Case report: A case of effective treatment of primary myelofibrosis with nodular panniculitis using ruxolitinib combined with corticosteroids.

We report the case of a 54-year-old healthy Han Chinese male presenting with fever, pallor, erythematous subcutaneous nodules on the limbs, and significant anemia as indicated by routine blood tests, with no response to antimicrobial therapy. Initial skin biopsy was inconclusive. The erythematous subcutaneous nodules on the limbs rapidly progressed to widespread subcutaneous nodules across the body, with worsening anemia. Bone marrow biopsy revealed multifocal fibroblastic proliferation with focal fibrosis, classified as MF-2, and positive for the JAK2V617F mutation alongside SRSF2 positivity. Whole-body PET-CT scans did not reveal any lymph nodes or suspect lesions with high SUV uptake. A subsequent skin biopsy identified the condition as nodular panniculitis (NP), leading to a final diagnosis of primary myelofibrosis(PMF)with NP. The patient initially received treatment with oral ruxolitinib and prednisone acetate, resulting in normalization of body temperature, resolution of erythematous nodules, and normalization of blood parameters.

Unveiling cold Code: Acinetobacter calcoaceticus TY1's adaptation strategies and applications in nitrogen treatment.

Overcoming low nitrogen removal efficiency at low temperatures is a challenge in biological treatment. This study investigated the cold-tolerant heterotrophic nitrification-aerobic denitrification by Acinetobacter calcoaceticus TY1. Transcriptomic and biochemical analyses indicated that strain TY1 upregulated genes for energy production, assimilation, cell motility, and antioxidant enzyme production under cold stress, maintaining functions such as energy supply, nitrogen utilization, and oxidative defense. Increasing the synthesis of extracellular polysaccharides, unsaturated fatty acids, and medium-chain fatty acids and secreting large amounts of antioxidant enzymes ensured cell membrane flexibility while enhancing the antioxidant system. Immobilization experiments showed that biofilms accelerated the removal of nitrogen pollutants and demonstrated good stability, with carriers being reusable to five times, maintaining high ammonia nitrogen (63.90 %) and total nitrogen (50.66 %) removal rates. These findings reveal the cold tolerance mechanisms of strain TY1 and its excellent practical potential as a candidate for wastewater treatment in cold regions.

Pharmacokinetic study of Q808 in rhesus monkey using liquid chromatography-tandem mass spectrometry.

Background: Q808 is a novel antiepileptic agent currently in development. In this study, we established and validated a LC-MS/MS method for the quantification of Q808 in Rhesus monkey plasma. Furthermore, we applied this method to investigate the pharmacokinetics of Q808 in Rhesus monkeys. Methods: Samples containing diazepam as an internal standard (IS) were subjected to liquid-liquid extraction (LLE) and separated using a Zorbax Extend C18 column. The detection of Q808 and IS was performed using multiple reaction monitoring mode (MRM), specifically monitoring precursor-to-product ion transitions at m/z 297.9 to 213.9 and m/z 285.2 to 193.1 for Q808 and IS, respectively. For the pharmacokinetic study of Q808, a total of 30 healthy Rhesus monkeys (half male and half female) were administered single oral doses, single IV doses, or multiple oral doses of Q808. Blood samples were collected at predetermined time points for subsequent pharmacokinetic analysis. Results: The developed LC-MS/MS method exhibited linearity within the concentration range of 1.5-750 ng/mL with intra-day precision ≤8.3% and inter-day precision ≤14.6%. Additionally, accuracy was found to be ≤ 3.4%. In the pharmacokinetic study involving single oral doses of Q808 in Rhesus monkeys, Q808 was absorbed with a median time to peak plasma concentration ranging from 4.50-6.00 h and was eliminated with a terminal elimination half-life (t1/2) between 9.34-11.31 h. No definitive conclusion regarding linear pharmacokinetic characteristics could be drawn. The absolute bioavailability was determined as 20.95%, indicating limited systemic exposure after oral administration. Multiple dosing did not result in significant accumulation based on an accumulation factor Rac value of 1.31. Conclusion: We have successfully developed and validated a rapid yet sensitive LC-MS/MS method for quantifying levels of Q808 in rhesus monkey plasma for the first time. The determination method and pharmacokinetic characteristics of Q808 in rhesus monkey support the next steps in drug development.

