The role of pre-existing anti-HLA antibodies in severe aplastic anemia patients undergoing allogenic hematopoietic stem cell transplantation.

The objective is to underscore the significance of pre-existing anti-HLA Abs in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for SAA. A retrospective analysis was conducted using data from 244 SAA patients who underwent allo-HSCT between January 2016 and October 2022. The patient cohort was divided into two groups based on the presence of pre-existing anti-HLA Abs. Out of 244 SAA patients, 82 were tested positive for anti-HLA Abs. 17 patients were tested with DSA in haplo-HSCT. We found that the presence of pre-existing anti-HLA Abs did not influence neutrophil engraftment (P=0.600); however, it resulted in delayed platelet recovery (P=0.006). Comparatively, patients with anti-HLA Abs demonstrated lower overall survival (OS) compared to their counter parts without anti-HLA Abs (P=0.001), with a correspondingly elevated transplant-related mortality (TRM) in the former group (P=0.002). Multivariate analysis established pre-existing anti-HLA Abs as an independent risk factor for impaired platelet recovery (HR 1.67, 95% CI 1.16-2.44, P=0.006) and OS (HR 2.19, 95%CI 1.03-4.67, P=0.043). However, there were no differences between DSA and non-DSA patients after desensitization in haplo-HSCT. In summary, the presence of pre-existing anti-HLA Abs in SAA patients undergoing allo-HSCT appears to detrimentally affect platelet recovery and overall prognosis.

Exploring natural killer cell-related biomarkers in multiple myeloma: a novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study.

BACKGROUND: Natural killer cells (NKs) may be involved in multiple myeloma (MM) progression. The present study elucidated the correlation between NKs and the progression of MM using single-cell binding transcriptome probes to identify NK cell-related biomarkers. METHODS: Single-cell analysis was performed including cell and subtype annotation, cell communication, and pseudotime analysis. Hallmark pathway enrichment analysis of NKs and NKs-related differentially expressed genes (DEGs) were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction (PPI) networks. Then, a risk model was structured based on biomarkers identified through univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis and subsequently validated. Additionally, correlation of clinical characteristics, gene set enrichment analysis, immune analysis, regulatory network, and drug forecasting were explored. RESULTS: A total of 13 cell clusters were obtained and annotated, including 8 cell populations that consisted of NKs. Utilizing 123 PPI network node genes, 8 NK-related DEGs were selected to construct a prognostic model. Immune cell infiltration results suggested that 11 immune cells exhibited marked differences in the high and low-risk groups. Finally, the model was used to screen potential drug targets to enhance immunotherapy efficacy. CONCLUSION: A new prognostic model for MM associated with NKs was constructed and validated. This model provides a fresh perspective for predicting patient outcomes, immunotherapeutic response, and candidate drugs.

Priestia megaterium ASC-1 Isolated from Pickled Cabbage Ameliorates Hyperuricemia by Degrading Uric Acid in Rats.

Pickled cabbage, a traditional fermented food rich in functional microorganisms, can effectively control hyperuricemia and gout. In this study, a Priestia megaterium ASC-1 strain with strong uric acid (UA) degradation ability was isolated from pickled cabbage. After oral administration for 15 days, ASC-1 was stably colonized in the rats in this study. ASC-1 significantly reduced UA levels (67.24%) in hyperuricemic rats. Additionally, ASC-1 alleviated hyperuricemia-related inflammatory response, oxidative stress, and blood urea nitrogen. Intestinal microbial diversity results showed that ASC-1 restored intestinal injury and gut flora dysbiosis caused by hyperuricemia. These findings suggest that P. megaterium ASC-1 may be used as a therapeutic adjuvant for the treatment of hyperuricemia.

Positive response of a hemodialysis patient with pure red cell aplasia on recombinant human erythropoietin therapy to cyclosporine and Roxadustat.

Recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia associated with chronic kidney disease (CKD). EPO-induced Pure Red Cell Aplasia (PRCA) is a rare condition of profound anemia with EPO treatment. Upon finding the development of EPO-induced PRCA, the treatment requires immediate withdrawal of EPO therapy and initiate new treatments with immunosuppression or renal transplantation. Anti-EPO antibody assay is not always positive in EPO-induced PRCA. Here, we report a case on the sudden development of PRCA in a hemodialysis patient receiving EPO and how we treated the condition successfully with cyclosporine and subsequently maintained the hemoglobin with Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Even though the anti-EPO antibody was negative by Enzyme Linked Immunosorbent Assay (ELISA) in our case, the clinical course, the markedly reduced reticulocyte count < 10,000/µL, the bone marrow (BM) biopsy revealing reduced erythroblasts, and its subsequent response to cyclosporine, were similar to EPO-induced PRCA. The clinical picture of EPO-induced PRCA, the limitation of the EPO-neutralizing antibody (Ab) assay, and treatment strategies were discussed.

