). The protein content of Meiren yak milk was significantly higher than that of Xiahe yak (p < 0.05), but not significantly different from that of Maqu yak (p > 0.05). The casein content in the milk of Maqu yak was significantly higher than that of Meiren yak and Xiahe yak (p < 0.05). There was no significant difference in the lactose content of yak milk in the three regions (p > 0.05). The content of glutamic acid in the milk of Meiren yak, Xiahe yak, and Maqu yak was noticeably high, which was 1.03 g/100 g, 1.07 g/100 g, and 1.10 g/100 g, respectively. The total amino acid (TAA) content was 4.78 g/100 g, 4.87 g/100 g, and 5.0 g/100 g, respectively. The ratios of essential amino acids (EAA) and total amino acids (TAA) in the milk of Meiren yak, Xiahe yak, and Maqu yak were 42.26%, 41.27%, and 41.39%, respectively, and the ratios of essential amino acids (EAA) and nonessential amino acids (NEAA) were 73.19%, 70.28%, and 70.61%, respectively. In the yak milk samples collected from three different regions, a total of 34 volatile flavor compounds were detected, including 10 aldehydes, five esters, six ketones, four alcohols, two acids, and seven others. The main flavor substances qualitatively obtained from Meiren yak milk were ethyl acetate, n-valeraldehyde, acetic acid, heptanal, and n-hexanal. Xiahe yak milk mainly contains ethyl acetate, isoamyl alcohol, n-valeraldehyde, heptanal, and ethyl butyrate. Maqu yak milk mainly contains ethyl acetate, n-valeraldehyde, isoamyl alcohol, heptanal, ethyl butyrate, and n-hexanal. Principal component analysis showed that the flavor difference between Xiahe yak and Maqu yak was small, while the flavor difference between Xiahe yak, Maqu yak, and Meiren yak was large. The findings of this research can serve as a foundation for the future advancement and application of yak milk. [ABSTRACT FROM AUTHOR]

Simple Summary: Exosomes are multivesicular bodies produced and secreted by living cells as membranous vesicles with a diameter of about 30–150 nm, density of 1.13–1.19 g/mL, and a typical "cup dish" shape. Exosomes carry proteins, miRNA, lncRNA, circRNA, and mRNA and their degradation fragments are involved in intracellular signal transduction important for regulation of cellular activities. Of these, miRNAs play an important role in the regulation of gene expression in important biological processes such as cell division, tissue development, and immune response. In this study, milk quality was determined and exosome miRNAs from yak and Jeryak milk sampled in June and December were characterized by sequencing. Differentially expressed miRNAs (DEMs) and pathways related to lactation performance were identified. In summary, this study provides data that can be used to develop alternative strategies for improving the lactation performance of yaks and Jeryaks. The Jeryak is the hybrid offspring of yaks and Jersey cattle and exhibit improved milk and meat yields. Biomolecules carried within milk exosomes are important for cell growth, development, immune regulation, and various pathophysiological processes. Previous studies showed that miRNAs regulate mammary gland development, lactation, and milk quality. This study explored the relationship between milk exosomes miRNAs and lactation performance. A comparison of the milk content showed that yak milk was of a better quality compared to Jeryak milk (casein, fat, TS, SNF, lactose). Milk collected in December was superior to that collected in June for both yak and Jeryak, except for lactose concentrations. Exosomes were extracted by density gradient centrifugation and miRNA expression profiles in milk exosomes from three yaks and three Jeryaks collected in June and December were detected by small RNA sequencing. In all, 22, 120, 78, and 62 differentially expressed miRNAs (DEMs) were identified in Jun_ JY vs. Jun_ Y (P1: Jeryak in June vs. Yak in June), Jun_ JY vs. Dec_ JY (P2: Jeryak in June vs. Jeryak in December), Dec_ JY vs. Dec_ Y (P3: Jeryak in December vs. Yak in December), and Jun_ Y vs. Dec_ Y (P4: Yak in June vs. Yak in December) groups. These DEMs were enriched in functions and signaling pathways related to lactation performance. In conclusion, these findings are a reference tool to study the molecular basis of lactation performance. [ABSTRACT FROM AUTHOR]

