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Microsporidia are prolific producers of effector molecules, encompassing both proteins and nonproteinaceous effectors, such as toxins, small RNAs, and small peptides. These secreted effectors play a pivotal role in the pathogenicity of microsporidia, enabling them to subvert the host's innate immunity and co‐opt metabolic pathways to fuel their own growth and proliferation. However, the genomes of microsporidia, despite falling within the size range of bacteria, exhibit significant reductions in both structural and physiological features, thereby affecting the repertoire of secretory effectors to varying extents. This review focuses on recent advances in understanding how microsporidia modulate host cells through the secretion of effectors, highlighting current challenges and proposed solutions in deciphering the complexities of microsporidial secretory effectors. [ABSTRACT FROM AUTHOR]

Fiber quality improvement is a primary goal in cotton breeding. Identification of fiber quality-related genes and understanding the underlying molecular mechanisms are essential prerequisites. Previously, studies determined that silencing the gene GhWRKY40 resulted in longer cotton fibers; however, both the underlying mechanisms and whether this transcription factor is additionally involved in the regulation of cotton fiber strength/fineness are unknown. In the current study, we verified that GhWRKY40 influences the fiber strength, fiber fineness, and fiber surface structure by using virus-induced gene silencing (VIGS). Potential proteins that may interact with the nucleus-localized GhWRKY40 were screened in a yeast two-hybrid (Y2H) nuclear-system cDNA library constructed from fibers at 0, 10, and 25 days post-anthesis (DPA) in two near-isogenic lines differing in fiber length and strength. An aspartyl protease/asparaginase-related protein, GhAPD6, was identified and confirmed by Y2H and split-luciferase complementation assays. The expression of GhAPD6 was approximately 30-fold higher in the GhWRKY40-VIGS lines at 10 DPA and aspartyl protease activity was significantly upregulated in the GhWRKY40-VIGS lines at 10–20 DPA. This study suggested that GhWRKY40 may interact with GhAPD6 to regulate fiber development in cotton. The results provide a theoretical reference for the selection and breeding of high-quality cotton fibers assisted by molecular technology. [ABSTRACT FROM AUTHOR]

To determine the pharmacokinetics (PK), safety, and bioequivalence profiles of 0.5‐g calcium dobesilate capsules in both fasting and fed states for the test drug and reference drug. A randomized‐sequence, single‐dose, open‐label, 2‐period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR202000268‐01). The fasting and fed studies, both involving 24 subjects, were conducted. A single dosage of either the reference or the test preparation was given to each eligible subject in a 1:1 ratio, followed by a 7‐day rest interval before the administration of the alternative formulation. After taking the capsules, plasma samples were taken for 48 hours, and using liquid chromatography‐tandem mass spectrometry, the calcium dobesilate level was determined. The PK parameters evaluated in the study included the maximum serum concentration (Cmax), area under the plasma concentration‐time curve (AUC) from time 0 to the last quantifiable concentration, AUC from time 0 to infinity, half‐life, time to Cmax, and terminal elimination rate constant. In addition, the safety evaluation encompassed monitoring fluctuations in vitals (temperature, pulse, and blood pressure) and laboratory tests (urinalysis, hepatic function, blood biochemistry, and hematology), as well as recording the emergence of adverse events (AEs). The geometric mean ratio (GMR) of the test/reference medications was used to assess bioequivalence by determining if the 90% confidence intervals of the GMR fell within the predefined range of 80%‐125%. AEs were assessed as safety end points. The study included 48 healthy Chinese volunteers (with n = 24 each for the fasting and the fed conditions), and no subjects dropped out for any reason. The differences in the PK metrics for the test and reference drugs for both conditions were insignificant (P >.05). For bioequivalence, irrespective of whether the food was consumed or not, the range of the 90% confidence intervals of the GMR for Cmax, AUC from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity was between 80% and 125%. In the experiment, no serious AEs were recorded. Our findings revealed that the calcium dobesilate capsules used as the reference and the test drugs were both bioequivalent. Irrespective of whether the healthy Chinese volunteers consumed food or not, the PK and safety profiles were comparable. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the blood concentration and pharmacokinetic (PK) parameters of 2 formulations under fasting and ed conditions in healthy Chinese volunteers and to evaluate whether the 2 preparations were bioequivalent. This trial screened 170 subjects. Thirteen subjects were assigned to the fasting trial and 18 subjects to the fed trial; 1 subject in the fed trial group was automatically withdrawn for personal reasons. Two cycles had a 14‐day washout period. This clinical study was a bioequivalence study, with PK parameters as end point indicators. The bioequivalence PK parameters were the maximal concentration (Cmax), area under the blood drug concentration‐time curve from 0 to 72 hours (AUC0‐72 h), and the time to peak plasma concentration (tmax) which were determined in human plasma by the liquid chromatography‐tandem mass spectrometry method, and nonatrioventricular model analysis was used to determine Cmax, AUC0‐72 h, tmax, and other PK parameters. The incidence of adverse events was calculated on the basis of System Organ Classification and Preferred Terms. The results showed that the amlodipine besylate tablets met the equivalence range requirements of bioequivalence in the guidelines for human bioavailability and bioequivalence testing under fasting and fed conditions, compared to the fasting test; the tmax of the fed test was almost unchanged; and the Cmax and AUC0‐72 h showed no difference between fasting and fed conditions. It was confirmed that both formulations were well tolerated, and no new safety signals were observed. [ABSTRACT FROM AUTHOR]

