Association of novel DNAH11 variants with asthenoteratozoospermia lead to male infertility.

BACKGROUND: Bi-allelic variants in DNAH11 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on human sperm flagellar and their involvement in male infertility remain largely unknown. METHODS: A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 variants. RESULTS: In this study, we identified seven novel variants in the DNAH11 gene in four asthenoteratozoospermia subjects. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated, instead of inner dynein arms (IDA) proteins DNAH1 and DNAH6. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11, resulting in the aberrant assembly of sperm flagella and contributing to asthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.

Borna disease virus 1 induces ferroptosis, contributing to lethal encephalitis.

Borna disease virus 1 (BoDV-1) is a neurotropic RNA virus that has been linked to fatal BoDV-1 encephalitis (BVE) in humans. Ferroptosis represents a newly recognized kind of programmed cell death that marked by iron overload and lipid peroxidation. Various viral infections are closely related to ferroptosis. However, the link between BoDV-1 infection and ferroptosis, as well as its role in BVE pathogenesis, remains inadequately understood. Herein, we used primary rat cortical neurons, human microglial HMC3 cells, and Sprague‒Dawley rats as models. BoDV-1 infection induced ferroptosis, as ferroptosis characteristics were detected (iron overload, reactive oxygen species buildup, decreased antioxidant capacity, lipid peroxidation, and mitochondrial damage). Analysis via qRT-PCR and Western blot demonstrated that BoDV-1-induced ferroptosis was mediated through Nrf2/HO-1/SLC7a11/GPX4 antioxidant pathway suppression. Nrf2 downregulation was due to BoDV-1 infection promoting Nrf2 ubiquitination and degradation. Following BoDV-1-induced ferroptosis, the PTGS2/PGE2 signaling pathway was activated, and various intracellular lipid peroxidation products and damage-associated molecular patterns were released, contributing to BVE occurrence and progression. More importantly, inhibiting ferroptosis or the ubiquitin‒proteasome system effectively alleviated BVE. Collectively, these findings demonstrate the interaction between BoDV-1 infection and ferroptosis and reveal BoDV-1-induced ferroptosis as an underlying pathogenic mechanism of BVE.

Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing.

Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.

Clusterin is upregulated by erastin, a ferroptosis inducer and exerts cytoprotective effects in pancreatic adenocarcinoma cells.

Ferroptosis is a novel form of cell death, which is distinguished from apoptosis and necrosis, and characterized by accumulation of lipid-based reactive oxygen species (ROS) in an iron-dependent manner. Erastin, a small molecule, was widely reported to trigger ferroptosis in various kinds of cancer cells, including pancreatic cancer cells by inducing ROS accumulation. However, how erastin treatment exerts cytotoxicity is not still fully understood. In this study, the effects of erastin in causing pancreatic cancer cell death via inducing ferroptosis and apoptosis are investigated. As expected, erastin treatment caused ROS accumulation, increase in iron concentration and non-apoptotic cell death, which is different from that of induced by apoptosis inducer, staurosporine. Interestingly, erastin treatment caused the upregulation of clusterin, which contributes to the regulation of malignant behaviors of pancreatic cancer, including preventing apoptosis and inducing chemoresistance. Without erastin treatment, overexpressed clusterin significantly promoted cell proliferation, which is consistent with its cytoprotective roles. After erastin treatment, overexpressed clusterin decreased erastin-induced ROS accumulation and cell death. By measuring iron concentration, reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), it is revealed that clusterin caused resistance to erastin-induced ferroptosis potentially via maintaining the enzymatic activity of GPX4, without disturbing GSH amount. Thus, ferroptosis inducer, erastin, may crosstalk with apoptotic cell death via regulating clusterin, indicating a more complex regulatory network between ferroptosis and apoptosis.

Time to surgery after completion of neoadjuvant chemotherapy does not negatively impact recurrence and survival outcomes in breast cancer patients.

