D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

RNA-binding proteins potentially regulate the alternative splicing of apoptotic genes during knee osteoarthritis progression.

BACKGROUND: Alternative splicing (AS) is a principal mode of genetic regulation and one of the most widely used mechanisms to generate structurally and functionally distinct mRNA and protein variants. Dysregulation of AS may result in aberrant transcription and protein products, leading to the emergence of human diseases. Although considered important for regulating gene expression, genome-wide AS dysregulation, underlying mechanisms, and clinical relevance in knee osteoarthritis (OA) remain unelucidated. Therefore, in this study, we elucidated and validated AS events and their regulatory mechanisms during OA progression. RESULTS: In this study, we identified differentially expressed genes between human OA and healthy meniscus samples. Among them, the OA-associated genes were primarily enriched in biological pathways such as extracellular matrix organization and ossification. The predominant OA-associated regulated AS (RAS) events were found to be involved in apoptosis during OA development. The expression of the apoptosis-related gene BCL2L13, XAF1, and NF2 were significantly different between OA and healthy meniscus samples. The construction of a covariation network of RNA-binding proteins (RBPs) and RAS genes revealed that differentially expressed RBP genes LAMA2 and CUL4B may regulate the apoptotic genes XAF1 and BCL2L13 to undergo AS events during OA progression. Finally, RT-qPCR revealed that CUL4B expression was significantly higher in OA meniscus samples than in normal controls and that the AS ratio of XAF1 was significantly different between control and OA samples; these findings were consistent with their expected expression and regulatory relationships. CONCLUSIONS: Differentially expressed RBPs may regulate the AS of apoptotic genes during knee OA progression. XAF1 and its regulator, CUL4B, may serve as novel biomarkers and potential therapeutic targets for this disease.

Two new quinoline alkaloid with neuroprotective activities from Xylaria longipes.

Two new quinoline alkaloids with an α, ß-unsaturated amide side chain, xylarinines A and B (1 and 2), were isolated from the ethyl acetate extracts of Xylaria longipes solid fermentation. The structures of these were primarily determined though NMR and HRESIMS data analysis. The absolute configuration of compound 1 was assigned using experimental and calculated ECD data. The neuroprotective effects of compounds 1 and 2 against glutamate-induced damage in PC12 cells were evaluated in vitro bioassay. The results demonstrated that both compounds significantly improved cell viability, inhibited apoptosis, decreased malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced intracellular reactive oxygen species (ROS) accumulation. These findings suggested that these mechanisms contribute to the neuroprotective effects of the compounds.

Meta-analysis of factors influencing anterior knee pain after total knee arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) is a mature procedure recommended for correcting knee osteoarthritis deformity, relieving pain, and restoring normal biomechanics. Although TKA is a successful and cost-effective procedure, patient dissatisfaction is as high as 50%. Knee pain after TKA is a significant cause of patient dissatisfaction; the most common location for residual pain is the anterior region. Between 4% and 40% of patients have anterior knee pain (AKP). AIM: To investigate the effect of various TKA procedures on postoperative AKP. METHODS: We searched PubMed, EMBASE, and Cochrane from January 2000 to September 2022. Randomized controlled trials with one intervention in the experimental group and no corresponding intervention (or other interventions) in the control group were collected. Two researchers independently read the title and abstract of the studies, preliminarily screened the articles, and read the full text in detail according to the selection criteria. Conflicts were resolved by consultation with a third researcher. And relevant data from the included studies were extracted and analyzed using Review Manager 5.4 software. RESULTS: There were 25 randomized controlled trials; 13 were comparative studies with or without patellar resurfacing. The meta-analysis showed no significant difference between the experimental and control groups (P = 0.61). Six studies were comparative studies of circumpatellar denervation vs non-denervation, divided into three subgroups for meta-analysis. The two-subgroup meta-analysis showed no significant difference between the experimental and the control groups (P = 0.31, P = 0.50). One subgroup meta-analysis showed a significant difference between the experimental and control groups (P = 0.001). Two studies compared fixed-bearing TKA and mobile-bearing TKA; the results meta-analysis showed no significant difference between the experimental and control groups (P = 0.630). Two studies compared lateral retinacular release vs non-release; the meta-analysis showed a significant difference between the experimental and control groups (P = 0.002); two other studies compared other factors. CONCLUSION: Patellar resurfacing, mobile-bearing TKA, and fixed-bearing TKA do not reduce the incidence of AKP. Lateral retinacular release can reduce AKP; however, whether circumpatellar denervation can reduce AKP is controversial.