Cattle-yak is a hybrid F1 generation of cattle and yak, which has a history of more than 3000 years and has shown better production performance and higher economic benefits than those of yaks. However, up to now, there has been no study on the transcriptome-wide m6A methylation profile of bovine skeletal muscle and its potential biological function during muscle development. Here, we observed significant changes in the expression levels of muscle-related marker genes and methylation-related enzymes during the development of cattle-yak, and the overall m6A content in the Longissimus dorsi muscle of 18-month-old cattle-yak decreased significantly. A total of 36,602 peaks, 11,223 genes and 8388 lncRNAs were identified in the two groups, including 2989 differential peaks (427 up-regulated peaks and 2562 down-regulated peaks), 1457 differentially expressed genes (833 up-regulated genes and 624 down-regulated genes) and 857 differentially expressed lncRNAs (293 up-regulated lncRNAs and 564 down-regulated lncRNAs). GO and KEGG analysis revealed that they were significantly enriched in some muscle-related pathways (Wnt signaling pathway and MAPK signaling pathway) and high-altitude adaptation-related pathway (HIF-1 signaling pathway). Moreover, m6A abundance was positively correlated with gene expression levels, while it was negatively correlated with lncRNA expression levels. This indicates that m6A modification played an important role in the Longissimus dorsi muscle development of cattle-yak; however, the regulation mechanism of m6A-modified mRNA and lncRNA may be different. This study was the first report of transcriptome-wide m6A-modified mRNAs and lncRNAs atlas in the Longissimus dorsi muscle development of cattle-yak, one which will provide new perspectives for genetic improvement in bovines. [ABSTRACT FROM AUTHOR]

Simple Summary: Yaks are among the largest high-altitude mammals in the world, and they are ideally adapted to the harsh environmental conditions of the plateau regions. Yaks are thus central to the lives of herdsmen and other local populations in these high-altitude areas. Copy number variations (CNVs) are an important cause of genomic variation in livestock and identifying advantageous CNVs can aid in livestock breeding efforts. In this study, an association between CNVs in the MICALL2 and MOGAT2 genes and Ashidan yak growth traits was confirmed, providing a theoretical foundation for Ashidan yak breeding and meat production efforts. Copy number variations (CNVs) are a result of genomic rearrangement affecting DNA regions over 1 kb in length, and can include inversions, translocations, deletions, and duplications. The molecule interacting with CasL-like protein 2 (MICALL2) gene is primarily associated with mitochondrial protein targeting and exhibits predicted stress fiber colocalization. The monoacylglycerol O-acyltransferase 2 (MOGAT2) gene encodes an enzyme responsible for catalyzing diacylglycerol synthesis from 2-monoacylglycerol and fatty acyl-CoA. For this study, blood samples were obtained from 315 yaks, and the body weight, body length, withers height, and chest girth of these animals were measured at 6, 12, 18, and 30 months of age. Genomic DNA was harvested from the collected blood samples, and CNVs in these samples were detected by qPCR. The resultant data were compared using ANOVAs, revealing significant associations between MICALL2 gene CNVs and body weight at 6 months of age (p < 0.05), body length and chest girth at 30 months of age (p < 0.05), and withers height at 18 months of age (p < 0.01) in Ashidan yaks. Similarly, MOGAT2 CNVs were significantly associated with body weight at 6 and 30 months of age (p < 0.05), and with withers height at 18 months of age (p < 0.01) in these Ashidan yaks. MICALL2 and MOGAT2 gene expression was further analyzed in yak tissue samples, revealing that MICALL2 was most highly expressed in the adipose tissue, whereas MOGAT2 was most highly expressed in the lung. These results thus confirmed the relationship between CNVs in the MICALL2 and MOGAT2 genes and Ashidan yak growth traits, providing a valuable gene locus that can be leveraged for future marker-assisted yak breeding efforts. [ABSTRACT FROM AUTHOR]

Tibet Gaoshan Yak (Bos grunniens) is a local Yak breed that mainly produces meat in Tibet Autonomous Region, China. In this study, the complete mitochondrial genome of Tibet Gaoshan Yak was sequenced. The total length of the mitochondrial genome is 16,323 bp, and the base composition is 33.71% for A, 13.21% for G, 27.27% for T, and 25.81% for C. The genome includes 13 protein-coding genes (ND1-ND6, ND4L, COX1-COX3, ATP6, ATP8, and CYTB), two rRNA genes (12S rRNA and 16SrRNA), 22 tRNA genes, and a noncoding control region (D-loop). Phylogenetic analysis showed that Tibet Gaoshan Yak has the closest relationship with Polled Yak. The sequence analysis provided in this study will be helpful to the management of Yak breeds, the origin, and evolution of Yak, and the protection and utilization of genetic resources. [ABSTRACT FROM AUTHOR]