Enhancing the Inhibition of Breast Cancer Growth Through Synergistic Modulation of the Tumor Microenvironment Using Combined Nano-Delivery Systems.

Purpose: Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells. Methods: Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro "condition medium of fibroblasts + MCF-7" cell model and in vivo "4T1/NIH-3T3" co-implantation mice model were established to evaluate the anti-tumor effect of drugs. Results: The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect. Conclusion: In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer.

Comparison of clinical characteristics and outcomes in primary neuroendocrine breast carcinoma versus invasive ductal carcinoma.

Background: Neuroendocrine breast carcinoma (NECB) is a rare, special histologic type of breast cancer. There are some small sample studies on the clinical outcomes of NECB patients, which are worthy of further discussion. Methods: We conducted a retrospective case-control study of clinical characteristics and outcomes among patients with primary NECB versus invasive carcinoma of no special type (NST) between November 2004 and November 2017 in the Peking Union Medical College Hospital, Beijing. NST patients were strictly matched 1:4 during the same period based on the TNM stage. Statistical comparisons were performed to determine the differences in survival between NST and NECB patients and to identify clinical factors that correlate with prognosis. Results: A total of 121 participants affected by primary NECB were included in our analysis from November 2004 to November 2017. Elderly persons (>60 years of age) were more likely to have primary NECB than young persons (p=0.001). In addition, primary NECB patients had significantly higher odds of having tumors 2-5 cm (36.5%) and >5 cm (6.1%) in size than NST patients. Despite a significant difference in tumor size, the proportion of patients with lymph node metastases showed no difference between the two groups (p=0.021). In addition, the rate of patients with ER-negative tumors in the NECB group (4.2%) was significantly lower than that in the primary NST group (29.8%). Significant differences were noted in the PR-negative (13.3% versus 36.6%, P<0.001) and HER2-negative (90.5% versus 76.4%, P=0.001) expression statuses among these patients. Of 121 primary NECB patients, 11 (9.1%) experienced relapses during the follow-up period. We found that tumor size was an independent risk factor for relapse. For hormone receptors on tumor cells, ER-positive breast cancer patients had significantly lower odds of relapse than receptor-negative patients. Conclusions: Our data demonstrate no significant difference in mortality and relapse between the primary NECB and NST groups. The tumor size in the primary NECB group was significantly larger than that in the NST group. In addition, the absence of ER independently increased the relapse rate for breast carcinoma patients.

Metabolic Profiles of Offspring Born From Biopsied Embryos from Toddlerhood to Preschool Age.

CONTEXT: Embryo biopsy, which is necessary for preimplantation genetic testing (PGT), has not been fully investigated regarding its potential influences and safety. Previous studies of children born from biopsied embryos (PGT children) have primarily centered around their growth and neuropsychological development, while there remains limited knowledge concerning their endocrine and metabolic parameters. OBJECTIVE: This study aims to examine the effect of trophectoderm (TE) biopsy on metabolic outcomes for PGT children. METHODS: A total of 1267 children from the Center for Reproductive Medicine, Shandong University, who were conceived through in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with and without PGT, were analyzed in this study. Three sets of measurements pertaining to growth and metabolism were taken at each predetermined follow-up time point. The linear regression models within a generalized estimating equation were employed to examine the associations between the PGT and each outcome measure and the approach of false discovery rate was used to correct for multiple comparisons. RESULTS: After controlling for confounding factors and correcting for multiple comparisons, no statistically significant difference was identified in any of the measured variables between the PGT children and children conceived by IVF alone (IVF children) and children conceived through IVF using ICSI (ICSI children). The same is true also for age- or sex-based subgroup analyses. CONCLUSION: Between the ages of 1 and 5 years, there are no clinically adverse metabolic outcomes observed in PGT children, and their metabolic profiles are essentially identical to those of IVF children and ICSI children.

