Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

A complete oral regimen for induction therapy of patients with high-risk APL: An oral etoposide instead of intravenous infusion for cytoreductive chemotherapy.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.

TET2 mutations contribute to adverse prognosis in acute myeloid leukemia (AML): results from a comprehensive analysis of 502 AML cases and the Beat AML public database.

Despite the high incidence of tet methylcytosine dioxygenase 2 (TET2) mutations in acute myeloid leukemia (AML), the prognostic implications of these mutations in three AML risk groups based on the 2022 ELN AML risk classification are still unclear. A total of 502 consecutive de novo AML patients who had next-generation sequencing data available between March 2011 and July 2021 at the Peking University Institute of Hematology were enrolled in this study. Univariate and multivariate Cox regression analyses were performed to explore the prognostic impact of TET2 mutations in the above cohort and the Beat AML cohort. Of the 502 total AML patients, 76 (15.1%) carried TET2 mutations. Multivariate analysis revealed TET2 mutations as independent risk factor for overall survival (OS) in both the total AML cohort (OR = 1.649, p = 0.009) and in the 2022 ELN intermediate-risk cohort (HR = 1.967, p = 0.05). Analysis of RNA-seq data from the Beat AML study revealed 1042 differentially expressed genes (DEGs) between the TET2-mutant and TET2 wild-type groups. The results of enrichment analysis indicated the DEGs to be notably enriched in categories related to the PI3K-Akt signaling pathway. Collectively, our findings indicate that mutations in TET2 are prognostically disadvantageous in AML patients. Assessment of TET2 mutational status contributes to the stratification of intermediate-risk AML patients. Multiple genes and pathways of potential therapeutic relevance may be differentially modulated by TET2 mutations in AML.

ZNF384 fusion transcript levels for measurable residual disease monitoring in adult B-cell acute lymphoblastic leukemia.

Zinc finger protein 384 (ZNF384) rearrangement defined a novel subtype of B-cell acute lymphoblastic leukemia (B-ALL). The prognostic significance of ZNF384 fusion transcript levels represented measurable residual disease remains to be explored. ZNF384 fusions were screened out in 57 adult B-ALL patients at diagnosis by real-time quantitative polymerase chain reaction and their transcript levels were serially monitored during treatment. The reduction of ZNF384 fusion transcript levels at the time of achieving complete remission had no significant impact on survival, whereas its ≥2.5-log reduction were significantly associated with higher relapse free survival (RFS) and overall survival (OS) rates after course 1 consolidation (p = 0.022 and = 0.0083) and course 2 consolidation (p = 0.0025 and = 0.0008). Compared with chemotherapy alone, allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved RFS and OS of patients with <2.5-log reduction after course 1 consolidation (p < 0.0001 and = 0.0002) and course 2 consolidation (p = 0.0003 and = 0.019), whereas exerted no significant effects in patients with ≥2.5-log reduction (all p > 0.05). ZNF384 fusion transcript levels after course 1 and course 2 consolidation strongly predict relapse and survival and may guide whether receiving allo-HSCT in adult B-ALL.

PD-1: A critical player and target for immune normalization.

Immune system imbalances contribute to the pathogenesis of several different diseases, and immunotherapy shows great therapeutic efficacy against tumours and infectious diseases with immune-mediated derivations. In recent years, molecules targeting the programmed cell death protein 1 (PD-1) immune checkpoint have attracted much attention, and related signalling pathways have been studied clearly. At present, several inhibitors and antibodies targeting PD-1 have been utilized as anti-tumour therapies. However, increasing evidence indicates that PD-1 blockade also has different degrees of adverse side effects, and these new explorations into the therapeutic safety of PD-1 inhibitors contribute to the emerging concept that immune normalization, rather than immune enhancement, is the ultimate goal of disease treatment. In this review, we summarize recent advancements in PD-1 research with regard to immune normalization and targeted therapy.

The impact of donor-specific anti-HLA antibody levels on primary poor graft function and graft rejection in rituximab desensitized haploidentical stem cell transplantation.