• The CNV of the HSF1 gene was detected in Ashidan yaks. • There were significant correlations between HSF1-CNV and growth traits of yaks. • The expression level of the HSF1 gene was variable in different tissues of yaks. Copy Number Variation (CNV) is the major manner for the variation of genome structure, which is associated with numerous important traits. The heat shock factor 1 (HSF1) gene is a stress response transcriptional regulator. It participates in the heat shock response, simultaneously participated in the development of tissue. The objective of this research was to explore the influence of CNV of the HSF1 gene on the growth traits of the Ashidan yak. In this study, the growth traits (withers height, body weight, chest girth, and body length) of 274 Ashidan yaks were divided into four stages (6, 12, 18, and 30 months old). Moreover, quantitative polymerase chain reaction (qPCR) was exploited for determining the HSF1 gene relative expression level, and SPSS software was utilized for the statistical analysis. The outcomes indicated that HSF1 -CNV was significantly associated with body length (p < 0.05) and was extremely significant associated with withers height (p < 0.01) of 18-month-old Ashidan yaks. Besides, the HSF1 relative expression in heart and muscle was higher than that existed in other tissues (p < 0.01). The outcomes suggested that the CNV of HSF1 gene would affect the growth and development of the Ashidan yak, which is conducive to the early breeding of yak. [ABSTRACT FROM AUTHOR]

Objectives: Nanosize titanium dioxide is used in water and air decontamination and in numerous home appliances and products designed for direct human use. However, the impact of nanoparticle on biological system is not known to us. Therefore, it is our urgent and primary task to ascertain the information about safety and potential hazards of products derived from nanomaterial to the health of mankind. Methods: We made use of MTT, bromodeoxyuridine (BrdU), and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays to testify the biological impact of nanosize TiO2 on olfactory bulb neurons cultured in vitro. Results: In this article, we elucidate the cytotoxicity of titanium dioxide to olfactory bulb neurons on cellular and molecular level. We come to a conclusion that nanosize titanium dioxide causes neuronal apoptosis, and it also down-regulate the expression of olfactory marker protein (OMP) and tyrosine hydroxylase (TH). Discussion: These results show that a relationship between nanoparticle exposure and pathogeny of neurodegenerative diseases may exist. [ABSTRACT FROM AUTHOR]

Objectives: Glioma is the most common brain tumor in central nervous system. Traditional therapies are not effective to cure this disease. Stat3 is a member of the signal transducer and activator of transcription family, and it has the potential to mediate cell survival, growth and differentiation. Methods: In this study, we testified that Stat3 was constitutively expressed in glioma cell line SHG44 and then investigated the role of a low level of Stat3 expression in glioma cells by constructing an interfering RNA expression plasmid. Results: The results showed that glioma cells underwent morphologic and biochemical changes after the RNAi treatment. Discussion: We hypothesized that a low level of Stat3 expression could induce apoptosis of glioma cell, which further proved that Stat3 played an important role in growth, survival and proliferation of glioma cells. This study provides a new alternative to gene therapy for glioma treatment. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat-containing G-protein coupled receptor 5-expressing (Lgr5+) cells have been identified as stem/progenitor cells in the circumvallate papillae, and single cultured Lgr5+ cells give rise to taste cells. Here we use circumvallate papilla tissue to establish a three-dimensional culture system (taste bud organoids) that develops phenotypic characteristics similar to native tissue, including a multilayered epithelium containing stem/progenitor in the outer layers and taste cells in the inner layers. Furthermore, characterization of the cell cycle of the taste bud progenitor niche reveals striking dynamics of taste bud development and regeneration. Using this taste bud organoid culture system and FUCCI2 transgenic mice, we identify the stem/progenitor cells have at least 5 distinct cell cycle populations by tracking within 24-hour synchronized oscillations of proliferation. Additionally, we demonstrate that stem/progenitor cells have motility to form taste bud organoids. Taste bud organoids provides a system for elucidating mechanisms of taste signaling, disease modeling, and taste tissue regeneration. [ABSTRACT FROM AUTHOR]