Analysis of the Immune Response by Standardized Whole-Blood Stimulation with Metabolism Modulation.

The immune system defends the body from infection and plays a vital role in a wide range of health conditions. Metabolism affects a series of physiological processes, including those linked to the function of human immune system. Cellular metabolism modulates immune cell activation and cytokine production. Understanding the relationship between metabolism and immune response has important implications for the development of immune-based therapeutics. However, the deployment of large-scale functional assays to investigate the metabolic regulation of immune response has been limited by the lack of standardized procedures. Here, we present a protocol for the analysis of immune response using standardized whole-blood stimulation with metabolism modulation. Diverse immune stimuli including pattern recognition receptor (PRR) ligands and microbial stimuli were incubated with fresh human whole blood. The metabolic inhibitors were used to modulate metabolic status in the immune cells. The variable immune responses after metabolic interventions were evaluated. We described in detail the main steps involved in the whole-blood stimulation and cytokines quantification, namely, collection and treatment of whole blood, preparation of samples and controls, cytokines detection, and stimulation with metabolic interventions. The metabolic inhibitors for anabolic pathways and catabolic pathways exert selective effects on the production of cytokines from immune cells. In addition to a robust and accurate assessment of immune response in cohort studies, the standardized whole-blood stimulation with metabolic regulation might provide new insights for modulating immunity. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00114-0.

A Paternò-Büchi Reaction of Aromatics with Quinones under Visible Light Irradiation.

Reported herein is a Paternò-Büchi reaction of aromatic double bonds with quinones under visible light irradiation. The reactions of aromatics with quinones exposed to blue LED irradiation yielded oxetanes at -78 °C, which was attributed to both the activation of double bonds in aromatics and the stabilization of oxetanes by thiadiazole, oxadiazole, or selenadiazole groups. The addition of Cu(OTf)2 to the reaction system at room temperature resulted in the formation of diaryl ethers via the copper-catalyzed ring opening of oxetanes in situ. Notably, the substrate scope was extended to general aromatics.

Comparison of the effect of tea shoots during different seasons in Arma chinensis (Hemiptera: Pentatomidae) reared on Ectropis grisescens (Lepidoptera: Geometridae) pupae.

In this study, we compared the growth, development, and fecundity of Arma chinensis (Fallou) reared on pupae of the geometrid Ectropis grisescens Warren fed on tea shoots during different seasons of the year. The raw data on life history were analyzed using the age-stage, 2-sex life table. When reared on spring or winter geometrid pupae, the duration of the immature stage of A. chinensis was significantly longer than in those produced during the summer or autumn. The survival rate of immature A. chinensis reared on autumn geometrid pupae was significantly lower compared to other treatments. Reproductive diapause was observed in adult A. chinensis reared on winter geometrid pupae. The adult preoviposition period (APOP), total preoviposition period (TPOP), and total longevity were significantly longer in A. chinensis reared on winter pupae than in the other treatments. The fecundity of A. chinensis reared on spring geometrid pupae was significantly lower than in the other treatments. The higher intrinsic rate of increase of the A. chinensis reared on summer pupae (r = 0.0966 day-1) and autumn pupae (r = 0.0983 day-1) resulted in higher fecundity, shorter immature duration, and shorter TPOP compared to the winter and spring populations. These findings can be utilized to enhance and sustain biological control of E. grisescens in tea plantations.

"Fishbone" Design of Amino/N-Spirocyclic Cations toward High-Performance Poly(triphenylene piperidine) Anion-Exchange Membranes for Fuel Cells.