BACKGROUND: The effect of time to surgery after completion of neoadjuvant chemotherapy and outcomes in breast cancer patients remains poorly defined. Acceptable time to surgery has frequently been arbitrarily defined as between four to eight weeks. This study aims to ascertain if time to surgery after completion of neoadjuvant chemotherapy impacts disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: This single-institution retrospective study included patients who underwent neoadjuvant therapy and subsequent surgery from 2006 to 2017. Demographic, clinicopathological factors, and surgical data from 259 patients were analyzed. 105 patients received surgery within 28 days (group 1). 128 patients received surgery within 29-56 days (group 2), and 26 patients received surgery after 57 days or more (group 3). DFS and OS among the three groups were compared. RESULTS: Age, race, pre-chemotherapy stage, tumor type, grade, hormone receptor status, Her2 status, focality, lymphovascular invasion, radiological response to chemotherapy, type of surgery, pathological response to chemotherapy, and receipt of adjuvant radiotherapy were not significantly different between the three groups. Only receipt of adjuvant chemotherapy was statistically significant (p = 0.0230). DFS and OS between the three groups were not found to be significantly different (p = 0.520 and p = 0.369, respectively). CONCLUSION: Time to surgery after completion of neoadjuvant chemotherapy did not appear to affect recurrence or survival outcomes. Findings from this study may allow more flexibility and reduce the burden of scheduling patients for surgery within the usual four-to-eight-week window in centers with resource and scheduling constraints.

Transforming care: Optimizing ERAS pathway in breast cancer surgery with latissimus dorsi flap.

INTRODUCTION: This study aims to establish, execute, and assess the effectiveness of a perioperative enhanced recovery after surgery (ERAS) clinical care pathway in breast reconstruction patients with LD flap breast cancer treatment. The goal is to improve early recovery outcomes, reduce hospitalization time, and enhance patient satisfaction by implementing a standardized approach to postoperative care. METHODS: This study was conducted at the University of Malaya Medical Center. The outcomes of 21 breast cancer patients who underwent autologous reconstructive breast surgery with the latissimus dorsi (LD) flap within six months before the implementation of the ERAS pathway (pre-ERAS) were compared with 26 patients who underwent the same surgery with the ultrasound-guided erector spinae plane (ESP) block for the (ERAS protocol implementation) cohort. The study was conducted from November 2019 to October 2020. The length of hospital stay, amount of analgesic usage, and incidence of postoperative nausea vomiting (PONV) were recorded. RESULTS: The implementation of the ERAS clinical care pathway resulted in shorter hospital stays compared with the preceding care. On average, ERAS patients were mostly discharged on Day 2 post-surgery, whereas pre-ERAS patients were mostly discharged on Day 7. ERAS patients had a lower incidence of PONV from Days 1 to 5, starting with 88.5% not experiencing the condition on Days 1 and 2 and increasing to 100% on Day 5. All pre-ERAS patients experienced PONV in the first 5 days post-surgery. Fewer ERAS patients required antiemetics post-surgery (88.5%) compared with pre-ERAS patients (42.9%). CONCLUSION: The implementation of the ERAS protocol as part of clinical care in autologous reconstructive breast surgery with the LD flap can improve recovery by shortening hospital stay, decreasing the use of analgesia, and alleviating PONV.

Effect of decentration and tilt on the in vitro optical quality of monofocal and trifocal intraocular lenses.

PURPOSE: To evaluate and compare the effect of decentration and tilt on the optical quality of monofocal and trifocal intraocular lenses (IOL). METHODS: Optical quality of a monofocal IOL (AcrySof IQ SN60WF; Alcon Laboratories, Inc., USA) and a trifocal IOL (AcrySof IQ PanOptix; Alcon Laboratories, Inc., USA) was assessed using an in vitro optical bench (OptiSpheric IOL R&D; Trioptics GmbH, Germany). At apertures of 3.0 mm and 4.5 mm, modulation transfer function (MTF) at spatial frequency of 50 lp/mm, MTF curve and the United States Air Force (USAF) resolution test chart of the two IOLs were measured and compared at their focus with different degrees of decentration and tilt. Optical quality at infinity, 60 cm and 40 cm and the through-focus MTF curves were compared when the two IOLs were centered at apertures of 3.0 mm and 4.5 mm. Spectral transmittance of the two IOLs was measured by the UV-visible spectrophotometer (UV 3300 PC; MAPADA, China). RESULTS: The SN60WF and the PanOptix filtered blue light from 400 to 500 nm. Both IOLs at the far focus and the PanOptix at the intermediate focus showed a decrease in optical quality with increasing decentration and tilt. The PanOptix demonstrated enhanced optical quality compared to the previous gradient at the near focus at a decentration range of 0.3-0.7 mm with a 3.0 mm aperture, and 0.5 mm with a 4.5 mm aperture, whereas other conditions exhibited diminished optical quality with increasing decentration and tilt at the focus of both IOLs. When the two IOLs were centered, the SN60WF had better optical quality at infinity, while the PanOptix had better optical quality at 60 cm and 40 cm defocus. The optical quality of the SN60WF exceeded that of the PanOptix at far focus, with a 3 mm aperture decentration up to 0.7 mm and a 4.5 mm aperture decentration up to 0.3 mm; this observation held true for all tilts, irrespective of aperture size. As both decentration and tilt increased, the optical quality of the SN60WF deteriorated more rapidly than that of the PanOptix at the far focal point. CONCLUSIONS: The SN60WF showed a decrease in optical quality with increasing decentration and tilt. Optical quality of the PanOptix at the near focus increased in some decentration conditions and decreased in some conditions, while it showed a decrease at the other focuses with increasing decentration. While tilt only had a negative effect on optical quality. When both IOLs were centered, the PanOptix provided a wider range of vision, while the SN60WF provided better far distance vision. At the far focus, the SN60WF has better resistance to tilt than the PanOptix, but the optical quality degrades more quickly when decentered and tilted.