Key message: GhAP genes were identified as the candidates involved in cotton fiber length under the scope of fine mapping a stable fiber length QTL, qFLD05. Moreover, the transcription factor GhWRKY40 positively regulated GhAP3 to decrease fiber length. Fiber length (FL) is an economically important fiber quality trait. Although several genes controlling cotton fiber development have been identified, our understanding of this process remains limited. In this study, an FL QTL (qFLD05) was fine-mapped to a 216.9-kb interval using a secondary F2:3 population derived from the upland hybrid cultivar Ji1518. This mapped genomic segment included 15 coding genes, four of which were annotated as aspartyl proteases (GhAP1-GhAP4). GhAPs were identified as candidates for qFLD05 as the sequence variations in GhAPs were associated with FL deviations in the mapping population, and functional validation of GhAP3 and GhAP4 indicated a longer FL following decreases in their expression levels through virus-induced gene silencing (VIGS). Subsequently, the potential involvement of GhWRKY40 in the regulatory network was revealed: GhWRKY40 positively regulated GhAP3’s expression according to transcriptional profiling, VIGS, yeast one-hybrid assays and dual-luciferase experiments. Furthermore, alterations in the expression of the eight previously reported cotton FL-responsive genes from the above three VIGS lines (GhAP3, GhAP4 and GhWRKY40) implied that MYB5_A12 was involved in the GhWRKY40-GhAP network. In short, we unveiled the unprecedented FL regulation roles of GhAPs in cotton, which was possibly further regulated by GhWRKY40. These findings will reveal the genetic basis of FL development associated with qFLD05 and be beneficial for the marker-assisted selection of long-staple cotton. [ABSTRACT FROM AUTHOR]

The automobile industry puts forward higher requirements for the design and manufacture of steel pistons. However, the welding of 42CrMo steel pistons still has unsolved technical problems, especially welding defects that cannot be directly detected, such as pores, which are easily generated inside the weld. A plasma experiment of laser-metal active gas arc (MAG) hybrid welding 42CrMo steel was conducted in this paper, and plasma signals inside and outside the keyhole were detected during the laser welding, leading laser laser-MAG hybrid welding, and leading arc laser-MAG hybrid welding of 42CrMo steel. The characteristic parameters such as electron temperature and electron density were calculated and analyzed to investigate the relationship between plasma behavior and the formation of weld porosity in the welding process of 42CrMo steel. Based on the fluctuations in plasma electron temperature and electron density, the prediction of pore formation in the weld of 42CrMo steel was made, aiming to provide guidance for achieving a stable and reliable laser-MAG hybrid welding process for 42CrMo steel. [ABSTRACT FROM AUTHOR]

Abstract: The survival rate of childhood acute lymphoblastic leukemia (ALL) has increased while that of Philadelphia‐positive (Ph+) ALL remains low. CD19 is a B‐cell specific molecule related to the survival and proliferation of normal B cells. However, there is little information available on the effects of CD19 on the biological behavior of Ph+ ALL cells. In this study, we explored a lentiviral vector‐mediated short hairpin RNA (shRNA) expression vector to stably reduce CD19 expression in Ph+ ALL cell line SUP‐B15 cells and investigated the effects of CD19 downregulation on cell proliferation, apoptosis, drug sensitivity, cell adhesion, cell migration and cell invasion in vitro. CD19 mRNA and protein expression levels were inhibited significantly by CD19 shRNA. Down‐regulation of CD19 could inhibit cell proliferation, adhesion, migration and invasion, and increase cell apoptosis and the efficacy of chemotherapeutic agents and imatinib in SUP‐B15 cells. Moreover, we found that down‐regulation of CD19 expression inhibits cell proliferation and induces apoptosis in SUP‐B15 cells in a p53‐dependent manner. Taken together, our results suggest that lentiviral vector‐mediated RNA interference of CD19 gene may be a promising strategy in the treatment of Ph+ ALL. [ABSTRACT FROM AUTHOR]