• The CNV of the HPGDS gene was detected in yak. • The expression level of the HPGDS gene was variable in different tissues of yaks. • The HPGDS gene was highly expressed in the spleen and lung of all ages. • There were significant correlations between HPGDS -CNV and growth traits of yaks. Copy number variation (CNV) is a structural variation at the submicroscopic level of the genome, which can affect gene-related phenotypes by changing genes dosage and transcript structure. Hematopoietic prostaglandin D synthase (HPGDS) is a member whose functions are closely related to weight gain and inflammatory diseases of the glutathione S-transferase (GSTs) family. In this study, the growth characteristics (body weight, withers height, body length, and chest girth) of 336 Ashidan yaks were monitored at four stages (6 months, 12 months, 18 months, and 30 months). In addition, CNV of the HPGDS gene was detected, discovered relationships of CNV with growth traits, and explored the level of gene expression. Based on the statistical analysis by IBM SPSS software, significant correlations were observed between HPGDS -CNV and body weight in 12-month-old yak (P < 0.01), 18-month-old yak (P < 0.001) and 30-month-old yak (P < 0.001) and body length in 18-month-old yak (P < 0.05) and 30-month-old yak (P < 0.05), respectively. Additionally, the individuals with gain copy number type performed better in body weight and body length than those with normal or loss copy number type. To our best of knowledge, this is the first time to make efforts to probe into the role of HPGDS -CNV and its interaction with livestock growth traits. Our results suggested that the CNV of the HPGDS gene may be an active candidate gene for the marker-assisted selection (MAS) of yaks. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal malignant tumors were relatively rare head and neck tumors with a low global incidence. There were various pathologic types of nasopharyngeal malignant tumors, and small cell neuroendocrine carcinoma (SCNEC) was a highly malignant subtype with rapid growth and early metastasis. SCNEC was rare in the nasopharynx, and its clinical presentation and treatment strategy were different from other types of nasopharyngeal malignancies, posing a challenge to clinicians. Therefore, a comprehensive analysis of its diagnosis and treatment was essential., Case Presentations: In February 2024, a 32-year-old male presented with nasal congestion, right ear stuffiness, right ear hearing loss, and right ear pain. Electron nasopharyngoscopy and nasopharyngeal magnetic resonance imaging (MRI) showed a large tumor in the nasopharynx. Pathologic examination confirmed the pathologic type as SCNEC. The patient was finally diagnosed with SCNEC. After chemotherapy, immunotherapy, and radiotherapy, the tumor size was significantly reduced, and the clinical symptoms were significantly improved., Conclusion: This case provided insights into the diagnosis and treatment of nasopharyngeal malignancies, particularly for a rare pathologic type (SCNEC), potentially enhancing the overall understanding of the disease., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Rationale: Gustation is important to several biological functions in mammals. However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function. This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function. Methods: We used both mice and taste organoid models to study the effect of cisplatin on taste buds. Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation. Results: Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation. The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment. Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids. LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy. LY411575 treatment could offset the increased number of Pax1 + or Pycr1 + cells induced by cisplatin in the circumvallate papilla and taste organoids. Conclusion: This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The article has been withdrawn at the request of the author of the journal Current HIV Research (CHIVR)., Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php, Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication, (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net)