Application of hospital-community-home linkage management model in patients with type 2 diabetic nephropathy.

OBJECTIVE: To explore the effect of the hospital-community-home (HCH) linkage management mode in patients with type 2 diabetic nephropathy (DN). METHOD: A total of 80 patients with type 2 DN hospitalised in the Department of Nephrology of our hospital between July 2021 and June 2022 were recruited and subsequently divided into the observation group and the control group using the random number table method, with 40 patients in each group. The control group received routine health education and discharge guidance. The HCH linkage management model was implemented for the observation group based on routine care. The improvements in compliance behaviour, biochemical parameters of renal function, blood glucose level and self-management ability were compared before the intervention and at 3 and 6 months after the intervention. RESULTS: After the intervention, the scores for compliance behaviour of the observation group were better than those of the control group, with a statistically significant difference (P < 0.05). The biochemical indicators of renal function and blood glucose level were significantly lower in the observation group compared with in the control group, with a statistically significant difference (P < 0.05). After the intervention, the observation group showed a great improvement in self-management ability and cognition of the disease, with significant differences (P < 0.05). CONCLUSION: The HCH linkage management mode can improve the compliance behaviour of patients with type 2 DN, effectively improve the renal function and blood sugar level of patients, enhance the self-management ability and cognition of the disease and delay the development of the disease.

AP-2α/AP-2ß Transcription Factors Are Key Regulators of Epidermal Homeostasis.

AP-2 transcription factors regulate ectodermal development, but their roles in epidermal homeostasis in adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2ß. Through inactivation of AP-2α, AP-2ß, or both in keratinocytes, we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (i) loss of AP-2ß in keratinocytes is compensated for by AP-2α, (ii) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (iii) the combined loss of AP-2α/AP-2ß results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2ß in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2ß in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of reduced AP-2α-dependent gene expression of CXCL14 and the keratin 15 gene K15 as an early pathogenic event toward the manifestation of skin inflammation. Thus, AP-2α and AP-2ß are critical regulators of epidermal homeostasis in adult skin.

Allogenic hematopoietic stem cell transplantation outcomes of patients aged ≥ 55 years with acute myeloid leukemia or myelodysplastic syndromes in China: a retrospective study.

BACKGROUND: Elderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe. METHODS: Our retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests. RESULTS: The median age of the cohort was 57 years (range: 55-75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P < 0.001, HR = 0.596), higher incidence of relapses (HR = 2.300, P = 0.013), and inferior relapse-free survival (RFS) (HR = 1.740, HR = 0.016) regardless of donor type. When it came to graft-versus-host-disease-free, relapse-free survival (GRFS), MUDs turned out to be superior to HIDs (HR = 0.472, P = 0.026) according to the multivariable analysis. In contrast, we found MSDs had an inferior GRFS to HIDs in parallel (HR = 1.621, P = 0.043). CONCLUSION: The choice of donor type did not significantly affect the outcomes of allo-HSCT. However, when considering the quality of post-transplant life, MUDs or HIDs from younger donors may be the optimal choice for elderly patients.

Bleeding Risk in Hemodialysis Patients.

Cardiovascular diseases are highly prevalent among patients on dialysis. For these diseases, antiplatelets and antithrombotic therapies including heparin, vitamin K antagonists, and direct oral anticoagulants, are being used. However, the benefit-risk balance of these therapies could differ for dialysis patients compared with the general population. This review article focuses on the bleeding risk associated with the use of heparin, antiplatelets, vitamin K antagonists, and direct oral anticoagulants in patients receiving hemodialysis.

Content-Addressable Memories and Transformable Logic Circuits Based on Ferroelectric Reconfigurable Transistors for In-Memory Computing.

As a promising alternative to the von Neumann architecture, in-memory computing holds the promise of delivering a high computing capacity while consuming low power. In this paper, we show that the ferroelectric reconfigurable transistor can serve as a versatile logic-in-memory unit that can perform logic operations and data storage concurrently. When functioning as memory, a ferroelectric reconfigurable transistor can implement content-addressable memory (CAM) with a 1-transistor-per-bit density. With the switchable polarity of the ferroelectric reconfigurable transistor, XOR/XNOR-like matching operation in CAM is realized in a single transistor, which can offer a significant improvement in area and energy efficiency compared to conventional CAMs. NAND- and NOR-arrays of CAMs are also demonstrated, which enable multibit matching in a single reading operation. In addition, the NOR array of CAM cells effectively measures the Hamming distance between the input query and the stored entries. When functioning as a logic element, a ferroelectric reconfigurable transistor can be switched between n- and p-type modes. Utilizing the switchable polarity of these ferroelectric Schottky barrier transistors, we demonstrate reconfigurable logic gates with NAND/NOR dual functions, whose input-output mapping can be transformed in real time without changing the layout, and the configuration is nonvolatile.

