Oteseconazole versus fluconazole for the treatment of severe vulvovaginal candidiasis: a multicenter, randomized, double-blinded, phase 3 trial.

Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.

Small G-Protein Rheb Gates Mammalian Target of Rapamycin Signaling to Regulate Morphine Tolerance in Mice.

BACKGROUND: Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on µ-opioid receptors and downstream of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. The hypothesis was that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance. METHODS: Male and female wild-type C57BL/6J mice or transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or morphine twice daily at 12-h intervals for 5 consecutive days to establish a tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. After 5 days, the spine was harvested for Western blot or immunofluorescence analysis. RESULTS: Chronic morphine administration resulted in the upregulation of spinal Rheb by 4.27 ± 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb impaired morphine analgesia, resulting in a tail-flick latency of 4.65 ± 1.10 s (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice (10 ± 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 signaling by rapamycin potentiated morphine-induced tolerance (maximum possible effect, 52.60 ± 9.56% in the morphine + rapamycin group vs. 16.60 ± 8.54% in the morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 5'-monophosphate-activated protein kinase inhibited Rheb upregulation and retarded the development of morphine-dependent tolerance (maximum possible effect, 39.51 ± 7.40% in morphine + metformin group vs. 15.58 ± 5.79% in morphine group; P < 0.0001). CONCLUSIONS: This study suggests spinal Rheb as a key molecular factor for regulating mammalian target of rapamycin signaling.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

Learning curve of dynamic navigation-assisted zygomatic implant surgery: An in vitro study.

STATEMENT OF PROBLEM: Dynamic computer-assisted zygomatic implant surgery (dCAZIS) has been reported to provide clinical efficacy with high accuracy and low risk of complications. However, the learning curve before performing dCAZIS effectively is unknown. PURPOSE: The purpose of this in vitro study was to explore the learning curve of dCAZIS in dentists with different levels of experience in implant dentistry and navigation surgery. MATERIAL AND METHODS: Six senior dental students were randomly divided into 3 groups for initial training (FH-CI group: pretraining on freehand conventional implant surgery; FH-ZI group: pretraining on freehand ZI surgery; DN-CI group: pretraining on conventional implant surgery under dynamic navigation). Then, every operator conducted 6 repeated dCAZIS training sessions on edentulous 3-dimensional (3D) printed skull models and was asked to complete a self-report questionnaire after each training session. A total of 36 postoperative cone beam computed tomography (CBCT) scans with 144 ZI osteotomy site preparations were obtained and superimposed over the preoperative design for accuracy measurements. The operation time, 3D deviations, and results of the self-reports were recorded. Comparisons among groups were analyzed with independent-sample Kruskal-Wallis tests (α=.05), and correlations between study outcomes and the number of practices were calculated. RESULTS: Operator experience and increased practice times did not significantly affect the accuracy of dCAZIS (P>.05). However, the operation time varied among groups (P<.001), and significantly shortened with more practice, reaching 11.51 ±1.68 minutes at the fifth attempt in the FH-CI group (P<.001 compared with the first practice), 14.48 ±3.07 minutes at the third attempt in the FH-ZI group (P=.038), and 8.68 ±0.58 minutes at the sixth attempt in the DN-CI group (P<.001). All groups reached their own learning curve plateau stage within 6 practice sessions. As the number of practice sessions increased, the results from the self-report questionnaires gradually improved. CONCLUSIONS: Among dentists with different levels of experience in implant dentistry and navigation surgery, dCAZIS was found to have a learning curve with respect to operation time but not implant accuracy. Experience in ZI surgery had little impact on the learning curve of dCAZIS, but experience in navigation surgery was a key factor.

Concomitant Near-Infrared Photothermy and Photoluminescence of Rod-Shaped Au52(PET)32 and Au66(PET)38 Synthesized Concurrently.