Single-cell transcriptome analyses reveal critical regulators of spermatogonial stem cell fate transitions.

BACKGROUND: Spermatogonial stem cells (SSCs) are the foundation cells for continual spermatogenesis and germline regeneration in mammals. SSC activities reside in the undifferentiated spermatogonial population, and currently, the molecular identities of SSCs and their committed progenitors remain unclear. RESULTS: We performed single-cell transcriptome analysis on isolated undifferentiated spermatogonia from mice to decipher the molecular signatures of SSC fate transitions. Through comprehensive analysis, we delineated the developmental trajectory and identified candidate transcription factors (TFs) involved in the fate transitions of SSCs and their progenitors in distinct states. Specifically, we characterized the Asingle spermatogonial subtype marked by the expression of Eomes. Eomes+ cells contained enriched transplantable SSCs, and more than 90% of the cells remained in the quiescent state. Conditional deletion of Eomes in the germline did not impact steady-state spermatogenesis but enhanced SSC regeneration. Forced expression of Eomes in spermatogenic cells disrupted spermatogenesis mainly by affecting the cell cycle progression of undifferentiated spermatogonia. After injury, Eomes+ cells re-enter the cell cycle and divide to expand the SSC pool. Eomes+ cells consisted of 7 different subsets of cells at single-cell resolution, and genes enriched in glycolysis/gluconeogenesis and the PI3/Akt signaling pathway participated in the SSC regeneration process. CONCLUSIONS: In this study, we explored the molecular characteristics and critical regulators of subpopulations of undifferentiated spermatogonia. The findings of the present study described a quiescent SSC subpopulation, Eomes+ spermatogonia, and provided a dynamic transcriptional map of SSC fate determination.

Heavy metals prediction in coastal marine sediments using hybridized machine learning models with metaheuristic optimization algorithm.

This study proposes different standalone models viz: Elman neural network (ENN), Boosted Tree algorithm (BTA), and f relevance vector machine (RVM) for modeling arsenic (As (mg/kg)) and zinc (Zn (mg/kg)) in marine sediments owing to anthropogenic activities. A heuristic algorithm based on the potential of RVM and a flower pollination algorithm (RVM-FPA) was developed to improve the prediction performance. Several evaluation indicators and graphical methods coupled with visualized cumulative probability function (CDF) were used to evaluate the accuracy of the models. Akaike (AIC) and Schwarz (SCI) information criteria based on Dickey-Fuller (ADF) and Philip Perron (PP) tests were introduced to check the reliability and stationarity of the data. The prediction performance in the verification phase indicated that RVM-M2 (PBAIS = -o.0465, MAE = 0.0335) and ENN-M2 (PBAIS = 0.0043, MAE = 0.0322) emerged as the best model for As (mg/kg) and Zn (mg/kg), respectively. In contrast with the standalone approaches, the simulated hybrid RVM-FPA proved merit and the most reliable, with a 5 % and 18 % predictive increase for As (mg/kg) and Zn (mg/kg), respectively. The study's findings validated the potential for estimating complex HMs through intelligent data-driven models and heuristic optimization. The study also generated valuable insights that can inform the decision-makers and stockholders for environmental management strategies.

Intelectin-1 is a novel prognostic biomarker for hepatocellular carcinoma.