This study investigates the influence of donor-specific anti-HLA antibodies (DSA) levels on primary poor graft function (PGF) and graft rejection (GR) after haploidentical stem cell transplantation (haplo-SCT) with rituximab desensitization. A total of 155 DSA-positive haplo-SCT candidates with mean fluorescence intensity (MFI) between 2000 and 10,000 were enrolled in this prospective clinical trial. Receiver operating characteristic (ROC) curves determined the optimal DSA MFI cutoff for identifying high-risk patients. Patients were categorized into two groups: DSA low-level group (2000 ≤ DSA MFI < 5000, Group A) and high-level group (5000 ≤ DSA MFI ≤ 10,000, Group B). The incidence of primary PGF was 6.5% (2.6%-10.3%), while GR incidence was 0.6% (0.0%-1.9%). Group A had significantly lower primary PGF rates than Group B (2.3% [0.0%-5.7%] vs. 12.9% [4.8%-21.0%], p = 0.017). Only one patient in Group B experienced GR. High DSA levels (5000 ≤ MFI ≤ 10,000) were identified as the sole independent risk factor for primary PGF and GR after haplo-SCT with rituximab desensitization (HR = 7.282, 95% CI 1.517-34.953, p = 0.013). The 4-year cumulative incidence of relapse, non-relapse mortality, disease-free survival, and overall survival were 14.7% (11.6%-17.8%), 16.3% (13.1%-19.4%), 69.0% (65.9%-76.2%), and 70.6% (66.4%-74.8%), respectively. DSA levels have an impact on efficiency of rituximab desensitization, and a DSA MFI threshold is provided for predicting primary PGF and GR.

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study.

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-ß/Smads pathway.

Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-ß/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-ß/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-ß/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-ß/Smads signaling pathway.

Myelodysplastic syndrome-like response after voriconazole treatment of systemic lupus erythematosus complicated with fungal infection: a case report.

Background: Voriconazole is mainly used to treat progressive and potentially life-threatening infections in immunocompromised patients. The adverse drug reactions related to voriconazole are varied. In some rare cases, the use of voriconazole can result in myelodysplastic syndrome (MDS)-like adverse reactions. Case presentation: Here, we present a rare case of systemic lupus erythematosus patient with a fungal infection that developed MDS-like adverse reactions after treatment with voriconazole. The patient was admitted to the hospital because of 3 days of chest tightness and dyspnea. After the admission, the patient's sputum culture showed Candida albicans infection, and voriconazole was prescribed to be taken orally. After using voriconazole, drug-related adverse reactions such as visual impairment, nausea, vomiting, hiccup, middle and lower abdominal pain, disorders of consciousness, delirium, hallucination, slow response, and subcutaneous ecchymosis appeared, as well as the gradually increased serum creatinine, oliguria, and aggravated lower limb edema. In addition, there was a decrease in peripheral blood cells, and MDS-like changes in bone marrow were indicated by bone marrow biopsy. After discontinuing voriconazole, drug-related adverse symptoms disappeared, and hematocytopenia and the changes in MDS were significantly improved, which was confirmed by a subsequent bone marrow puncture at a 6 months interval. Conclusion: This case reminded us that when using voriconazole for treatment, individual differences in patients should be considered, and the blood concentration of voriconazole should be closely monitored. Otherwise, potential drugs that affect voriconazole metabolism should be noted, and related adverse symptoms of patients should be closely observed during medication to reduce the occurrence of adverse drug events.

Biological control of Magnaporthe oryzae using natively isolated Bacillus subtilis G5 from Oryza officinalis roots.

Rice blast, caused by Magnaporthe oryzae, is a major threat to global rice production causing significant crop losses and impacting grain quality. The annual loss of rice production due to this disease ranges from 10% to 30%. The use of biologically controlled strains, instead of chemical pesticides, to control plant diseases has become a research hotspot. In this study, an antagonistic endophytic bacterial strain was isolated from the roots of Oryza officinalis using the traditional isolation and culture methods. A phylogenetic tree based on 16S RNA and whole-genome sequencing identified isolate G5 as a strain of Bacillus subtilis. This isolate displayed strong antagonistic effects against different physiological strains of M. oryzae. After co-culture in LB medium for 7 days, the inhibition rates of the mycelial growth of four strains of M. oryzae, ZB15, WH97, Guy11, and T-39800E were 98.07 ± 0.0034%, 98.59 ± 0.0051%, 99.16 ± 0.0012%, and 98.69 ± 0.0065%, respectively. Isolate G5 significantly inhibited the formation of conidia of M. oryzae, with an inhibition rate of 97% at an OD600 of 2. Isolate G5 was able to provide 66.81% protection against rice blast under potted conditions. Whole-genome sequencing revealed that the genome size of isolate G5 was 4,065,878 bp, including 4,182 coding genes. Using the anti-SMASH software, 14 secondary metabolite synthesis gene clusters were predicted to encode antifungal substances, such as fengycin, surfactin, and bacilysin. The G5 isolate also contained genes related to plant growth promotion. These findings provide a theoretical basis for expounding the biocontrol mechanisms of this strain and suggest further development of biogenic agents that could effectively inhibit rice blast pathogen growth and reduce crop damage, while being environmentally friendly, conducive to ecological development, and a sustainable alternative to chemical pesticides. This study also enriches the relevant research on endophytes of wild rice, which proves that wild rice is a valuable microbial resource bank.