N-Spirocyclic cations have excellent alkali resistance stability, and precise design of the structure of N-spirocyclic anion-exchange membranes (AEMs) improves their comprehensive performance. Here, we design and synthesize high-performance poly(triphenylene piperidine) membranes based on the "fishbone" design of amino/N-spirocyclic cations. The "fishbone" design does not disrupt the overall stabilized conformation but promotes a microphase separation structure, while exerting the synergistic effect of piperidine cations and spirocyclic cations, resulting in a membrane with good conductivity and alkali resistance stability. The hydroxide conductivity of the QPTPip-ASU-X membrane reached up to 133.5 mS cm-1 at 80 °C. The QPTPip-ASU-15 membrane was immersed in a 2 M NaOH solution at 80 °C for 1200 h, and the conductivity was maintained at 91.02%. In addition, the QPTPip-ASU-5 membrane had the highest peak power density of 255 mW cm-2.

Adipose knockout of H-ferritin improves energy metabolism in mice.

OBJECTIVE: Ferritin, the principal iron storage protein, is essential to iron homeostasis. How iron homeostasis affects the adipose tissue is not well understood. We investigated the role of ferritin heavy chain in adipocytes in energy metabolism. METHODS: We generated adipocyte-specific ferritin heavy chain (Fth, also known as Fth1) knockout mice, herein referred to as FthAKO. These mice were analyzed for iron homeostasis, oxidative stress, mitochondrial biogenesis and activity, adaptive thermogenesis, insulin sensitivity, and metabolic measurements. Mouse embryonic fibroblasts and primary mouse adipocytes were used for in vitro experiments. RESULTS: In FthAKO mice, the adipose iron homeostasis was disrupted, accompanied by elevated expression of adipokines, dramatically induced heme oxygenase 1(Hmox1) expression, and a notable decrease in the mitochondrial ROS level. Cytosolic ROS elevation in the adipose tissue of FthAKO mice was very mild, and we only observed this in the brown adipose tissue (BAT) but not in the white adipose tissue (WAT). FthAKO mice presented an altered metabolic profile and showed increased insulin sensitivity, glucose tolerance, and improved adaptive thermogenesis. Interestingly, loss of ferritin resulted in enhanced mitochondrial respiration capacity and a preference for lipid metabolism. CONCLUSIONS: These findings indicate that ferritin in adipocytes is indispensable to intracellular iron homeostasis and regulates systemic lipid and glucose metabolism.

Extended culture may contribute to poor intellectual performance of children born after frozen embryo transfer.

Frozen embryo transfer (FET) is becoming popular in recent years. However, whether embryos freezing or other factors may affect intellectual performance in offspring is still unknown. We compared the Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV) questionnaire scores between children born after fresh embryo transfer (fresh ET) and FET. They were matched in a 1:1 ratio on their sex and age (±1 month). 326 children were included in each group. We found children born after FET scored lower on the WISC-IV questionnaire (p = 0.002). In subgroup analysis, the full-scale scores are similar between fresh ET and FET in the cleavage-stage transfer group (p = 0.57). In the FET group, the blastocyst-stage transfer group had lower full-scale scores compared with the cleavage-stage transfer group (p = 0.004). Children born after FET scored lower on WISC-IV questionnaire might be linked to extended culture of embryos rather than the freezing process.

Rib segmentation in chest x-ray images based on unsupervised domain adaptation.

Rib segmentation in 2D chest x-ray images is a crucial and challenging task. On one hand, chest x-ray images serve as the most prevalent form of medical imaging due to their convenience, affordability, and minimal radiation exposure. However, on the other hand, these images present intricate challenges including overlapping anatomical structures, substantial noise and artifacts, inherent anatomical complexity. Currently, most methods employ deep convolutional networks for rib segmentation, necessitating an extensive quantity of accurately labeled data for effective training. Nonetheless, achieving precise pixel-level labeling in chest x-ray images presents a notable difficulty. Additionally, many methods neglect the challenge of predicting fractured results and subsequent post-processing difficulties. In contrast, CT images benefit from being able to directly label as the 3D structure and patterns of organs or tissues. In this paper, we redesign rib segmentation task for chest x-ray images and propose a concise and efficient cross-modal method based on unsupervised domain adaptation with centerline loss function to prevent result discontinuity and address rigorous post-processing. We utilize digital reconstruction radiography images and the labels generated from 3D CT images to guide rib segmentation on unlabeled 2D chest x-ray images. Remarkably, our model achieved a higher dice score on the test samples and the results are highly interpretable, without requiring any annotated rib markings on chest x-ray images. Our code and demo will be released in 'https://github.com/jialin-zhao/RibsegBasedonUDA'.