To determine the prognostic value of baseline mean platelet volume (MPV) in diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively analyzed 161 DLBCL patients who received R-CHOP chemotherapy. The associations between MPV and clinicopathological factors were assessed. A low MPV (MPV ≤ 9.1 fl, cut-off was calculated by receiver operating characteristics) was not associated with any other clinicopathological factors. Patients with MPV ≤ 9.1 fl experienced a shorter progression-free survival (PFS) (2-year PFS rate, 60.6% vs 84.0%, P = 0.003) and overall survival (OS) (2-year OS rate, 70.4% vs 87.9%, P = 0.030), compared with those with MPV > 9.1 fl. The multivariate analysis demonstrated that MPV ≤ 9.1 fl was an independent prognostic factor of OS (Hazard Ratio [HR] = 0.588, P = 0.045) and PFS (HR = 0.456, P = 0.010). Therefore, we demonstrated that low baseline MPV is an independent prognostic marker of poor outcome in patients with DLBCL. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, followed by the soft tissue. Lung metastases (LM) and bone metastases (BM) are the most common types of metastases. From 2010 to 2018, the Surveillance, Epidemiology, and End Results database diagnosed 242 cases of ES with LM, 186 cases of ES with BM, and 74 cases of ES with LM and BM. Univariate and multivariate logistic regression analyses were used to determine the risk factors for LM and/or BM, and Kaplan-Meier curves and Cox regression analysis were used to determine the prognostic factors for LM and/or BM. Tumor size ≥50 mm, N1 stage, BM, liver metastases, and surgical treatment were significantly correlated with LM; tumor size >100 mm, brain metastases, LM, surgical treatment, and chemotherapy were significantly correlated with BM; female, N1 stage, brain metastases, liver metastases, and surgical treatment were significantly correlated with LM and BM. Older age, BM, higher T stage, no surgical treatment, and no chemotherapy were harmful to the survival of ES patients with LM; older age, female, LM, and no chemotherapy were harmful to the survival of ES patients with BM; older age and no chemotherapy were harmful to the survival of ES patients with LM and BM. Larger tumor size, N1 stages, and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Microsporidia are intracellular eukaryotic pathogens that pose a substantial threat to immunocompromised hosts. The way these pathogens manipulate host cells during infection remains poorly understood. Using a proximity biotinylation strategy we established that microsporidian EnP1 is a nucleus-targeted effector that modifies the host cell environment. EnP1's translocation to the host nucleus is meditated by nuclear localization signals (NLSs). In the nucleus, EnP1 interacts with host histone H2B. This interaction disrupts H2B monoubiquitination (H2Bub), subsequently impacting p53 expression. Crucially, this inhibition of p53 weakens its control over the downstream target gene SLC7A11, enhancing the host cell's resilience against ferroptosis during microsporidian infection. This favorable condition promotes the proliferation of microsporidia within the host cell. These findings shed light on the molecular mechanisms by which microsporidia modify their host cells to facilitate their survival., Competing Interests: Competing interests statement:The authors declare no competing interest.

High fiber strength (FS) premium cotton has significant market demand. Consequently, enhancing FS is a major objective in breeding quality cotton. However, there is a notable lack of known functionally applicable genes that can be targeted for breeding. To address this issue, our study used specific length-amplified fragment sequencing combined with bulk segregant analysis to study FS trait in an F 2 population. Subsequently, we integrated these results with previous quantitative trait locus mapping results regarding fiber quality, which used simple sequence repeat markers in F 2 , F 2:3 , and recombinant inbred line populations. We identified a stable quantitative trait locus qFS A06 associated with FS located on chromosome A06 (90.74-90.83 Mb). Within this interval, we cloned a gene, GhALDH7B4_A06 , which harbored a critical mutation site in coding sequences that is distinct in the two parents of the tested cotton line. In the paternal parent Ji228, the gene is normal and referred to as GhALDH7B4_A06 O ; however, there is a nonsense mutation in the maternal parent Ji567 that results in premature termination of protein translation, and this gene is designated as truncated GhALDH7B4_A06 S . Validation using recombinant inbred lines and gene expression analysis revealed that this mutation site is correlated with cotton FS. Virus-induced gene silencing of GhALDH7B4 in cotton caused significant decreases in FS and fiber micronaire. Conversely, GhALDH7B4_A06 O overexpression in Arabidopsis boosted cell wall component contents in the stem. The findings of our study provide a candidate gene for improving cotton fiber quality through molecular breeding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Liu, Li, Wang, Zhang, Cai and Zhang.)