Immunochemotherapy alone or immunochemotherapy plus subsequent locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma.

BACKGROUND: To demonstrate whether the benefit of locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma remains in the immunotherapy era and which patients can benefit from radiotherapy. MATERIALS AND METHODS: A total of 273 histopathology-confirmed de novo metastatic nasopharyngeal carcinoma was enrolled between May 2017 and October 2021 if receiving immunochemotherapy with or without subsequent intensity-modulated radiotherapy to the nasopharynx and neck. We compared the progression-free survival, overall survival, and safety between the two groups. Additionally, subgroup analysis was conducted and a scoring model was developed to identify suitable patients for radiation. RESULTS: There were 95 (34.8 %) patients with immunochemotherapy alone, and 178 (65.2 %) with immunochemotherapy plus subsequent locoregional radiotherapy. With a median follow-up time of 18 months, patients with immunochemotherapy plus subsequent radiotherapy had higher 1-year progression-free survival (80.6 % vs. 65.1 %, P < 0.001) and overall survival (98.3 % vs. 89.5 %, P = 0.001) than those with immunochemotherapy alone. The benefit was retained in multivariate analysis and propensity score-matched analysis. Mainly, it was more significant in patients with oligometastases, EBV DNA below 20,200 copies/mL, and complete or partial relapse after immunochemotherapy. The combined treatment added grade 3 or 4 anemia and radiotherapy-related toxicities. CONCLUSION: Immunochemotherapy plus subsequent locoregional radiotherapy prolonged the survival of de novo metastatic nasopharyngeal carcinoma with tolerable toxicities. A scoring model based on oligometastases, EBV DNA level, and response after immunochemotherapy could facilitate individualized management.

The Association of the Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, Lymphocyte-to-Monocyte Ratio and Systemic Inflammation Response Index with Short-Term Functional Outcome in Patients with Acute Ischemic Stroke.

Background and Purpose: The aim of this study was to explore the relationship between functional prognosis and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic inflammatory response index (SIRI) in patients with acute ischemic stroke (AIS) at discharge. Methods: A total of 861 patients with AIS were enrolled between January 2019 and December 2021. Blood cell counts were collected on admission. Logistic regression analysis was performed to assess the relationship between NLR, PLR, LMR, SIRI and adverse functional outcomes (modified Rankin scale score of 3-6) at discharge. We also used receiver operating characteristic (ROC) curves to estimate the overall ability of NLR, PLR, LMR and SIRI to judge short-term functional outcomes. Associations between NLR, PLR, LMR, and SIRI with length of hospital stay were analyzed by Spearman correlation test. Results: A total of 194 patients (22.5%) had poor functional outcomes at discharge. Multivariate logistic regression analysis showed that NLR (odds ratio [OR], 1.060; 95% confidence interval [CI] 1.004-1.120, P=0.037), PLR (OR, 1.003; 95% CI 1.000-1.005, P=0.018), LMR (OR, 0.872; 95% CI 0.774-0.981, P=0.023) and SIRI (OR, 1.099; 95% CI 1.020-1.184, P=0.013) were independent factors for poor functional outcome. The odds ratios of the highest versus lowest quartiles of NLR, PLR and SIRI were 2.495 (95% CI 1.394-4.466), 1.959 (95% CI 1.138-3.373) and 1.866 (95% CI 1.106-3.146), respectively. The odds ratio of the lowest versus highest quartile of LMR was 2.300 (95% CI 1.331-3.975). The areas under the curve (AUCs) of the NLR, PLR, LMR, and SIRI to discriminate poor functional prognosis were 0.644, 0.587, 0.628, and 0.651, respectively. NLR, LMR, and SIRI were related with the length of hospital stay (P<0.05). Conclusion: NLR, PLR, LMR, and SIRI were associated with functional outcome at discharge in AIS patients. NLR, LMR and SIRI were related to hospitalization days in patients with AIS.

