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Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells （SSCs） produce hap- loid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine （m6A）, an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages： undifferentiated spermatogonia, type At spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactiva- tion of the m6A RNA methyltransferase Mettl3 or Mettll4 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Com- bined deletion of Mettl3 and Mettll4 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettll4 in advanced germ cells show normal spermatogenesis. The sper- matids from d6uble-mutant mice exhibit impaired translation of haploid-specific genes that are esseritial for spermio- genesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.

PurposeThis study aims to investigate why and how shared service centres (SSCs) are implemented as well as how they affect audit firm practice and audit quality.Design/methodology/approachIn this qualitative study guided by the theoretical framework of institutional theory, the authors conducted 25 semi-structured interviews in seven European countries, including 16 interviews with audit partners from Big 4 firms, 6 with audit team members, 2 with interviewees from second-tier audit firms and 1 with a member of an oversight body.FindingsThe authors show that the central rationale for audit firms to implement SSCs is economic rather than external legitimacy. The authors find that SSC implementation has substantial effects on audit practices, particularly those related to standardisation, coordination and monitoring activities. The authors also highlight the potential impacts on audit quality.Originality/valueBy exploring the motivation for and effects of SSC implementation amongst audit firms, the authors offer insights into the best practices related to subsequent change processes and audit quality.

Threats to biodiversity are well documented. However, to effectively conserve species and their habitats, we need to know which conservation interventions do (or do not) work. Evidence-based conservation evaluates interventions within a scientific framework. The Conservation Evidence project has summarized thousands of studies testing conservation interventions and compiled these as synopses for various habitats and taxa. In the present article, we analyzed the interventions assessed in the primate synopsis and compared these with other taxa. We found that despite intensive efforts to study primates and the extensive threats they face, less than 1% of primate studies evaluated conservation effectiveness. The studies often lacked quantitative data, failed to undertake postimplementation monitoring of populations or individuals, or implemented several interventions at once. Furthermore, the studies were biased toward specific taxa, geographic regions, and interventions. We describe barriers for testing primate conservation interventions and propose actions to improve the conservation evidence base to protect this endangered and globally important taxon.

Background. Systemic sclerosis (SSc) is a systemic, autoimmune, heterogeneous disease, characterized by fibrosis and vasculopathy of skin and internal organs. Disease prognosis is mainly driven by autoantibody profile and specific organs involvement. The renin-angiotensin and endothelin systems have been implicated in the pathogenesis of vascular dysfunction. Antibodies (abs) against the angiotensin II type 1-receptor (AT1R) and the endothelin type A-receptor (ETAR) have been hypothesized to play a pathogenetic role in SSc, although their role in SSc remains unclear. Severe vascular disease manifestations have been associated with higher titers of anti-AT1R and anti-ETAR abs, which also appear to predict SSc-related mortality. Aim of the study was to estimate the prevalence of these autoabs in an SSc cohort and to evaluate their possible correlation with clinical and laboratory characteristics.   Materials and Methods. A cross-sectional monocentric study enrolling SSc patients was conducted. Demographic, clinical and laboratory data were collected and nailfold capillaroscopy was performed. Sera were tested by enzyme-linked immunosorbent assay for anti-AT1R and anti-ETAR abs, indirect immunofluorescence on Hep2 cells for anti-nuclear (ANA) abs, immunoblotting, fluorescent enzyme and chemiluminescence immunoassays for exctractable nuclear antigens (ENA) abs. Patients under anti-endothelin receptor antagonists were excluded. Categorical variables were compared using the chi-squared test, continuous variables were compared using t-test or Mann Whitney U test. Variables with statistical significance were tested in a multivariate regression model, corrected for selected confounders.   Results. A population of 80 SSc patients was enrolled. 6 patients resulted to be positive for both anti-ETAR and anti-AT1R abs, 8 patients only for anti-ETAR abs. Table 1 shows demographic and clinical data of the study population. Characteristics of patients anti-ETAR/AT1R abs positive were compared to patients negative for both the autoabs: anti-ETAR/AT1R abs positive patients resulted to have a significant higher prevalence of ischemic digital ulcers (IDU) (p=0.017). Patients positive for anti-ETAR/AT1R abs had a significant higher risk of having IDU independently from ongoing treatment with prostanoids (OR 5.7, 95%CI 1-33.26). Figure 1 shows the proportion of patients with IDU in the two groups. Patients positive for anti-ETAR/AT1R abs showed higher risk for presenting an early scleroderma pattern at the capillaroscopy rather than the other patterns, although the result did not reach the statistical significance (OR 4.5, 95%CI 0.4-49.6). Normal capillaroscopy was the reference group. Finally, patients under steroid treatment showed half-risk of presenting anti-ETAR/AT1R abs positivity, although the result was not statistically significant (OR 0.5, 95% CI 0.11-2.28).   Conclusions. Anti-ETAR/AT1R abs could be involved in peripheral vasculopathy in SSc patients, both in early and in late phases of the disease. Further studies are needed to evaluate their potential predictive value aimed at selection of patients at risk for early treatment or prevention therapy.