Osteosarcoma (OS) is one of the most prevalent malignant bone tumors. The proportion of patients with limb OS was relatively high. Lung metastasis (LM) and bone metastasis are the first and second most common metastatic types of OS, respectively. A total of 270 new cases of LM, 55 new cases of bone metastases (BM), and 36 new cases of lung and BM were diagnosed in the surveillance, epidemiology and end results database from 2010 to 2019. Univariate and multivariate logistic regression analyses were used to identify the risk factors for lung and/or BM, and Cox regression analyses were performed to identify the prognostic factors for lung and/or BM. Kaplan-Meier curves and log-rank tests were used to analyze the overall survival of limb OS patients with lung and/or BM. Female sex, telangiectatic OS type, central OS type, T3 stage, N1 stage, BM, surgical treatments, radiotherapy and chemotherapy were significantly correlated with LM. T3 stage, LM, liver metastases, and radiotherapy significantly correlated with BM. The small cell OS type, T2 stage, T3 stage, N1 stage, liver metastases, and radiotherapy were significantly correlated with lung and BM. Among limb OS patients with LM, the mean survival months of older age, black race, N1 stage, BM, brain metastases, no surgery, and no chemotherapy were lower than those of the control group. In limb OS patients with LM and BM, the mean survival months in the no surgery group was lower than in the surgery group. T stage and radiotherapy significantly influence the occurrence of limb OS with lung and/or BM. Surgery at the primary site has been shown to be effective in improving the survival rate of patients with lung and/or BM., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fourier-transform spectral imaging captures frequency-resolved images with high spectral resolution, broad spectral range, high photon flux, and low stray light. In this technique, spectral information is resolved by taking Fourier transformation of the interference signals of two copies of the incident light at different time delays. The time delay should be scanned at a high sampling rate beyond the Nyquist limit to avoid aliasing, at the price of low measurement efficiency and stringent requirements on motion control for time delay scan. Here we propose, what we believe to be, a new perspective on Fourier-transform spectral imaging based on a generalized central slice theorem analogous to computerized tomography, using an angularly dispersive optics decouples measurements of the spectral envelope and the central frequency. Thus, as the central frequency is directly determined by the angular dispersion, the smooth spectral-spatial intensity envelope is reconstructed from interferograms measured at a sub-Nyquist time delay sampling rate. This perspective enables high-efficiency hyperspectral imaging and even spatiotemporal optical field characterization of femtosecond laser pulses without a loss of spectral and spatial resolutions.

Osteosarcoma (OS) is one of the most prevalent malignant bone tumors. The proportion of limb OS is relatively high, and lung metastases (LM) are one of the most prevalent metastatic types. A total of 1694 new cases of limb OS were identified in the surveillance, epidemiology and end results (SEER) database from 2010 to 2018. Cox regression analyze was performed to identify prognostic factors for limb OS with LM, and univariate and multivariate logistic regression analyses were used to assess risk factors for LM. Kaplan-Meier analysis was performed to calculate overall survival for LM, and a log-rank test was used for comparison. A total of 287 patients (16.94%) were diagnosed with limb OS with LM. 25 to 59 years old (odds ratio, OR 0.68; 95% confidence interval, CI: 0.46-0.99), larger than 100 mm tumors (OR 3.65, 95% CI: 1.54-8.64), telangiectatic osteosarcoma type (OR 0.24, 95% CI: 0.07-0.81), central osteosarcoma type (OR 0.44, 95% CI: 0.19-0.99), T2 stage (OR 2.59, 95% CI: 1.18-5.69), N1 stage (OR 7.79, 95% CI: 3.90-15.56), presence of bone metastases (OR 4.58, 95% CI: 2.43-8.63) and surgical treatments of primary site (OR 0.22, 95% CI: 0.14-0.33) were significant correlations with lung metastases. Elderly age, black race and absence of surgery were harmful for survival. Age between 25 and 59 years, telangiectatic osteosarcoma and central osteosarcoma were identified as high-risk factors in limb OS patients with LM, and surgical treatment of the primary site significantly increased the survival rate of LM in these patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Phase I clinical trials play an important role in the follow-up clinical trials and even the drug registration and marketing. However, the screening success ratio in phase I clinical trials is low, and the screening process of the trials consumes a significant amount of human and material resources, but the results are unsatisfactory. At present, there is no large sample data analysis for screening failure in phase I clinical trials. It is therefore urgent to find the reasons for screening failure in phase I clinical trials., Methods: A total of 1,058 healthy volunteers who failed the screening in 11 phase I clinical trials were retrospectively collected from October 2018 to June 2021 in Cangzhou Central Hospital. Data on all participants who failed screening for the study were analyzed (descriptive analysis) and reasons for their non-randomization were classified, as well as the differences of main screening failures between four years., Results: A total of 1,466 healthy volunteers were enrolled in the 11 trials, and among them 1,058 subjects failed the screening. The total screening success ratio of our study was only 27.8%, the highest being 38.5% and the lowest being 18.2%. The top 3 reasons for non-randomization were abnormalities in blood biochemistry tests (23.3%), vital sign examination (19.3%), and electrocardiogram (ECG) (16.6%). Abnormal blood biochemistry was the main reason between 2019 and 2021, except for 2018 in which it was the second reason., Conclusions: Screening failure is a burdensome issue which various clinical trial sites must contend with. Investigators can still take some effective measures by strengthening the in-depth understanding of informed consent, paying attention to the quality of test samples, a correcting definition of no clinical significance (NCS). Also, low-cost and non-invasive examinations can be arranged first to better protect the volunteers and reduce the screening costs of clinical trials. To our delight, we find people's attention to the annual physical examination may help to screen healthy volunteers. Overall, this study shows that it is crucial and professional to develop a screening plan to minimize the resultant impact on timelines and budgets of phase I clinical trials enrolling healthy volunteers.