Gold nanoclusters exhibiting concomitant photothermy (PT) and photoluminescence (PL) under near-infrared (NIR) light irradiation are rarely reported, and some fundamental issues remain unresolved for such materials. Herein, we concurrently synthesized two novel rod-shaped Au nanoclusters, Au52(PET)32 and Au66(PET)38 (PET = 2-phenylethanethiolate), and precisely revealed that their kernels were 4 × 4 × 6 and 5 × 4 × 6 face-centered cubic (fcc) structures, respectively, based on the numbers of Au layers in the [100], [010], and [001] directions. Following the structural growth mode from Au52(PET)32 to Au66(PET)38, we predicted six more novel nanoclusters. The concurrent synthesis provides rational comparison of the two nanoclusters on the stability, absorption, emission and photothermy, and reveals the aspect ratio-related properties. An interesting finding is that the two nanoclusters exhibit concomitant PT and PL under 785 nm light irradiation, and the PT and PL are in balance, which was explained by the qualitative evaluation of the radiative and non-radiative rates. The ligand effects on PT and PL were also investigated.

Early embryonic lethality of mice lacking POLD2.

As a highly conserved DNA polymerase (Pol), Pol δ plays crucial roles in chromosomal DNA synthesis and various DNA repair pathways. However, the function of POLD2, the second small subunit of DNA Pol δ (p50 subunit), has not been characterized in vivo during mammalian development. Here, we report for the first time, the essential role of subunit POLD2 during early murine embryogenesis. Although Pold2 mutant mouse embryos exhibit normal morphology at E3.5 blastocyst stage, they cannot be recovered at gastrulation stages. Outgrowth assays reveal that mutant blastocysts cannot hatch from the zona pellucida, indicating impaired blastocyst function. Notably, these phenotypes can be recapitulated by small interfering RNA (siRNA)-mediated knockdown, which also exhibit slowed cellular proliferation together with skewed primitive endoderm and epiblast allocation during the second cell lineage specification. In summary, our study demonstrates that POLD2 is essential for the earliest steps of mammalian development, and the retarded proliferation and embryogenesis may also alter the following cell lineage specifications in the mouse blastocyst embryos.

HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships.

PURPOSE: The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3). METHODS: The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards. RESULTS: A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4-7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58-1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease. CONCLUSIONS: A hotspot mutation, potential hotspot mutation and genotype-phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.

A map of the spatial distribution and tumour-associated macrophage states in glioblastoma and grade 4 IDH-mutant astrocytoma.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Identification of mutations in 15 nephrolithiasis-related genes leading to a molecular diagnosis in 85 Chinese pediatric patients.

BACKGROUND: The aim of this study was to describe the genotypic and phenotypic characteristics of Chinese pediatric patients with hereditary nephrolithiasis. METHODS: Whole-exome sequencing (WES) was performed on 218 Chinese pediatric patients with kidney stones, and genetic and clinical data were collected and analyzed retrospectively. RESULTS: The median age at onset in our cohort was 2.5 years (age range, 0.3-13 years). We detected 79 causative mutations in 15 genes, leading to a molecular diagnosis in 38.99% (85/218) of all cases. Monogenic mutations were present in 80 cases, and digenic mutations were present in 5 cases; 34.18% (27/79) of mutations were not included in the databases. Six common mutant genes, i.e., HOGA1, AGXT, GRHPR, SLC3A1, SLC7A9, and SLC4A1, were found in 84.71% of the patients overall. Furthermore, three mutations (A278A, c.834_834 + 1GG > TT, and C257G) in HOGA1, two mutations (K12QfX156 and S275RfX28) in AGXT, and one mutation (C289DfX22) in GRHPR represented hotspot mutations. The patients with HOGA1 mutations had the earliest onset age (0.8 years), followed by those with SLC7A9 (1.8 years), SLC4A1 (2.7 years), AGXT (4.3 years), SLC3A1 (4.8 years), and GRHPR (8 years) mutations (p = 0.002). Nephrocalcinosis was most commonly observed in patients with AGXT gene mutations. CONCLUSIONS: Fifteen causative genes were detected in 85 Chinese pediatric patients with kidney stone diseases. The most common mutant genes, novel mutations, hotspot mutations, and genotype-phenotype correlations were also found. This study contributes to the understanding of genetic profiles and clinical courses in pediatric patients with hereditary nephrolithiasis. A higher resolution version of the Graphical abstract is available as Supplementary information.

A pilot randomized trial of self-compassion writing for young adult women engaged in emotional eating in the context of appearance-related cyberbullying.