Nurses' Work-Family Strategies during COVID-19 Lockdown and Their Association with Individual Health and Family Relations.

The COVID-19 lockdown forced people to stay at home and address their family duties more equally. However, since nurses themselves were involved in the closed-loop management in hospitals and unable to return home, there was also an increased likelihood of non-traditional work-family strategies emerging. To ascertain the extant and implications of this phenomenon, this cross-sectional study explores work-family management strategies among nurses during the COVID-19 lockdown and their association with nurses' individual health, family relationships, and job performance. Survey data were collected from 287 nurses who were involved in the closed-loop management in Shanghai hospitals from March to June 2022. Latent Class Analysis of seven categorical variables of nurses' work-family status (e.g., the division of childcare labor) produced a best-fit solution of five strategies (BLRT (p) < 0.001, LMR (p) = 0.79, AIC = 5611.34, BIC = 6302.39, SSA-BIC = 5703.65, Entropy = 0.938): (1) fully outsourcing to grandparents, (2) partially outsourcing to grandparents, with the husband filling in the gap, (3) the husband does it all, (4) egalitarian remote workers, and (5) a neo-traditional strategy. Nurses who applied the egalitarian strategy had less psychological distress and relationship tension and better performance than those who applied the neo-traditional strategy and performed most of the childcare. The "husband does it all" strategy and the outsourcing strategies seem to have double-edged effects, with better job performance and family relations but also more distress and fewer sleeping hours among nurses. Overall, with a view to future risk mitigation, policymakers and practitioners should be aware of the diversity of the work-family strategies among nurse families during the lockdown period, and their association with individual and family outcomes, and provide tailored support.

Promoting Photosynthetic Production of Dammarenediol-II in Chlamydomonas reinhardtii via Gene Loading and Culture Optimization.

Ginsenosides are major bioactive compounds found in Panax ginseng that exhibit various pharmaceutical properties. Dammarenediol-II, the nucleus of dammarane-type ginsenosides, is a promising candidate for pharmacologically active triterpenes. Dammarenediol-II synthase (DDS) cyclizes 2,3-oxidosqualene to produce dammarenediol-II. Based on the native terpenoids synthetic pathway, a dammarane-type ginsenosides synthetic pathway was established in Chlamydomonas reinhardtii by introducing P. ginseng PgDDS, CYP450 enzyme (PgCYP716A47), or/and Arabidopsis thaliana NADPH-cytochrome P450 reductase gene (AtCPR), which is responsible for producing dammarane-type ginsenosides. To enhance productivity, strategies such as "gene loading" and "culture optimizing" were employed. Multiple copies of transgene expression cassettes were introduced into the genome to increase the expression of the key rate-limiting enzyme gene, PgDDS, significantly improving the titer of dammarenediol-II to approximately 0.2 mg/L. Following the culture optimization in an opt2 medium supplemented with 1.5 mM methyl jasmonate under a light:dark regimen, the titer of dammarenediol-II increased more than 13-fold to approximately 2.6 mg/L. The C. reinhardtii strains engineered in this study constitute a good platform for the further production of ginsenosides in microalgae.

Deep Immunophenotyping of Human Whole Blood by Standardized Multi-parametric Flow Cytometry Analyses.