Objective: We aimed to evaluate the effectiveness of topical tranexamic acid (TXA) versus topical vasoconstrictors in the management of epistaxis via a systematic review and meta-analysis., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were followed for the meta-analysis. We systematically searched Embase, Web of Science, Cochrane Library, CNKI, and PubMed for randomized controlled trials (from inception to August 2022; no language restrictions), comparing the effect of topical TXA and topical vasoconstrictors on the treatment of epistaxis. The Q test was used to evaluate heterogeneity, and funnel plots were utilized to identify bias. For the meta-analysis, the fixedeffects model was employed, and the t-test was utilized to determine significance., Results: Of 1012 identified studies, 5 were found to be eligible for our analysis. In total, 598 patients were included; 297 of them received TXA and 301 received vasoconstrictors. Hemostasis was more likely to be achieved at the first re-assessment in patients treated with TXA. Subgroup analysis indicated patients treated with TXA to have less likelihood of bleeding recurrence, compared to patients treated with vasoconstrictors. The detected time interval of rebleeding was 10 min, between 24 h to 72 h, and after 7 days, respectively, and the differences were significant between the two groups of patients treated with TXA and vasoconstrictors., Conclusion: Topical TXA was associated with better post-treatment hemorrhagic arrest rates compared to topical vasoconstrictors in the management of epistaxis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Olfactory sensory neurons (OSNs) located in the olfactory epithelium (OE) detect thousands of volatile environmental odors to form the sense of smell. OSNs are generated from basal cells, which show the characteristics of progenitor/stem cells. In the mammalian OE, persistent neurogenesis occurs during lifetime, providing a unique model to study the tissue turnover and fate determination of stem cells. Methods: Immunohistochemical analysis and RNAscope in situ hybridization indicated the localization of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) in the intact and injured OE. Lineage tracing was conducted to analyze the dynamic role of Lgr5 + cells in the OE homeostasis and regeneration. We also used DTR-driven genetic depletion of Lgr5 + cells and lentivirus-mediated Lgr5 downregulation to demonstrate the essential role of Lgr5 + cells in the OE regeneration. Results: We show that Lgr5 marks horizontal basal cells (HBCs) in the OE of adults but not newborns. We revisit the role of Lgr5 + cells in the OE homeostasis and regeneration, and find that Lgr5 + cells participate in the OE homeostasis from neonatal to one-month-old age, as well as in the OE regeneration post injury. During the OE regeneration, Lgr5 is transiently expressed in apical supporting cells, immature neurons, and mature sensory neurons. The Lgr5 + cells become or generate HBCs in the regenerated OE. DTR-driven cell depletion shows that Lgr5 + cells are not necessary in the adult OE homeostasis, but required in the recovery of OE from injury. Lgr5 down-regulation by lentiviral infection also demonstrates the essential role of Lgr5 expression in the OE regeneration. Conclusion: Our study elucidates the role of Lgr5 + cells in the OE homeostasis and regeneration, potentially providing a candidate to cell-based therapy against olfactory dysfunction., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diverse. This work investigated how the amino-acid sequences of olfactory receptors (ORs)-the largest GPCR family-encode diversified responses to various ligands. We established a proteochemometric (PCM) model based on OR sequence similarities and ligand physicochemical features to predict OR responses to odorants using supervised machine learning. The PCM model was constructed with the aid of site-directed mutagenesis, in vitro functional assays, and molecular simulations. We found that the ligand selectivity of the ORs is mostly encoded in the residues up to 8 Å around the orthosteric pocket. Subsequent predictions using Random Forest (RF) showed a hit rate of up to 58%, as assessed by in vitro functional assays of 111 ORs and 7 odorants of distinct scaffolds. Sixty-four new OR-odorant pairs were discovered, and 25 ORs were deorphanized here. The best model demonstrated a 56% deorphanization rate. The PCM-RF approach will accelerate OR-odorant mapping and OR deorphanization., Competing Interests: The authors declare the following competing financial interest(s): H.M. has received royalties from ChemCom, research grants from Givaudan, and consultant fees from Kao., (© 2022 The Authors. Published by American Chemical Society.)