The molecular mechanisms of hepatocellular carcinoma (HCC) are still not well understood. Gene microarray analysis showed that the expression of Intelectin-1 (ITLN-1) in tumor-adjacent normal liver tissue was 454.8 times higher than in the corresponding cancer tissue. ITLN-1 is a secreted soluble glycoprotein which has been reported to be associated with the occurrence and development of various tumor types. However, the prognostic significance of ITLN-1 in HCC remain unclear. Real-time fluorescence quantitative polymerase chain reaction was used to investigate 149 liver cancer cases for ITLN-1 mRNA expression. Immunohistochemistry and western blot analysis were used to ascertain protein expression of ITLN-1 in cancer and para-carcinomatous tissue, and further to evaluate the correlation between ITLN-1 mRNA expression and surgical prognosis after liver resection. The ITLN-1 mRNA and protein levels were significantly higher in adjacent normal liver tissues than HCC tissues. Real-time fluorescence quantitative polymerase chain reaction showed that the ITLN-1 expression was decreased in 78.5% (117/149) of HCC tissues compared with their corresponding adjacent liver tissues. Moreover, its low expression was significantly correlated with increased tumor size, tumor differentiation degree, degree of liver cirrhosis, capsule integrity, vascular invasion and tumor recurrence. Patients with high ITLN-1 expression had significantly better overall and recurrence-free survival after curative liver resection. Multivariate cox regression analysis showed that ITLN-1 was an independent predictor of surgical outcomes in HCC patients. The present study suggested that low ITLN-1 expression was associated with poor clinical outcome for HCC patients, indicating a novel biomarker for prognosis evaluation and a potential therapeutic target for HCC patients.

Isolated medial patellofemoral ligament reconstruction improves static bipedal balance control in young patients with recurrent lateral patellar instability.

BACKGROUND: Knee stability can be safely and reliably restored using medial patellofemoral ligament (MPFL) reconstruction, which is widely recognized in patients with recurrent lateral patellar instability. However, the literature regarding its influence on static balance control is limited. Thus, this study aimed to assess the impact of MPFL reconstruction on balance control and determine its functional significance. METHODS: The study comprised 26 patients with recurrent lateral patellar instability, scheduled for MPFL reconstruction, and 26 matched healthy controls who underwent double-leg stance static posturographic tests pre- and postoperatively on a vertical force platform. Four test conditions were performed with their eyes open and closed, without and with foam support to evaluate the balance control of all participants. The International Knee Documentation Committee subjective knee form, Lysholm knee scoring scale, Tampa scale for kinesiophobia, and active range of motion of the affected knee were synchronously obtained and assessed. RESULTS: More postural sway was observed in patients compared to the healthy controls, 11 ± 5 days preoperatively (p < 0.01). However, 374 ± 23 days postoperatively, postural sway between the patients and control subjects was comparable (p > 0.05). Patients following MPFL reconstruction demonstrated better postural stability (p < 0.01). Significant ameliorations were found in all clinical assessments in the study patients postoperatively (p < 0.01). CONCLUSIONS: Patients with recurrent lateral patellar instability have inefficient balance control. Static bipedal balance control can be improved under surface perturbation in these patients one year after isolated MPFL reconstruction that enhances the possibility of normal restoration of postural stability. Structural recovery of the ligament could help restore the sensorimotor efficiency and generate the compensatory and anticipatory balance regulation strategies, thereby improving joint function.

High tibial osteotomy improves balance control in patients with knee osteoarthritis and a varus deformity.

BACKGROUND: Impaired knee stability is observed in patients with medial compartment knee osteoarthritis (OA) and varus malalignment. Although high tibial osteotomy (HTO) is widely used to treat OA-related knee varus deformity, its long-term influence on balance control in OA patients is poorly reported. This study aimed to evaluate the impact of HTO on balance control and assess its biological and functional significance. METHODS: Thirty-two patients with medial compartment knee OA as well as varus deformity who were scheduled for HTO underwent static posturographic tests one month pre- and three months as well as one year postoperatively, respectively, along with forty matched control subjects. Radiographic and clinical evaluations were synchronously carried out on patients pre- and postoperatively. RESULTS: Decreased postural sway was observed in patients one year after HTO. When compared to the control subjects, more postural sway was found in patients one month pre- and three months postoperatively. No difference was observed between the patients and control subjects one year postoperatively. The alignment and joint function of the affected knees significantly improved after HTO. CONCLUSIONS: This study revealed that HTO improves balance control in patients with knee OA and varus deformity. Correct alignment and improved joint function enhance the likelihood of normal postural stability. Hence, this intervention allows the knee joint to recover its corrective compensatory role in postural regulation and should be taken into account for managing knee OA patients.