The effect of the mitochondria-targeted antioxidant Mito-tempo during sperm ultra-rapid freezing.

During the freeze-thaw process, human spermatozoa are susceptible to oxidative stress, which may cause cryodamage and reduce sperm quality. As a novel mitochondria-targeted antioxidant, Mito-tempo has been used for sperm cryopreservation. However, it is currently unknown what role it will play in the process of sperm ultra-rapid freezing. The purpose of this study was to investigate whether Mito-tempo can improve sperm quality during ultra-rapid freezing. In this study, samples with the addition of Mito-tempo (0, 5, 10, 20, and 40 µM) to sperm freezing medium were selected to evaluate the changes in sperm quality, antioxidant capacity and ultrastructure after ultra-rapid freezing. After ultra-rapid freezing, the quality and antioxidant function of the spermatozoa were significantly reduced and the spermatozoa ultrastructure was destroyed. The addition of 10 µM Mito-tempo significantly increased post thaw sperm motility, viability, plasma membrane integrity and mitochondrial membrane potential (P < 0.05). Moreover, the DNA fragmentation index (DFI), ROS levels and MDA content were reduced, and the antioxidant enzyme (CAT and SOD) activities were enhanced in the 10 µM Mito-tempo group (P < 0.05). Moreover, Mito-tempo protected sperm ultrastructure from damage. In conclusion, Mito-tempo improved the quality and antioxidant function of sperm after ultra-rapid freezing while reducing freezing-induced ultrastructural damage.

Genomic Insights into Idiopathic Granulomatous Mastitis through Whole-Exome Sequencing: A Case Report of Eight Patients.

Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2. Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1, CEP170, and CTR9, recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored.

Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice.

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.

Pregnancy-associated breast cancer: a multicenter study comparing clinicopathological factors, diagnosis and treatment outcomes with non-pregnant patients.

PURPOSE: Pregnancy-associated breast cancer (PABC), defined as breast carcinoma diagnosed during pregnancy or in the first post-partum year, is one of the most common gestation-related malignancies with reported differences in tumor characteristics and outcomes. This multicenter study aims to review cases of PABC in Singapore, including their clinicopathological features, treatment, and clinical outcomes compared to non-PABC patients. METHODS: Demographic, histopathologic and clinical outcomes of 93 PABC patients obtained from our database were compared to 1424 non-PABC patients. RESULTS: PABC patients presented at a younger age. They had higher tumor and nodal stages, higher tumor grade, were more likely to be hormone receptor negative and had a higher incidence of multicentric and multifocal tumors. Histological examination after definitive surgery showed no significant difference in tumor size and number of positive lymph nodes suggesting similar neoadjuvant treatment effects. Despite this, PABC patients had worse outcomes with poorer overall survival and disease-free survival, OS (P < 0.0001) and DFS (P < 0.0001). Termination of pregnancy did not improve survival. CONCLUSION: Patients with PABC present at a higher stage with more aggressive disease and have poorer outcomes compared to non-PABC patients. Reducing delay in diagnosis and treatment may help improve survival.