OBJECTIVE: To investigate the effectiveness of a 10-min self-compassion writing in alleviating body dissatisfaction, self-objectification, and emotional eating in young adult women engaged in emotional eating in the context of appearance-related cyberbullying. METHOD: A total of 175 Chinese young adult women (Mage = 20.90, SD = 1.65) were randomly assigned to one of the three groups: self-compassion, distraction, or control group. At baseline, participants completed assessments of trait and state body dissatisfaction, trait self-objectification, trait self-compassion, emotional eating, and positive and negative affect. Then they needed to recall an appearance-related cyberbullying victimization experience, after which state body dissatisfaction, state self-objectification, and positive and negative affect were measured. After the intervention, participants completed measures of state body dissatisfaction, state self-objectification, positive and negative affect, state self-compassion, and a food-choosing task. At 1-month follow-up, participants completed measures of trait body dissatisfaction, trait self-objectification, trait self-compassion, and emotional eating. RESULTS: At post-intervention, state body dissatisfaction and negative affect were significantly lower, and positive affect was significantly higher in both the self-compassion and distraction groups compared to control. State self-objectification was significantly lower in the self-compassion group than in the other two groups. At 1-month follow-up, the self-compassion group showed significantly lower levels of body dissatisfaction than the control group. DISCUSSION: The findings provide initial evidence for the potential of self-compassion writing in reducing state self-objectification and state body dissatisfaction in the context of appearance-related cyberbullying. PUBLIC SIGNIFICANCE: Appearance-related cyberbullying, a common phenomenon in social networking sites, has been documented to associate with appearance-related concerns and disordered eating in young adult women. However, effective interventions that can reduce these negative associations are scarce. This study preliminarily found that a brief self-compassion writing could be a potential intervention for reducing state self-objectification and state body dissatisfaction in young adult women who had suffered appearance-related cyberbullying.

Clinical efficacy of computer-assisted zygomatic implant surgery: A systematic scoping review.

STATEMENT OF PROBLEM: Digital technology can improve the success of zygomatic implant (ZI) surgery. However, the reliability and efficacy of computer-assisted zygomatic implant surgery (CAZIS) need further analysis. PURPOSE: The purpose of this scoping review was to provide an overview of the placement accuracy, implant survival, and complications of CAZIS. MATERIAL AND METHODS: A systematic search of English and Mandarin Chinese publications up to May 2023 was conducted in PubMed, Web of Science, Embase, and Wanfang database. The nonpeer-reviewed literature was searched in the trial register (clinicaltrials.gov). Clinical studies and cadaver studies on CAZIS were included. After data extraction and collection, the findings were critically reviewed, analyzed, interpreted, and discussed. RESULTS: Forty-one studies met the inclusion criteria. After excluding publications with duplicate data, retaining the most recent, 28 articles were included in this scoping review. Of these, 18 were on static computer-assisted zygomatic implant surgery (sCAZIS), 8 on dynamic computer-assisted zygomatic implant surgery (dCAZIS), and 2 on robot-assisted zygomatic implant surgery (rAZIS). Excluding the outliers, the mean deviations of ZIs in the sCAZIS group (with 8 articles reporting implant placement accuracy, 183 ZIs involved) were: 1.15 ±1.37 mm (coronal deviation), 2.29 ±1.95 mm (apical deviation), and 3.32 ±3.36 degrees (angular deviation). The mean deviations of dCAZIS (3 articles, 251 ZIs) were: 1.60 ±0.74 mm (coronal), 2.27 ±1.05 mm (apical), and 2.89 ±1.69 degrees (angular). The mean deviations of rAZIS (2 articles, 5 ZIs) were: 0.82 ±0.21 mm (coronal), 1.25 ±0.52 mm (apical), and 1.46 ±0.35 degrees (angular). Among the CAZIS reported in the literature, the implant survival rate was high (96.3% for sCAZIS, 98.2% for dCAZIS, and 100% for rAZIS, specified in 14 of 21 clinical studies). The incidence of complications was low, but, because of the few relevant studies (4/21 specified), valid conclusions regarding complications could not be drawn. CONCLUSIONS: CAZIS has demonstrated clinical efficacy with high implant survival rates and placement accuracy. Of the 3 guided approaches, rAZIS showed the smallest 3-dimensional deviation.

Exploring training dental implant placement using static or dynamic devices among dental students.