Single-cell transcriptomic characterization of sheep conceptus elongation and implantation.

Bidirectional communication between the developing conceptus and endometrium is essential for pregnancy recognition and establishment in ruminants. We dissect the transcriptomic dynamics of sheep conceptus and corresponding endometrium at pre- and peri-implantation stages using single-cell RNA sequencing. Spherical blastocysts contain five cell types, with 68.62% trophectoderm cells. Strikingly, elongated conceptuses differentiate into 17 cell types, indicating dramatic cell fate specifications. Cell-type-specific gene expression delineates the features of distinctive trophectoderm lineages and indicates that the transition from polar trophectoderm to trophoblast increases interferon-tau expression and likely drives elongation initiation. We identify 13 endometrium-derived cell types and elucidate their molecular responses to conceptus development. Integrated analyses uncover multiple paired transcripts mediating the dialogues between extraembryonic membrane and endometrium, including IGF2-IGF1R, FGF19-FGFR1, NPY-NPY1R, PROS1-AXL, and ADGRE5-CD55. These data provide insight into the molecular regulation of conceptus elongation and represent a valuable resource for functional investigations of pre- and peri-implantation ruminant development.

Pancreatic lipase-related protein 2 is selectively expressed by peritubular myoid cells in the murine testis and sustains long-term spermatogenesis.

Spermatogenesis is a complicated process of germ cell differentiation that occurs within the seminiferous tubule in the testis. Peritubular myoid cells (PTMCs) produce major components of the basement membrane that separates and ensures the structural integrity of seminiferous tubules. These cells secrete niche factors to promote spermatogonial stem cell (SSC) maintenance and mediate androgen signals to direct spermatid development. However, the regulatory mechanisms underlying the identity and function of PTMCs have not been fully elucidated. In the present study, we showed that the expression of pancreatic lipase-related protein 2 (Pnliprp2) was restricted in PTMCs in the testis and that its genetic ablation caused age-dependent defects in spermatogenesis. The fertility of Pnliprp2 knockout animals (Pnliprp2-/-) was normal at a young age but declined sharply beginning at 9 months. Pnliprp2 deletion impaired the homeostasis of undifferentiated spermatogonia and severely disrupted the development and function of spermatids. Integrated analyses of single-cell RNA-seq and metabolomics data revealed that glyceride metabolism was changed in PTMCs from Pnliprp2-/- mice. Further analysis found that 60 metabolites were altered in the sperm of the Pnliprp2-/- animals; notably, lipid metabolism was significantly dysregulated. Collectively, these results revealed that Pnliprp2 was exclusively expressed in PTMCs in the testis and played a novel role in supporting continual spermatogenesis in mice. The outcomes of these findings highlight the function of lipid metabolism in reproduction and provide new insights into the regulation of PTMCs in mammals.

Effect of autogenous osteochondral mosaicplasty on the balance control of patients with cartilage defects of the knee: a pilot study.