Tibet Gaoshan Yak ( Bos grunniens ) is a local Yak breed that mainly produces meat in Tibet Autonomous Region, China. In this study, the complete mitochondrial genome of Tibet Gaoshan Yak was sequenced. The total length of the mitochondrial genome is 16,323 bp, and the base composition is 33.71% for A, 13.21% for G, 27.27% for T, and 25.81% for C. The genome includes 13 protein-coding genes ( ND1-ND6 , ND4L , COX1-COX3 , ATP6 , ATP8, and CYTB ), two rRNA genes (12S rRNA and 16SrRNA), 22 tRNA genes, and a noncoding control region (D-loop). Phylogenetic analysis showed that Tibet Gaoshan Yak has the closest relationship with Polled Yak. The sequence analysis provided in this study will be helpful to the management of Yak breeds, the origin, and evolution of Yak, and the protection and utilization of genetic resources., Competing Interests: The authors declare that there are no financial and personal relationships with other people or organizations that can inappropriately influence our work, and no professional or other personal interest of any nature or kind in any product, service and company that could be construed as influencing the position presented in, or the review of the manuscript., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The adult olfactory epithelium (OE) regenerates sensory neurons and nonsensory supporting cells from resident stem cells after injury. How supporting cells contribute to OE regeneration remains largely unknown. In this study, we elucidated a novel role of Ym2 (also known as Chil4 or Chi3l4), a chitinase-like protein expressed in supporting cells, in regulating regeneration of the injured OE in vivo in both male and female mice and cell proliferation/differentiation in OE colonies in vitro We found that Ym2 expression was enhanced in supporting cells after OE injury. Genetic knockdown of Ym2 in supporting cells attenuated recovery of the injured OE, while Ym2 overexpression by lentiviral infection accelerated OE regeneration. Similarly, Ym2 bidirectionally regulated cell proliferation and differentiation in OE colonies. Furthermore, anti-inflammatory treatment reduced Ym2 expression and delayed OE regeneration in vivo and cell proliferation/differentiation in vitro , which were counteracted by Ym2 overexpression. Collectively, this study revealed a novel role of Ym2 in OE regeneration and cell proliferation/differentiation of OE colonies via interaction with inflammatory responses, providing new clues to the function of supporting cells in these processes. SIGNIFICANCE STATEMENT The mammalian olfactory epithelium (OE) is a unique neural tissue that regenerates sensory neurons and nonsensory supporting cells throughout life and postinjury. How supporting cells contribute to this process is not entirely understood. Here we report that OE injury causes upregulation of a chitinase-like protein, Ym2, in supporting cells, which facilitates OE regeneration. Moreover, anti-inflammatory treatment reduces Ym2 expression and delays OE regeneration, which are counteracted by Ym2 overexpression. This study reveals an important role of supporting cells in OE regeneration and provides a critical link between Ym2 and inflammation in this process., (Copyright © 2021 the authors.)