Immunophenotyping is proving crucial to understanding the role of the immune system in health and disease. High-throughput flow cytometry has been used extensively to reveal changes in immune cell composition and function at the single-cell level. Here, we describe six optimized 11-color flow cytometry panels for deep immunophenotyping of human whole blood. A total of 51 surface antibodies, which are readily available and validated, were selected to identify the key immune cell populations and evaluate their functional state in a single assay. The gating strategies for effective flow cytometry data analysis are included in the protocol. To ensure data reproducibility, we provide detailed procedures in three parts, including (1) instrument characterization and detector gain optimization, (2) antibody titration and sample staining, and (3) data acquisition and quality checks. This standardized approach has been applied to a variety of donors for a better understanding of the complexity of the human immune system. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00092-9.

Preliminary Investigation of Essentially Derived Variety of Tea Tree and Development of SNP Markers.

The continuous emergence of Essentially Derived Varieties (EDVs) in the process of tea tree breeding will endanger and affect the innovation ability and development potential of tea tree breeding. In this study, genotyping by sequencing (GBS) technology was used to screen high-quality genomic SNPs for the first time to investigate the derived relationships of 349 tea trees from 12 provinces in China. A total of 973 SNPs uniformly covering 15 tea tree chromosomes with high discrimination capacity were screened as the core SNP set. A genetic similarity analysis showed that 136 pairs of tea trees had a genetic similarity coefficient (GS) > 90%, among which 60 varieties/strains were identified as EDVs, including 22 registered varieties (19 were indisputably EDVs). Furthermore, 21 SNPs with 100% identification of 349 tea trees were selected as rapid identification markers, of which 14 SNP markers could be used for 100% identification of non-EDV. These results provide the basis for the analysis of the genetic background of tea trees in molecular-assisted breeding.

Dual ligand-induced photoelectrochemical sensing by integrating Pt/MoS2 heterostructure and Au polyhedra for sensitive detection of SARS-CoV-2.

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with discovery of multiple mutants, has caused widespread panic and concern worldwide. The rapid antigen detection method via a single ligand recognition, although currently implemented in many countries, remains challenging for mutated antigens. Herein, we present a novel strategy using a dual recognition by two types of targeted ligands, based on photoelectrochemical (PEC) sensing for detection of SARS-CoV-2 spike protein. To demonstrate this strategy, the specific antibodies are modified onto the photoactive material with a supported nanostructure, created by loading the Pt nanoparticles onto MoS2 nanosheets (Pt/MoS2) to boost photon-to-electricity conversion efficiency. By subsequent binding of the targeted aptamers to the Au polyhedra, which act as a signal amplifier to suppress PEC photocurrent by competing with the Pt/MoS2 for the absorption of excitation light energy, the dual recognition is successfully achieved. The constructed biosensor not only shows satisfactory stability, high sensitivity, and selectivity, but is effective for test of the pseudovirus of SARS-CoV-2. The work provides useful advance for the development of PEC biosensors for sensitive detection of SARS-CoV-2.

Metabolic Engineering of the Isopentenol Utilization Pathway Enhanced the Production of Terpenoids in Chlamydomonas reinhardtii.

Eukaryotic green microalgae show considerable promise for the sustainable light-driven biosynthesis of high-value fine chemicals, especially terpenoids because of their fast and inexpensive phototrophic growth. Here, the novel isopentenol utilization pathway (IUP) was introduced into Chlamydomonas reinhardtii to enhance the hemiterpene (isopentenyl pyrophosphate, IPP) titers. Then, diphosphate isomerase (IDI) and limonene synthase (MsLS) were further inserted for limonene production. Transgenic algae showed 8.6-fold increase in IPP compared with the wild type, and 23-fold increase in limonene production compared with a single MsLS expressing strain. Following the culture optimization, the highest limonene production reached 117 µg/L, when the strain was cultured in a opt2 medium supplemented with 10 mM isoprenol under a light: dark regimen. This demonstrates that transgenic algae expressing the IUP represent an ideal chassis for the high-value terpenoid production. The IUP will facilitate further the metabolic and enzyme engineering to enhance the terpenoid titers by significantly reducing the number of enzyme steps required for an optimal biosynthesis.