BACKGROUND: Autogenous osteochondral mosaicplasty (AOM) is a widely used optimal surgical technique for cartilage repair in young patients with focal articular cartilage defects. However, the alterations in balance control in these patients after AOM have not been sufficiently investigated. This study aimed to compare different balance control performances between the patients with knee cartilage defects and healthy controls before and after AOM, as well as evaluate the influence of AOM on balance control in these patients. METHODS: Static posturographic tests were performed in twenty-four patients who were scheduled for AOM two weeks pre-, three months, and one year postoperatively, along with thirty matched controls, respectively. All participants underwent posturography under four standing conditions: eyes open and closed, without and with foam support to assess the balance control ability. Subsequently, patient-reported outcome measures (PROMs) were synchronously obtained and analyzed. RESULTS: Compared to the control subjects, less efficient balance control was observed in study patients at three testing phases (p < 0.05), whereas no alterations in postural control were visible in these patients within a year following AOM (p > 0.05). Significant improvements were found in all PROMs such as the International Knee Documentation Committee, the Lysholm Knee Score, and the visual analogue scale in the study patients postoperatively (p < 0.01). CONCLUSION: The results indicated that patients with knee cartilage defects have a prominent balance control deficit compared to healthy individuals. Furthermore, AOM does not improve balance control in these patients for at least one year postoperatively, and more effective approaches for postural regulation are required for the management of cartilage defect patients.

Machine learning algorithms for high-resolution prediction of spatiotemporal distribution of air pollution from meteorological and soil parameters.

This study uses machine learning (ML) models for a high-resolution prediction (0.1°×0.1°) of air fine particular matter (PM2.5) concentration, the most harmful to human health, from meteorological and soil data. Iraq was considered the study area to implement the method. Different lags and the changing patterns of four European Reanalysis (ERA5) meteorological variables, rainfall, mean temperature, wind speed and relative humidity, and one soil parameter, the soil moisture, were used to select the suitable set of predictors using a non-greedy algorithm known as simulated annealing (SA). The selected predictors were used to simulate the temporal and spatial variability of air PM2.5 concentration over Iraq during the early summer (May-July), the most polluted months, using three advanced ML models, extremely randomized trees (ERT), stochastic gradient descent backpropagation (SGD-BP) and long short-term memory (LSTM) integrated with Bayesian optimizer. The spatial distribution of the annual average PM2.5 revealed the population of the whole of Iraq is exposed to a pollution level above the standard limit. The changes in temperature and soil moisture and the mean wind speed and humidity of the month before the early summer can predict the temporal and spatial variability of PM2.5 over Iraq during May-July. Results revealed the higher performance of LSTM with normalized root-mean-square error and Kling-Gupta efficiency of 13.4% and 0.89, compared to 16.02% and 0.81 for SDG-BP and 17.9% and 0.74 for ERT. The LSTM could also reconstruct the observed spatial distribution of PM2.5 with MapCurve and Cramer's V values of 0.95 and 0.91, compared to 0.9 and 0.86 for SGD-BP and 0.83 and 0.76 for ERT. The study provided a methodology for forecasting spatial variability of PM2.5 concentration at high resolution during the peak pollution months from freely available data, which can be replicated in other regions for generating high-resolution PM2.5 forecasting maps.

Primary lacrimal sac lymphoma: a case-based retrospective study in a Chinese population.

AIM: To determine the clinical characteristics, pathological types, tumor markers, treatments, and outcomes of Chinese patients with primary lacrimal sac lymphoma. METHODS: This case-based retrospective study analyzed 15 Chinese patients with primary lacrimal sac lymphoma. The clinical data collected included gender, age at diagnosis, symptoms, imaging examination results, pathologic diagnosis, pathogen identification, tumor markers, treatments, follow-up, and prognosis. Descriptive statistics were used to characterize the patients. Progression-free survival (PFS) was defined as the time from surgery to the last follow-up, first record of tumor recurrence, or death. RESULTS: There were 7 males and 8 females with unilateral primary lacrimal sac lymphoma in the left eye (n=6) or right eye (n=9). The initial symptom in 13 patients was epiphora, and 2 patients had redness and swelling in the lacrimal sac area. All patients ultimately developed epiphora, and 12 had masses in the lacrimal sac area. Analysis of preoperative plasma tumor markers indicated 14 patients had elevated homocysteine, 9 had elevated ß2-microglobulin, and 2 had elevated lactate dehydrogenase (LDH); 2 patients had elevations of all three markers, and 1 patient had no elevation of any marker. All patients underwent surgical resection and 12 patients received postoperative chemotherapy. The pathological types were DLBCL (n=8), MALT lymphoma (n=5), and NK/T-cell lymphoma, nasal type (n=2). The mean follow-up time was 25.8mo (range: 4-41) and 2 patients died. Seven patients who underwent mass excision combined with dacryocystorhinostomy (DCR) had no postoperative epiphora. Eight patients who only underwent mass excision had varying degrees of postoperative epiphora. Preoperative LDH elevation and NK/T-cell lymphoma, nasal type were associated with poor prognoses. CONCLUSION: Early diagnosis and treatment can lead to a good prognosis for most patients with primary lacrimal sac lymphoma. Mass resection combined with DCR can reduce the occurrence of post-surgical epiphora. The pathology type and tumor marker status are associated with prognosis.