BACKGROUND: Static computer-assisted surgery (s-CAIS) and dynamic computer-assisted implant surgery (d-CAIS) are the main digital approaches in guiding dental implant placement. PURPOSE: The aim of this study was to explore and compare the learning curves for s-CAIS and d-CAIS by beginners. MATERIALS AND METHODS: Three dental students used each dental model for drilling five positions with missing teeth. Operators performed the drilling test for five sets of dental models with an interval of 7 ± 1 days assisted by the d-CAIS system. After a six-month break, the same students performed the drilling test again in the same way but with the s-CAIS system. A total of thirty models were used, and 150 implants were inserted. The operation time and relative deviations were recorded and calculated. Correlations between various deviation parameters and attempts were tested with independent-samples Kruskal-Wallis tests. RESULTS: A significant difference between the two groups was found in the operation time (p < .001). For accuracy, the difference was found in the first attempt of coronal and apical deviations but disappeared as the training went on. As the practice progressed, improvement was evident in the d-CAIS group but not in the s-CAIS group. When reaching the plateau stage of the learning curve of the d-CAIS group (after five attempts), the influence of different methods of guidance was limited between the two groups. CONCLUSIONS: A learning curve effect was found in d-CAIS but not in s-CAIS in vitro tests by beginners. The operating procedure of dynamic navigated and static template-guided implant placement was easy to master.

High levels of TIMP1 are associated with increased extracellular matrix stiffness in isocitrate dehydrogenase 1-wild type gliomas.

Glioma progression is accompanied with increased tumor tissue stiffness, yet the underlying mechanisms are unclear. Herein, we employed atomic force microscopy analysis to show that tissue stiffness was higher in isocitrate dehydrogenase (IDH)-wild type gliomas than IDH-mutant gliomas. Bioinformatic analyses revealed that tissue inhibitor of metalloproteinase-1 (TIMP1) was one of the preferentially upregulated genes in IDH-wild type gliomas as compared to IDH-mutant gliomas, and its higher expression indicated worse prognosis of glioma patients. TIMP1 intensity determined by immunofluorescence staining on glioma tissues positively correlated with glioma tissue stiffness. Mechanistically, TIMP1 expression was positively correlated with the gene expression of two predominant extracellular matrix components, tenascin C and fibronectin, both of which were also highly expressed in IDH-wild type gliomas. By introducing IDH1-R132H-containing vectors into human IDH1-wild type glioma cells to obtain an IDH1-mutant cell line, we found that IDH1 mutation increased the TIMP1 promoter methylation through methylation-specific PCR. More importantly, IDH1-R132H mutation decreased both the expression of TIMP1, fibronectin, tenascin C, and the tumor tissue stiffness in IDH1-mutant glioma xenografts in contrast to IDH1-wild type counterparts. Moreover, TIMP1 knockdown in IDH-wild type glioma cells inhibited the expression of tenascin C and fibronectin, and decreased tissue stiffness in intracranial glioma xenografts. Conclusively, we revealed an IDH mutation status-mediated mechanism in regulating glioma tissue stiffness through modulating TIMP1 and downstream extracellular matrix components.

Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells.

Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.

High potential of stable carbon sequestration in phytoliths of China's grasslands.

Phytolith carbon (C) sequestration plays a key role in mitigating global climate change at a centennial to millennial time scale. However, previous estimates of phytolith-occluded carbon (PhytOC) storage and potential in China's grasslands have large uncertainties mainly due to multiple data sources. This contributes to the uncertainty in predicting long-term C sequestration in terrestrial ecosystems using Earth System Models. In this study, we carried out an intensive field investigation (79 sites, 237 soil profiles [0-100 cm], and 61 vegetation assessments) to quantify PhytOC storage in China's grasslands and to better explore the biogeographical patterns and influencing factors. Generally, PhytOC production flux and soil PhytOC density in both the Tibetan Plateau and the Inner Mongolian Plateau had a decreasing trend from the Northeast to the Southwest. The aboveground PhytOC production rate in China's grassland was 0.48 × 106 t CO2 a-1 , and the soil PhytOC storage was 383 × 106 t CO2 . About 45% of soil PhytOC was stored in the deep soil layers (50-100 cm), highlighting the importance of deep soil layers for C stock assessments. Importantly, the Tibetan Plateau had the greatest contribution (more than 70%) to the PhytOC storage in China's grasslands. The results of multiple regression analysis indicated that altitude and soil texture significantly influenced the spatial distribution of soil PhytOC, explaining 78.1% of the total variation. Soil phytolith turnover time in China's grasslands was mainly controlled by climatic conditions, with the turnover time on the Tibetan Plateau being significantly longer than that on the Inner Mongolian Plateau. Our results offer more accurate estimates of the potential for phytolith C sequestration from ecological restoration projects in degraded grassland ecosystems. These estimates are essential to parameterizing and validating global C models.