Investigation on Influencing Factors and Triage Accuracy in General Clinic of Syndrome Hospital.

Objective: The general practice (GP) system is associated with patient-centeredness, high-quality general practitioners, and comprehensive digital information technology. Therefore, it has been promoted greatly over the recent years in China. However, there is a relatively insufficient number of patients in the general outpatient department of comprehensive tertiary hospitals in China. Therefore, the aim of the present paper is to analyze the specific influencing factors and triage accuracy in the general clinic of Syndrome Hospital. Methods: The work involves the use of a questionnaire designed to probe the influencing factors, through the survey of 389 patients. According to different departments, the patients were enrolled into a GP group (n = 126) and a specialized practice (SP) group (n = 263). The basic information and survey results of the patients were obtained, and the reasons influencing the choice of the department were analyzed. In addition, the triage accuracy by general practitioners was assessed. Results: The age, position, current residence, education level, payment method, annual income, awareness of GP diagnosis and treatment policies, self-conscious severity of disease, and registration method of patients in the GP group were obviously different from those in the SP group (P < .05). Self-payment, annual income ≤ 5 w, high and medium level of awareness of GP diagnosis and treatment policies, and on-site registration were the influencing factors for patients' choice of GP. The triage accuracy of general practitioners (89.29%) was higher than that of guidance doctors, registered triage, and online expert consultation (76.05%) (P < .05). Conclusion: The GP diagnosis and treatment policies exhibited a high value of clinical promotion. Self-payment, low annual income, awareness of GP policies, and registration mode affected the patients' choice of GP, and the triage accuracy by general practitioners was higher compared to SP.

TRPV4 in adipose tissue ameliorates diet-induced obesity by promoting white adipocyte browning.

The induction of adipocyte browning to increase energy expenditure is a promising strategy to combat obesity. Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensations. However, the function of TRPV4 in energy metabolism remains controversial. This study revealed the role of TRPV4 in adipose tissue in the development of obesity. Adipose-specific TRPV4 overexpression protected mice against diet-induced obesity (DIO) and promoted white fat browning. TRPV4 overexpression was also associated with decreased adipose inflammation and improved insulin sensitivity. Mechanistically, TRPV4 could directly promote white adipocyte browning via the AKT pathway. Consistently, adipose-specific TRPV4 knockout exacerbated DIO with impaired thermogenesis and activated inflammation. Corroborating our findings in mice, TRPV4 expression was low in the white adipose tissue of obese people. Our results positioned TRPV4 as a potential regulator of obesity and energy expenditure in mice and humans.

Electronic Structure and Reactivity of Mononuclear Nonheme Iron-Peroxo Complexes as a Biomimetic Model of Rieske Oxygenases: Ring Size Effects of Macrocyclic Ligands.

We report the macrocyclic ring size-electronic structure-electrophilic reactivity correlation of mononuclear nonheme iron(III)-peroxo complexes bearing N-tetramethylated cyclam analogues (n-TMC), [FeIII(O2)(12-TMC)]+ (1), [FeIII(O2)(13-TMC)]+ (2), and [FeIII(O2)(14-TMC)]+ (3), as a model study of Rieske oxygenases. The Fe(III)-peroxo complexes show the same δ and pseudo-σ bonds between iron and the peroxo ligand. However, the strength of these interactions varies depending on the ring size of the n-TMC ligands; the overall Fe-O bond strength and the strength of the Fe-O2 δ bond increase gradually as the ring size of the n-TMC ligands becomes smaller, such as from 14-TMC to 13-TMC to 12-TMC. MCD spectroscopy plays a key role in assigning the characteristic low-energy δ → δ* LMCT band, which provides direct insight into the strength of the Fe-O2 δ bond and which, in turn, is correlated with the superoxo character of the iron-peroxo group. In oxidation reactions, reactivities of 1-3 toward hydrocarbon C-H bond activation are compared, revealing the reactivity order of 1 > 2 > 3; the [FeIII(O2)(n-TMC)]+ complex with a smaller n-TMC ring size, 12-TMC, is much more reactive than that with a larger n-TMC ring size, 14-TMC. DFT analysis shows that the Fe(III)-peroxo complex is not reactive toward C-H bonds, but it is the end-on Fe(II)-superoxo valence tautomer that is responsible for the observed reactivity. The hydrogen atom abstraction (HAA) reactivity of these intermediates is correlated with the overall donicity of the n-TMC ligand, which modulates the energy of the singly occupied π* superoxo frontier orbital that serves as the electron acceptor in the HAA reaction. The implications of these results for the mechanism of Rieske oxygenases are further discussed.

AP-2α/AP-2ß transcription factors are key regulators of epidermal homeostasis.

AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2ß. Through inactivation of AP-2α, AP-2ß, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2ß in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2ß results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2ß in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2ß in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2ß are critical regulators of epidermal homeostasis in the adult skin.

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis.

Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a long-standing enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we found that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss and that disease mutations are dominant negative, resulting in lack of KCTD1/KCTD15 function. We demonstrated that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes resulted in abnormal skin appendages but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells resulted in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells, giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 complexes as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

Low-Thermal-Budget Ferroelectric Field-Effect Transistors Based on CuInP2S6 and InZnO.

In this paper, we demonstrate low-thermal-budget ferroelectric field-effect transistors (FeFETs) based on the two-dimensional ferroelectric CuInP2S6 (CIPS) and oxide semiconductor InZnO (IZO). The CIPS/IZO FeFETs exhibit nonvolatile memory windows of ∼1 V, low off-state drain currents, and high carrier mobilities. The ferroelectric CIPS layer serves a dual purpose by providing electrostatic doping in IZO and acting as a passivation layer for the IZO channel. We also investigate the CIPS/IZO FeFETs as artificial synaptic devices for neural networks. The CIPS/IZO synapse demonstrates a sizable dynamic ratio (125) and maintains stable multilevel states. Neural networks based on CIPS/IZO FeFETs achieve an accuracy rate of over 80% in recognizing MNIST handwritten digits. These ferroelectric transistors can be vertically stacked on silicon complementary metal-oxide semiconductor (CMOS) with a low thermal budget, offering broad applications in CMOS+X technologies and energy-efficient 3D neural networks.

Branched Porous Ni3N as a Catalytic Electrode for Selective Semidehydrogenation of Tetrahydroisoquinoline.

Oxygen evolution in electrochemical water splitting needs a high overpotential that significantly reduces the energy efficiency. To explore an alternative anodic reaction to promote the production of hydrogen at the other end of water splitting and at the same time to get high-value-added chemicals is highly desirable. Herein, we demonstrate a novel branched porous Ni3N catalyst that is prepared for dehydrogenation of tetrahydroisoquinoline, which acts as an anodic oxidation reaction to promote H2 formation on the other end. Interestingly, the Ni3N catalytic electrode can induce effective semidehydrogenation with the selective formation of dihydroisoquinoline, which is difficult to be obtained by the usual direct synthesis route. The catalytic electrode exhibits a low potential of 1.55 V (vs RHE) for a catalytic current density of 61 mA cm-2 with dehydrogenation of tetrahydroisoquinoline and hydrogen production. In situ Raman spectra studies suggest that NiOOH is formed on the electrode surface, which mediates the oxidation semidehydrogenation process. This work also provides a strategy to fabricate nitride materials for applications beyond selective semidehydrogenation of tetrahydroisoquinoline.

Correction: Probing antiferromagnetism in exfoliated Fe3GeTe2 using magneto-transport measurements.

Correction for 'Probing antiferromagnetism in exfoliated Fe3GeTe2 using magneto-transport measurements' by Stasiu T. Chyczewski et al., Nanoscale, 2023, https://doi.org/10.1039/D3NR01022H.

A Carboxyl Group-Functionalized Ionic Liquid Hybrid Adsorbent for Solid-Phase Extraction and Determination of Trace Diclofenac Sodium in Milk Samples.

A simple and efficient sample pretreatment technology is very important for the accurate determination of trace drug residues in foods to ensure food safety. Herein, we report a new carboxyl group-functionalized ionic liquid hybrid solid- phase adsorbent (PS-IL-COOH) for the highly efficient extraction and quantitative determination of diclofenac sodium (DS) residue in milk samples. It was found that the adsorption efficiency of PS-IL-COOH for the ppb level of DS was greater than 93.0%, the adsorption capacity was 934.1 mg/g, and the enrichment factor was 620.0, which surpass most of the previously reported values for DS adsorbents. The high concentration of salts did not interfere with the adsorption of DS. Importantly, the recovery of DS was above 90% after 16 adsorption--regeneration cycles. The synergistic effect of the multiple interactions was found to be the main factor for the high efficiency of DS adsorption. The proposed method was applied to the extraction and detection of DS in milk samples, with the relative recovery ranging from 88.2 to 103.0%.

Generation of two induced pluripotent stem cell lines from patients with Down syndrome.

Down syndrome (DS) is caused by trisomy of Homo sapiens chromosome 21 (HSA21) and is by far the most common chromosomal disorder accompanied by neurodevelopmental disorders and congenital heart disease. Here, we generated two induced pluripotent stem cell (iPSC) lines from two patients with DS. These two lines exhibited normal morphology, trisomy 21 karyotype, pluripotency and differentiation capability into derivatives of three germ layers. The patient-specific iPSC lines arean invaluable resource in research to model DS-related cellular and molecular pathologies and test possible therapeutic strategies for DS.