Background. Pulmonary hypertension (PH) is one of the most severe and potentially life-threatening complications of systemic sclerosis (SSc), with a major impact on prognosis and patient quality of life. It is often related to microvascular dysfunction and, in some cases, to interstitial lung involvement. Early diagnosis is essential but remains challenging, as initial symptoms are frequently nonspecific and may overlap with other manifestations of the disease. In this context, the use of multimodal screening strategies combining clinical, functional, imaging, and microvascular assessments may significantly improve early identification of patients at risk.   Objectives. To assess the prevalence of PH in a cohort of patients with SSc, and to analyze its correlations with pulmonary function parameters, echocardiographic findings, and microvascular abnormalities observed through nailfold videocapillaroscopy. Materials and Methods. We conducted a retrospective analysis of 120 patients with SSc followed at our center. Pulmonary hypertension was defined echocardiographically as a systolic pulmonary artery pressure greater than 30 mmHg. All patients underwent high-resolution computed tomography (HRCT) of the chest, pulmonary function tests, echocardiography, and nailfold videocapillaroscopy. Clinical, serological, and instrumental data were collected and analyzed. Statistical analysis included t tests, chi-square tests, and logistic regression.   Results. Twenty-seven percent of patients met criteria for PH. Subjects with PH exhibited a significant reduction in DLCO (mean 47.2 ± 13.3 vs 58.8 ± 11.8; p<0.001), a lower FVC/DLCO ratio, and signs of right ventricular dysfunction (mean TAPSE: 19.5 ± 3.8 mm vs 23.1 ± 3.1 mm; p<0.001). Capillaroscopic findings showed a significantly higher prevalence of the “late” pattern in patients with PH (62% vs 23%; p<0.01), characterized by avascular areas, giant capillaries, and loss of microvascular architecture. sPAP was inversely correlated with DLCO (r = –0.56) and positively correlated with capillaroscopic damage score (r = 0.42). A significant association between anti-centromere antibody positivity and PH was also observed (p=0.03).   Conclusions. Our findings confirm a high prevalence of PH among patients with SSc and highlight its association with impaired pulmonary function, right-heart dysfunction, and advanced microvascular damage on videocapillaroscopy. The integration of pulmonary function tests, echocardiography, and nailfold videocapillaroscopy may represent a non-invasive and effective approach for the early identification of patients at risk of developing PH. These results support the adoption of integrated, multidisciplinary screening models in clinical practice to ensure early diagnosis and monitoring of pulmonary hypertension in systemic sclerosis. Future prospective studies will be essential to confirm these data and to evaluate their long-term prognostic impact.

Soluble solid content (SSC), pH, and vitamin C (VC) are considered as key parameters for strawberry quality. Spectral, color, and textural features from hyperspectral reflectance imaging of 400–1000 nm was to develop the non-destructive detection approaches for SSC, pH, and VC of strawberries by integrating various multivariate methods as partial least-squares regression (PLSR), support vector regression, and locally weighted regression (LWR). SSC, pH, and VC of 120 strawberries were statistically analyzed to facilitate the partitioning of data sets, which helped optimize the model. PLSR, with spectral and color features, obtained the optimal prediction of SSC with determination coefficient of prediction (Rp2) of 0.9370 and the root mean square error of prediction (RMSEP) of 0.1145. Through spectral features, the best prediction for pH was obtained by LWR with Rp2 = 0.8493 and RMSEP = 0.0501. Combination of spectral and textural features with PLSR provided the best results of VC with Rp2 = 0.8769 and RMSEP = 0.0279. Competitive adaptive reweighted sampling and uninformative variable elimination (UVE) were used to select important variables from the above features. Based on the important variables, the accuracy of SSC, pH, and VC prediction both gain the promotion. Finally, the distribution maps of SSC, pH, and VC over time were generated, and the change trend of three quality parameters was observed. Thus, the proposed method can nondestructively and accurately determine SSC, pH, and VC of strawberries and is expected to design and construct the simple sensors for the above quality parameters of strawberries.

Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of death. It has been proposed that the processes of autophagy and apoptosis could play a significant role in the pathogenesis and clinical course of different autoimmune diseases, and accordingly in SSc. In this manuscript, we review the current knowledge of autophagy and apoptosis processes in the skin and lungs of patients with SSc. Profiling of markers involved in these processes in skin cells can be useful to recognize the stage of fibrosis and can be used in the clinical stratification of patients. Furthermore, the knowledge of the molecular mechanisms underlying these processes enables the repurposing of already known drugs and the development of new biological therapeutics that aim to reverse fibrosis by promoting apoptosis and regulate autophagy in personalized treatment approach. In SSc-ILD patients, the molecular signature of the lung tissues of each patient could be a distinctive criterion in order to establish the correct lung pattern, which directly impacts the course and prognosis of the disease. In this case, resolving the role of tissue-specific markers, which could be detected in the circulation using sensitive molecular methods, would be an important step toward development of non-invasive diagnostic procedures that enable early and precise diagnosis and preventing the high mortality of this rare disease.

Background Paphiopedilum is the largest genus of slipper orchids. Previous studies showed that the phylogenetic relationships of this genus are not well resolved, and sparse taxon sampling documented inverted repeat ( IR) expansion and small single copy (SSC) contraction of the chloroplast genomes of Paphiopedilum . Results Here, we sequenced, assembled, and annotated 77 plastomes of Paphiopedilum species (size range of 152,130 – 164,092 bp). The phylogeny based on the plastome resolved the relationships of the genus except for the phylogenetic position of two unstable species. We used phylogenetic and comparative genomic approaches to elucidate the plastome evolution of Paphiopedilum . The plastomes of Paphiopedilum have a conserved genome structure and gene content except in the SSC region. The large single copy/inverted repeat (LSC/IR) boundaries are relatively stable, while the boundaries of the inverted repeat and small single copy region (IR/SSC) varied among species. Corresponding to the IR/SSC boundary shifts, the chloroplast genomes of the genus experienced IR expansion and SSC contraction. The IR region incorporated one to six genes of the SSC region. Unexpectedly, great variation in the size, gene order, and gene content of the SSC regions was found, especially in the subg. Parvisepalum . Furthermore, Paphiopedilum provides evidence for the ongoing degradation of the ndh genes in the photoautotrophic plants. The estimated substitution rates of the protein coding genes show accelerated rates of evolution in clpP , psbH , and psbZ . Genes transferred to the IR region due to the boundary shift also have higher substitution rates. Conclusions We found IR expansion and SSC contraction in the chloroplast genomes of Paphiopedilum with dense sampling, and the genus shows variation in the size, gene order, and gene content of the SSC region. This genus provides an ideal system to investigate the dynamics of plastome evolution.

The diagnosis and classification of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is essential to improve the prognosis of systemic sclerosis (SSc) patients. The risk-stratification of disease severity and follow-up requires a multidisciplinary approach, integrating high-resolution computed tomography (HRTC) of the lung, pulmonary function tests (PFT), along with clinical and symptomatic evaluations. The use of HRCT in detecting SSc-ILD is not so much based on a definitive validation, but rather reflects the widespread clinician recognition of dissatisfaction with other modalities. However, due to the heterogeneity of SSc-ILD and the potential absence of symptoms in early or mild disease, it is prudent to consider as many parameters as possible in the assessment and monitoring of newly diagnosed patients. An early diagnosis meets the primary goal, i.e., the prevention of disease progression. The current first line treatment regimens are mainly centered on immunosuppressive therapy. This review assesses the role HRCT plays in optimizing care and improving clinical outcomes in SSc-ILD patients.