LRRC23 deficiency causes male infertility with idiopathic asthenozoospermia by disrupting the assembly of radial spokes.

Asthenozoospermia (AZS) is the primary cause of infertility in males. The radial spoke (RS) is an axonemal structure, connecting the peripheral doublet microtubules with the central pair of microtubules. This T-shaped multiprotein complex functions as a mechanochemical sensor to promote sperm motility. LRRC23 is a novel subunit of the RS complex that is necessary for flagellar assembly and movement in mice. However, the importance of LRRC23 in modulating RS formation in humans remains unclear. Here, we identified a homozygous nonsense mutation in LRRC23 (c.376C>T:p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection. This study provides strong preliminary evidence that LRRC23 defects are potential causative factors of AZS in humans, which expands our knowledge for improved genetic counseling and better reproductive recommendations for patients with AZS.

Network Evolution Model-based prediction of tumor mutation burden from radiomic-clinical features in endometrial cancers.

BACKGROUND: Endometrial Cancer (EC) is one of the most prevalent malignancies that affect the female population globally. In the context of immunotherapy, Tumor Mutation Burden (TMB) in the DNA polymerase epsilon (POLE) subtype of this cancer holds promise as a viable therapeutic target. METHODS: We devised a method known as NEM-TIE to forecast the TMB status of patients with endometrial cancer. This approach utilized a combination of the Network Evolution Model, Transfer Information Entropy, Clique Percolation (CP) methodology, and Support Vector Machine (SVM) classification. To construct the Network Evolution Model, we employed an adjacency matrix that utilized transfer information entropy to assess the information gain between nodes of radiomic-clinical features. Subsequently, using the CP algorithm, we unearthed potentially pivotal modules in the Network Evolution Model. Finally, the SVM classifier extracted essential features from the module set. RESULTS: Upon analyzing the importance of modules, we discovered that the dependence count energy in tumor volumes-of-interest holds immense significance in distinguishing TMB statuses among patients with endometrial cancer. Using the 13 radiomic-clinical features extracted via NEM-TIE, we demonstrated that the area under the receiver operating characteristic curve (AUROC) in the test set is 0.98 (95% confidence interval: 0.95-1.00), surpassing the performance of existing techniques such as the mRMR and Laplacian methods. CONCLUSIONS: Our study proposed the NEM-TIE method as a means to identify the TMB status of patients with endometrial cancer. The integration of radiomic-clinical data utilizing the NEM-TIE method may offer a novel technology for supplementary diagnosis.

Concordance of PGT for aneuploidies between blastocyst biopsies and spent blastocyst culture medium.

RESEARCH QUESTION: Non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) avoids the possible detrimental impact of invasive PGT-A on embryo development and clinical outcomes. Does cell-free DNA (cfDNA) from spent blastocyst culture medium (BCM) reflect embryonic chromosome status better than trophectoderm (TE) biopsy? DESIGN: In this study, 35 donated embryos were used for research and the BCM, TE biopsy, inner cell mass (ICM) and residual blastocyst (RB) were individually picked up from these embryos. Whole genome amplification (WGA) was performed and amplified DNA was subject to next-generation sequencing. Chromosome status concordance was compared among the groups of samples. RESULTS: The WGA success rates were 97.0% (TE biopsy), 100% (ICM), 97.0% (RB) and 88.6% (BCM). Using ICM as the gold standard, the chromosomal ploidy concordance rates for BCM, TE biopsy and RB were 58.33% (14/24), 68.75% (22/32) and 78.57% (22/28); the diagnostic concordance rates were 83.33% (20/24), 87.50% (28/32) and 92.86% (26/28); and the sex concordance rates were 92.31% (24/26), 100% (32/32) and 100% (28/28), respectively. Considering RB the gold standard, the chromosome ploidy concordance rates for BCM and TE biopsy were 61.90% (13/21) and 81.48% (22/27); the diagnostic concordance rates were 71.43% (15/21) and 88.89% (24/27); and the sex concordance rates were 91.30% (21/23) and 100% (27/27), respectively. CONCLUSIONS: The results of niPGT-A of cfDNA of spent BCM are comparable to those of invasive PGT-A of TE biopsies. Modifications of embryo culture conditions and testing methods will help reduce maternal DNA contamination and improve the reliability of niPGT-A.