Olfactory dysfunctions, including hyposmia and anosmia, affect ~100 million people around the world and the underlying causes are not fully understood. Degeneration of olfactory sensory neurons and incapacity of globose basal cells to generate olfactory sensory neurons are found in elder people and patients with smell disorders. Thus, olfactory stem cell may function as a promising tool to replace inactivated globose basal cells and to generate sensory neurons. Methods: We established clonal expansion of cells from the murine olfactory epithelium as well as colony growth from human olfactory mucosa using Matrigel-based three-dimensional system. These colonies were characterized by immunostaining against olfactory epithelium cellular markers and by calcium imaging of responses to odors. Chemical addition was optimized to promote Lgr5 expression, colony growth and sensory neuron generation, tested by quantitative PCR and immunostaining against progenitor and neuronal markers. The differential transcriptomes in multiple signaling pathways between colonies under different base media and chemical cocktails were determined by RNA-Seq. Results: In defined culture media, we found that VPA and CHIR99021 induced the highest Lgr5 expression level, while LY411575 resulted in the most abundant yield of OMP + mature sensory neurons in murine colonies. Different base culture media with drug cocktails led to apparent morphological alteration from filled to cystic appearance, accompanied with massive transcriptional changes in multiple signaling pathways. Generation of sensory neurons in human colonies was affected through TGF-β signaling, while Lgr5 expression and cell proliferation was regulated by VPA. Conclusion: Our findings suggest that targeting expansion of olfactory epithelium/mucosa colonies in vitro potentially results in discovery of new source to cell replacement-based therapy against smell loss., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The Notch signaling pathway regulates stem cell proliferation and differentiation in multiple tissues and organs, and is required for tissue maintenance. However, the role of Notch in regulation of olfactory epithelium (OE) progenitor/stem cells to maintain tissue function is still not clear. A recent study reported that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in globose basal cells (GBCs) localized in OE. Through lineage tracing in vivo, we found that Lgr5 + cells act as progenitor/stem cells in OE. The generation of daughter cells from Lgr5 + progenitor/stem cells is delicately regulated by the Notch signaling pathway, which not only controls the proliferation of Lgr5 + cells and their immediate progenies but also affects their subsequent terminal differentiation. In conditionally cultured OE organoids in vitro, inhibition of Notch signaling promotes neuronal differentiation. Besides, OE lesion through methimazole administration in mice induces generation of more Notch1 + cells in the horizontal basal cell (HBC) layer, and organoids derived from lesioned OE possesses more proliferative Notch1 + HBCs. In summary, we concluded that Notch signaling regulates Lgr5 + GBCs by controlling cellular proliferation and differentiation as well as maintaining epithelial cell homeostasis in normal OE. Meanwhile, Notch1 also marks HBCs in lesioned OE and Notch1 + HBCs are transiently present in OE after injury. This implies that Notch1 + cells in OE may have dual roles, functioning as GBCs in early development of OE and HBCs in restoring the lesioned OE. Stem Cells 2018;36:1259-1272., (© AlphaMed Press 2018.)

Taste cells in taste buds are epithelial sensory cells. Old taste bud cells die and are replaced by new ones generated from taste stem cells. Identifying and characterizing adult taste stem cells is therefore important to understand how peripheral taste tissues are maintained. SOX2 is expressed in oral epithelium including gustatory papillae and has been proposed to be a marker of adult taste stem/progenitor cells. Nevertheless, this hypothesis has never been directly tested. Here, by single-color genetic lineage tracing using Sox2-CreERT2 strain, we reveal that all types of taste bud cells distributed throughout the oral epithelium are derived from stem cells that express SOX2. Short-term tracing shows that SOX2-positive taste stem cells actively supply taste bud cells. At the base of epithelium outside taste buds are distributed proliferation marker- and SOX2-positive cells. Consistently, taste stem cells identified by Lgr5 expression in the circumvallate papillae also express SOX2. Together, taste stem cells distributed in oral epithelia express SOX2., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)