This study examined the prognostic value of the baseline red blood cell distribution width (RDW) in diffuse large B cell lymphoma (DLBCL) patients. The associations between RDW and clinical characteristics were assessed in 161 DLBCL patients from 2005 to 2016. The log-rank test, univariate analysis, and Cox regression analysis were used to evaluate the relationship between RDW and survival. A RDW of 14.1% was considered to be the optimal cut-off value for predicting prognosis. A high RDW was associated with more frequent B symptoms (P=0.001), a higher International Prognostic Index score (P=0.032), more extranodal sites of disease (P=0.035), and significantly lower Eastern Cooperative Oncology Group performance status (P=0.031). The log-rank test demonstrated that patients with a high RDW had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P<0.001) and progression-free survival (PFS) (2-year PFS rate, 44.7% vs. 81.8%, P<0.001). The multivariate analysis demonstrated that RDW ≥14.1% was an independent predictor of OS (odds ratio [OR] = 0.345, P<0.001) and PFS (OR = 0.393, P=0.001). We demonstrated that a high RDW predicted an unfavorable prognosis in patients with DLBCL.

We retrospectively analyzed LMR at diagnosis and at completion of first-line therapy and prognosis in173 patients with DLBCL from 2005 to 2016. We found that patients with an LMR < 3.2 at diagnosis, as well as at completion of first-line therapy, had significantly lower PFS and OS rates than those with an LMR ≥ 3.2 (P<0.05). Patients with LMR that recovered from the low level at diagnosis showed superior overall survival (OS) (P=0.000) and progression-free survival (PFS) (P=0.001) compared with patients who failed to achieve a higher value at the completion of therapy. The multivariate analysis demonstrated that LMR values that did not increase upon completion of first-line therapy were an independent predictor for inferior OS (P=0.021) and PFS (P=0.046). In conclusion, LMR at diagnosis and at completion of first-line therapy is a simple biomarker to predict clinical outcomes in DLBCL. LMR recovery from low levels at diagnosis, irrespective of whether LMR reached the cutoff value, was associated with improved clinical outcomes.

Angiopoietin-1 (Ang-1) plays a critical role in the regulation of endothelial cell survival and vascular maturation and stability. However, its role in hematopoiesis is not clear. Here, we determined effect of Ang-1 on the recovery of hematopoiesis in radiated mice. By injecting an Ang-1 plasmid, we found that Ang-1 was preferentially expressed in bone marrow (BM) of femur from radiated mice. This injection resulted in elevated blood counts and serum VEGF level. The blockade in S phase of cell cycle in mouse BM stromal cells following radiation was attenuated by injection of Ang-1 plasmid. In addition, injection of Ang-1 plasmid attenuated the radiation-mediated inhibition of Tie2 expression. Furthermore, through analyzing Notch1 expression, we found that injection of Ang-1 plasmid increased Notch mRNA expression in radiated mice. In conclusion, these findings suggest that Ang-1 facilitates the recovery of hematopoiesis in radiated mice with the involvement of Notch signaling pathway.