NEMO involves in NF-κB activation by interaction with p65 and promoting its nuclear translocation in large yellow croaker (Larimichthys crocea).

NEMO (nuclear factor-κB essential modulator) plays an important role in activating NF-κB signaling pathway, p65 is a pivotal positive-regulator of NF-κB family. However, the role of NEMO in p65-triggered immune activation in teleost is largely unknown. In the present study, the cDNA sequence of LcNEMO was identified from the large yellow croaker (Larimichthys crocea). The predicated LcNEMO protein encoded 565 amino acids, consisting of a N-terminal NEMO domain, followed by two coiled coil (CC) motifs, a CC2-leucine zipper (CC2-LZ) domain, and a C-terminal zinc finger (ZnF) domain. Quantitative PCR showed that the strongest constitutive expression of LcNEMO was detected in blood and the inductive expression of it significantly enhanced after LPS and poly I:C challenge. The effect of LcNEMO on p65, RelB and cRel associated-immune activation detected by dual-luciferase reporter system assay indicated that Lcp65-triggered NF-κB, TNF-α and IL-1ß activation could be significantly enhanced by LcNEMO. Furthermore, Co-IP revealed that the protein-protein interaction was existed between LcNEMO and Lcp65. Western blot and confocal microscope observation displayed that Lcp65 nuclear translocation could be promoted by LcNEMO with a dose- and time-dependent manner, which was further verified by RNA interference of LcNEMO expression. Our findings suggest that LcNEMO may be crucial in immune response by promoting p65-mediated immune activation.

Clinicodemographic correlates of psychotic features in bipolar disorder - a multicenter study in China.

BACKGROUND: Psychotic symptoms are prevalent in patients with bipolar disorder (BD). However, nearly all previous studies on differences in sociodemographic and clinical factors between patients with (BD P +) and without (BD P-) psychotic symptoms were conducted in Western populations, and limited information is known in China. METHOD: A total of 555 patients with BD from seven centers across China were recruited. A standardized procedure was used to collect patients' sociodemographic and clinical characteristics. The patients were divided into BD P + or BD P- groups based on the presence of lifetime psychotic symptoms. Mann-Whitney U test or chi-square test was used to analyze differences in sociodemographic and clinical factors between patients with BD P + and BD P-. Multiple logistic regression analysis was conducted to explore factors that were independently correlated with psychotic symptoms in BD. All the above analyses were re-conducted after the patients were divided into BD I and BD II group according to their types of diagnosis. RESULTS: A total of 35 patients refused to participate, and the remaining 520 patients were included in the analyses. Compared with patients with BD P-, those with BD P + were more likely to be diagnosed with BD I and mania/hypomania/mixed polarity in the first mood episode. Moreover, they were more likely to be misdiagnosed as schizophrenia than major depressive disorder, were hospitalized more often, used antidepressants less frequently, and used more antipsychotics and mood stabilizers. Multivariate analyses revealed that diagnosis of BD I, more frequent misdiagnosis as schizophrenia and other mental disorders, less frequent misdiagnosis as major depressive disorder, more frequent lifetime suicidal behavior, more frequent hospitalizations, less frequent use of antidepressants, more frequent use of antipsychotics and mood stabilizers were independently correlated with psychotic symptoms in BD. After dividing the patients into BD I and BD II groups, we observed notable differences in sociodemographic and clinical factors, as well as clinicodemographic correlates of psychotic features between the two groups. CONCLUSIONS: Differences in clinical factors between patients with BD P + and BD P- showed cross-cultural consistency, but results on the clinicodemographic correlates of psychotic features were not. Notable differences between patients with BD I and BD II were found. Future work exploring the psychotic features of BD needs to take types of diagnosis and cultural differences into consideration. TRIAL REGISTRATION: This study was first registered on the website of the ClinicalTrials.gov ( https://clinicaltrials.gov/ ) on 18/01/2013. Its registration number is NCT01770704.

Convergence insufficiency symptom survey: A tool to evaluate convergence excess in young adults.