Low estrogen level in aged mice leads to abnormal oogenesis affecting the quality of surrounded nucleolus-type immature oocytes.

CONTEXT: With aging, various problems in the reproductive system emerge, especially in females. However, our understanding of reproductive aging in livestock and humans is limited. AIMS: We aimed to investigate reproductive changes between young and aged mice. METHODS: Eight- to ten-week-old female mice were used as the young group, and 10-month-old mice were studied as the aged group. Reproductive changes were investigated from physiological, histological, cytological, and epigenetic perspectives. KEY RESULTS: The estrus cycle was shortened (P <0.0001), and the estradiol (E2) concentration was lower in aged mice (P <0.01), whereas the progesterone (P4) concentration did not differ between young and aged mice (P >0.05). The histological results revealed a lower number of antral follicles in the ovary and disordered epithelial tissue structures in the oviducts in aged mice. During oogenesis, the surrounded nucleolus (SN)-type oocytes in aged mice exhibited increased mitochondrial agglutination (P <0.05) and cellular apoptosis (P <0.01) as well as decreased H3K36 triple-methylation (P <0.001). Although many defects existed, the oocytes from aged mice could normally support cellular reprogramming after somatic cell nuclear transfer. CONCLUSIONS: Our results indicate that the reduced levels of reproductive hormones in aged females lead to shorter estrus cycles and reduced follicular development, leading to abnormal oogenesis, particularly in SN-type immature oocytes. IMPLICATIONS: These results provide new insight that enhance our understanding and improve the reproductive ability of aged females.

Cyberbullying victimization and disordered eating behaviors: The mediating roles of self-compassion and self-objectification.

Previous studies have demonstrated the correlations between cyberbullying victimization and disordered eating behaviors in adolescents, however, limited attention has been paid to the long-term effects and underlying mechanisms, and studies focused on young adults are scarce. This study explored the association between cyberbullying victimization and disordered eating behaviors and the underlying mechanisms in a sample of young adults using a longitudinal design. A total of 955 Chinese young adults completed the Cyber Victim Subscale of the Cyber Victim and Bullying Scale, the Self-surveillance Subscale of the Objectified Body Consciousness Scale, the Self-compassion Scale-Short Form, and the Dutch Eating Behaviors Questionnaire three times with a 3-months interval. The results indicated that cyberbullying victimization was positively correlated with emotional eating and external eating after six months, but not with restrained eating. Moreover, self-compassion and self-objectification mediated the associations between cyberbullying victimization and the three kinds of disordered eating behaviors, however, in different ways. In the associations of cyberbullying victimization with restrained eating and external eating, the independent mediating effect of self-objectification and the serial mediating effect were significant, while in the association between cyberbullying victimization and emotional eating, only the independent mediating effect of self-compassion was significant. The findings indicated that the relations between cyberbullying with different kinds of disordered eating behaviors might have different mediation mechanisms, which sheds light on the prevention and intervention for disordered eating behaviors associated with cyberbullying in the future.

Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance.

BACKGROUND AND PURPOSE: The aim of this work was to investigate the role and signal transduction of toll-like receptor 4 (TLR4), TGF-ß-activated kinase 1 (TAK1) and nod-like receptor protein 3 (NLRP3) in microglial in the development of morphine-induced antinociceptive tolerance. METHODS: TLR4 and NLRP3 knockout mice and 5Z-7-oxozeaeno (a selective inhibitor against TAK1 activity) were used to observe their effect on the development of morphine tolerance. Intrathecal injections of morphine (0.75 mg/kg once daily for 7 days) were used to establish anti-nociceptive tolerance, which was measured by the tail-flick test. Spinal TLR4, TAK1, and NLRP3 expression levels and phosphorylation of TAK1 were evaluated by Western blotting and immunofluorescence. RESULTS: Repeated treatment with morphine increased total expression of spinal TLR4, TAK1, and NLRP3 and phosphorylation of TAK1 in wild-type mice. TLR4 knockout attenuated morphine-induced tolerance and inhibited the chronic morphine-induced increase in NLRP3 and phosphorylation of TAK1. Compared with controls, mice that received 5Z-7-oxozeaenol showed decreased development of morphine tolerance and inhibition on repeated morphine-induced increase of NLRP3 but not TLR4. NLRP3 knockout mice showed resistance to morphine-induced analgesic tolerance with no effect on chronic morphine-induced expression of TLR4 and TAK1. TLR4, TAK1, and NLRP3 were collectively co-localized together and with the microglia marker Iba1. CONCLUSIONS: Microglial TLR4 regulates TAK1 expression and phosphorylation and results in NLRP3 activation contributes to the development of morphine tolerance through regulating neuroinflammation. Targeting TLR4-TAK1-NLRP3 signaling to regulate neuro-inflammation will be alternative therapeutics and strategies for chronic morphine-induced antinociceptive tolerance.