Preliminary study on the efficacy of lacrimal duct reconstruction with pedicled conjunctival flap in the treatment of severe lacrimal canalicular obstruction with conjunctivochalasis.

AIM: To determine the efficacy and safety of pedicled conjunctival lacrimal duct reconstruction in the treatment of severe obstruction of superior and inferior lacrimal canaliculi with conjunctivochalasis. METHODS: This study was performed as a retrospective analysis of patients who received conjunctival dacryocystorhinostomy with pedicled conjunctival flap reconstruction combined with tube intubation due to severe superior and inferior lacrimal canalicular obstruction with conjunctivochalasis from January 2019 to October 2019. The clinical data included the degree of preoperative epiphora and postoperative relief, preoperative examination of lacrimal duct computed tomography and ultrasound biomicroscopy, postoperative evaluation of lacrimal duct function by chloramphenicol taste and fluorescein dye disappearance test, etc. Syringing was carried out to determine the reconstruction and patency of the lacrimal duct. RESULTS: All 9 patients (9 eyes) had severe canalicular obstruction with conjunctivochalasis. The patients included 4 males and 5 females aged between 47-65y with an average age of 52.2±6.7y. At 3mo follow-up, the tube was removed and the patients were followed for a further 3mo. After tube removal, 6 patients showed no epiphora. These patients also had positive chloramphenicol tastes and normal fluorescein dye disappearance test results. Two patientshad epiphora. Also, syringing showed partial patency of the reconstructed lacrimal duct. One patient had no improvement in epiphora with negative chloramphenicol taste and fluorescein dye disappearance test results and obstruction of the reconstructed lacrimal duct. The total effective rate of the operation was 8/9, with no serious complications. CONCLUSION: Pedicled conjunctival lacrimal duct reconstruction conjunctival dacryocystorhinostomy is safe and effective for superior and inferior canalicular obstruction with conjunctivochalasis.

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome.

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene. METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing. RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a "pathogenic mutation" according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.

Statistical and spatial analysis for soil heavy metals over the Murray-Darling river basin in Australia.

Heavy metals (HMs) are a vital elements for investigating the pollutant level of sediments and water bodies. The Murray-Darling river basin area located in Australia is experiencing severe damage to increased crop productivity, loss of soil fertility, and pollution levels within the vicinity of the river system. This basin is the most effective primary production area in Australia where agricultural productivity is increased the gross domastic product in the entire mainland. In this study, HMs contaminations are examined for eight study sites selected for the Murray-Darling river basin where the inverse Distance Weighting interpolation method is used to identify the distribution of HMs. To pursue this, four different pollution indices namely the Geo-accumulation index (Igeo), Contamination factor (CF), Pollution load index (PLI), single-factor pollution index (SPLI), and the heavy metal pollution index (HPI) are computed. Following this, the Pearson correlation matrix is used to identify the relationships among the two HM parameters. The results indicate that the conductivity and N (%) are relatively high in respect to using Igeo and PLI indexes for study sites 4, 6, and 7 with 2.93, 3.20, and 1.38, respectively. The average HPI is 216.9071 that also indicates higher level pollution in the Murray-Darling river basin and the highest HPI value is noted in sample site 1 (353.5817). The study also shows that the levels of Co, P, Conductivity, Al, and Mn are mostly affected by HMs and that these indices indicate the maximum HM pollution level in the Murray-Darling river basin. Finally, the results show that the high HM contamination level appears to influence human health and local environmental conditions.