PURPOSE: To determine the effectiveness of the Convergence Insufficiency Symptom Survey (CISS) in evaluating visual symptoms in young adults with convergence excess (CE). METHODS: A cross-sectional study was performed based on a population of optometry students. Comprehensive binocular vision tests including cover test, near point of convergence, fusional vergence and accommodative amplitude, were performed. Participants were categorised into three groups: normal binocular vision (NBV), CE and CE + accommodative insufficiency (AI) (i.e., CE + AI). The CISS was administered to each participant. An analysis of variance with Bonferroni correction was performed to compare clinical measures among the three groups. A receiver-operating characteristic (ROC) curve was constructed to evaluate the ability of CISS to differentiate CE from the NBV population. RESULTS: A total of 181 participants were enrolled, including 96 in the NBV group, 66 in the CE group and 19 in the CE + AI group. A significant difference in CISS score was detected between the three groups (p < 0.001). Post-hoc tests showed significantly higher CISS scores in the CE group (16.7 ± 10.8) and the CE + AI group (19.7 ± 10.9) compared with the NBV group (12.2 ± 7.8) (p = 0.01 and p = 0.005, respectively), with no difference between the CE and the CE + AI groups (p = 0.52). The ROC curve showed the CISS poorly (but significantly) differentiated CE from NBV (area under the curve = 0.62, p = 0.01). The optimal cutoff value for a CISS score to differentiate CE was 16, with sensitivity and specificity of 52% and 72%, respectively. CONCLUSIONS: Young adults with CE had significantly higher CISS scores than those with NBV. Although using the CISS solely for diagnosing CE is not recommended, it can be used to provide a measure of symptoms in individuals identified as having CE based on clinical measurements.

A pan-cancer analysis of Dyskeratosis congenita 1 (DKC1) as a prognostic biomarker.

BACKGROUND: Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial. METHODS: We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-ß-gal staining on DKC1-deleted MDA-231 cells. RESULTS: Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence. CONCLUSIONS: Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.

Laser Cooling of a Lattice Vibration in van der Waals Semiconductor.

Laser cooling atoms and molecules to ultralow temperatures has produced plenty of opportunities in fundamental physics, precision metrology, and quantum science. Although theoretically proposed over 40 years, the laser cooling of certain lattice vibrations (i.e., phonon) remains a challenge owing to the complexity of solid structures. Here, we demonstrate Raman cooling of a longitudinal optical phonon in two-dimensional semiconductor WS2 by red-detuning excitation at the sideband of the exciton (bound electron-hole pair). Strong coupling between the phonon and exciton and appreciable optomechanical coupling rates provide access to cooling high-frequency phonons that are robust against thermal decoherence even at room temperature. Our experiment opens possibilities of laser cooling and control of individual optical phonon and, eventually, possible cooling of matter in van der Waals semiconductor.

Profiling Microbial Communities in Idiopathic Granulomatous Mastitis.

Idiopathic granulomatous mastitis (IGM) is a rare and benign inflammatory breast disease with ambiguous aetiology. Contrastingly, lactational mastitis (LM) is commonly diagnosed in breastfeeding women. To investigate IGM aetiology, we profiled the microbial flora of pus and skin in patients with IGM and LM. A total of 26 patients with IGM and 6 patients with LM were included in the study. The 16S rRNA sequencing libraries were constructed from 16S rRNA gene amplified from total DNA extracted from pus and skin swabs in patients with IGM and LM controls. Constructed libraries were multiplexed and paired-end sequenced on HiSeq4000. Metagenomic analysis was conducted using modified microbiome abundance analysis suite customised R-resource for paired pus and skin samples. Microbiome multivariable association analyses were performed using linear models. A total of 21 IGM and 3 LM paired pus and skin samples underwent metagenomic analysis. Bray−Curtis ecological dissimilarity distance showed dissimilarity across four sample types (IGM pus, IGM skin, LM pus, and LM skin; PERMANOVA, p < 0.001). No characteristic dominant genus was observed across the IGM samples. The IGM pus samples were more diverse than corresponding IGM skin samples (Shannon and Simpson index; Wilcoxon paired signed-rank tests, p = 0.022 and p = 0.07). Corynebacterium kroppenstedtii, reportedly associated with IGM in the literature, was higher in IGM pus samples than paired skin samples (Wilcoxon, p = 0.022). Three other species and nineteen genera were statistically significant in paired IGM pus−skin comparison after antibiotic treatment adjustment and multiple comparisons correction. Microbial profiles are unique between patients with IGM and LM. Inter-patient variability and polymicrobial IGM pus samples cannot implicate specific genus or species as an infectious cause for IGM.