Evaluation of vitrectomy combined preoperative intravitreal ranibizumab and postoperative intravitreal triamcinolone acetonide for proliferative diabetic retinopathy.

BACKGROUND: To explore the treatment efficacy of the combination of preoperative intravitreal ranibizumab (IVR) and postoperative intravitreal triamcinolone acetonide (IVTA) in patients undergoing pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). METHODS: A retrospective comparative study was performed on 128 eyes of 128 patients who had PDR and underwent PPV. Patients who received a single PPV were assigned to Group A. Those who received PPV with preoperative IVR were assigned to Group B. Patients in Group C underwent PPV combined preoperative IVR and postoperative IVTA. Intraoperative findings, changes in mean best-corrected visual acuity (BCVA) and postoperative adverse events, were retrospectively evaluated at 6-month follow-up. RESULTS: The incidences of iatrogenic breaks, severe intraoperative bleeding, using long-term internal tamponade agents, recurrent vitreous hemorrhage (VH), and duration of surgery were statistically significantly less in Group B and Group C than in Group A. The postoperative BCVA was statistically significantly better in Groups B and Group C than in Group A, respectively, at 1 month after surgery. The mean 3-month postoperative visual acuity was better in Group C. The incidence of high intraocular pressure (IOP) was significantly higher in Group C at the first postoperative week. There were no statistically significant differences in the incidence of exudative retinal detachment and choroidal detachment among the three groups. CONCLUSION: In patients undergoing PPV for PDR, preoperative IVR significantly reduced the occurrence of intraoperative and postoperative complications, and the combination of preoperative IVR and postoperative IVTA can better improve the postoperative visual outcome.

Tumor mutational burden is associated with poor outcomes in diffuse glioma.

BACKGROUND: Tumor mutational burden (TMB) is a potential biomarker for immune checkpoint therapy and prognosis. The impact of TMB on clinical outcomes and the correlation coefficient between exome sequencing and targeted sequencing in glioma have not yet been explored. METHODS: Somatic mutations in the coding regions of 897 primary gliomas and the clinical and RNA-seq data of 654 patients in The Cancer Genome Atlas (TCGA) database were analyzed as a training set, while another 286 patients in the Chinese Glioma Genome Atlas (CGGA) database were used for validation. Descriptive and correlational analyses were conducted with TMB. Enrichment map analysis and gene set enrichment analysis (GSEA) were also performed. RESULTS: TMB was higher for the group of mutant genes that are frequently mutated in glioblastomas (GBMs) and lower for the group of mutant genes that are frequently mutated in lower-grade gliomas (LGGs). Patients with a higher TMB exhibited shorter overall survival. TMB was associated with grade, age, subtype and mutations affecting genomic structure. Moreover, univariate and multivariate analyses showed that TMB was an independent prognostic factor for glioma. The signaling pathways of the cell cycle were enriched in the TMBHigh group. TMB was higher in the mismatch repair (MMR) gene mutant group than in the wild-type group, but the MMR pathway was enriched in the TMBHigh group of gliomas without mutations in classical MMR genes. The correlation between TMBs calculated through exome sequencing and targeted sequencing was moderate, and panel-based TMB was not correlated with prognosis. CONCLUSIONS: TMB is associated with poor outcomes in diffuse glioma. The high proliferative activity in the TMBHigh group could account for the shorter survival of these patients. This association was not reflected by a pan-cancer targeted sequencing panel.