ARHGEF15 is expressed in undifferentiated spermatogonia but is not required for spermatogenesis in mice.

Spermatogenesis is a continual process that relies on the activities of undifferentiated spermatogonia, which contain spermatogonial stem cells (SSCs) that serve as the basis of spermatogenesis. The gene expression pattern and molecular control of fate decisions of undifferentiated spermatogonia are not well understood. Rho guanine nucleotide exchange factor 15 (ARHGEF15, also known as EPHEXIN5) is a guanine nucleotide-exchange factor (GEF) that activates the Rho protein. Here, we reported that ARHGEF15 was expressed in undifferentiated spermatogonia and spermatocytes in mouse testes; however, its deletion did not affect spermatogenesis. Arhgef15-/- mice were fertile, and histological examination of the seminiferous tubules of Arhgef15-/- mice revealed complete spermatogenesis with the presence of all types of spermatogenic cells. Proliferation and differentiation of the undifferentiated spermatogonia were not impacted; however, further analysis showed that Arhgef15 deletion resulted in decreased expression of Nanos2, Lin28a and Ddx4. Together, these findings suggest that ARHGEF15 was specifically enriched in undifferentiated spermatogonia and regulated gene expression but dispensable for spermatogenesis in mice.

Applications of chitosan-based biomaterials: From preparation to spinal cord injury neuroprosthetic treatment.

Spinal cord injury (SCI)-related disabilities are a serious problem in the modern society. Further, the treatment of SCI is highly challenging and is urgently required in clinical practice. Research on nerve tissue engineering is an emerging approach for improving the treatment outcomes of SCI. Chitosan (CS) is a cationic polysaccharide derived from natural biomaterials. Chitosan has been found to exhibit excellent biological properties, such as nontoxicity, biocompatibility, biodegradation, and antibacterial activity. Recently, chitosan-based biomaterials have attracted significant attention for SCI repair in nerve tissue engineering applications. These studies revealed that chitosan-based biomaterials have various functions and mechanisms to promote SCI repair, such as promoting neural cell growth, guiding nerve tissue regeneration, delivering nerve growth factors, and as a vector for gene therapy. Chitosan-based biomaterials have proven to have excellent potential for the treatment of SCI. This review aims to introduce the recent advances in chitosan-based biomaterials for SCI treatment and to highlight the prospects for further application.

Megacities' environmental assessment for Iraq region using satellite image and geo-spatial tools.

Urban areas are quickly established, and the overwhelming population pressure is triggering heat stress in the metropolitan cities. Climate change impact is the key aspect for maintaining the urban areas and building proper urban planning because spreading of the urban area destroyed the vegetated land and increased heat variation. Remote sensing-based on Landsat images are used for investigating the vegetation circumstances, thermal variation, urban expansion, and surface urban heat island or SUHI in the three megacities of Iraq like Baghdad, Erbil, and Basrah. Four satellite imageries are used aimed at land use and land cover (LULC) study from 1990 to 2020, which indicate the land transformation of those three major cities in Iraq. The average annually temperature is increased during  30 years like Baghdad (0.16 °C), Basrah (0.44 °C), and Erbil (0.32 °C). The built-up area is increased 147.1 km2 (Erbil), 217.86 km2 (Baghdad), and 294.43 km2 (Erbil), which indicated the SUHI affects the entire area of the three cities. The bare land is increased in Baghdad city, which indicated the local climatic condition and affected the livelihood. Basrah City is affected by anthropogenic activities and most areas of Basrah were converted into built-up land in the last 30 years. In Erbil, agricultural land (295.81 km2) is increased. The SUHI study results indicated the climate change effect in those three cities in Iraq. This study's results are more useful for planning, management, and sustainable development of urban areas.