Phonological and morphological literacy skills in English and Chinese: A cross-linguistic neuroimaging comparison of Chinese-English bilingual and monolingual English children.

Over the course of literacy development, children learn to recognize word sounds and meanings in print. Yet, they do so differently across alphabetic and character-based orthographies such as English and Chinese. To uncover cross-linguistic influences on children's literacy, we asked young Chinese-English simultaneous bilinguals and English monolinguals (N = 119, ages 5-10) to complete phonological and morphological awareness (MA) literacy tasks. Children completed the tasks in the auditory modality in each of their languages during functional near-infrared spectroscopy neuroimaging. Cross-linguistically, comparisons between bilinguals' two languages revealed that the task that was more central to reading in a given orthography, such as phonological awareness (PA) in English and MA in Chinese, elicited less activation in the left inferior frontal and parietal regions. Group comparisons between bilinguals and monolinguals in English, their shared language of academic instruction, revealed that the left inferior frontal was less active during phonology but more active during morphology in bilinguals relative to monolinguals. MA skills are generally considered to have greater language specificity than PA skills. Bilingual literacy training in a skill that is maximally similar across languages, such as PA, may therefore yield greater automaticity for this skill, as reflected in the lower activation in bilinguals relative to monolinguals. This interpretation is supported by negative correlations between proficiency and brain activation. Together, these findings suggest that both the structural characteristics and literacy experiences with a given language can exert specific influences on bilingual and monolingual children's emerging brain networks for learning to read.

The effects of probiotics supplementation on glycaemic control among adults with type 2 diabetes mellitus: a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: This systematic review and meta-analysis study aimed to evaluate the effectiveness of probiotics supplementation on glycaemic control in patients with type 2 diabetes mellitus (T2DM) based on the data from the randomised clinical trials (RCTs). METHODS: PubMed, Web of Sciences, Embase, and Cochrane Library were searched from the inception to October 2022, and RCTs about probiotics and T2DM were collected. The standardised mean difference (SMD) with 95% confidence interval (CI) was used to estimate the effects of probiotics supplementation on glycaemic control related parameters, e.g. fasting blood glucose (FBG), insulin, haemoglobin A1c (HbA1c), and homeostasis model of assessment of insulin resistance (HOMA-IR). RESULTS: Thirty RCTs including 1,827 T2MD patients were identified. Compared with the placebo group, the probiotics supplementation group had a significant decrease in the parameters of glycaemic control, including FBG (SMD = - 0.331, 95% CI - 0.424 to - 0.238, Peffect < 0.001), insulin (SMD = - 0.185, 95% CI - 0.313 to - 0.056, Peffect = 0.005), HbA1c (SMD = - 0.421, 95% CI - 0.584 to - 0.258, Peffect < 0.001), and HOMA-IR (SMD = - 0.224, 95% CI - 0.342 to - 0.105, Peffect < 0.001). Further subgroup analyses showed that the effect was larger in the subgroups of Caucasians, high baseline body mass index (BMI ≥ 30.0 kg/m2), Bifidobacterium and food-type probiotics (Psubgroup < 0.050). CONCLUSION: This study supported that probiotics supplementation had favourable effects on glycaemic control in T2DM patients. It may be a promising adjuvant therapy for patients with T2DM.

The role of m6A demethylase FTO in chemotherapy resistance mediating acute myeloid leukemia relapse.

Acute myeloid leukemia (AML) is the most common hematopoietic malignancies, and chemotherapy resistance is one of the main causes of relapse. Because of lower survival rate for patients with relapse, it is pivotal to identify etiological factors responsible for chemo-resistance. In this work, direct MeRIP-seq analysis of sequential samples at stage of complete remission (CR) and relapse identifies that dysregulated N6-methyladenosine (m6A) methylation is involved in this progression, and hypomethylated RNAs are related to cell differentiation. m6A demethylase FTO is overexpressed in relapse samples, which enhances the drug resistance of AML cells in vivo and in vitro. In addition, FTO knockdown cells exhibit stronger capacity of differentiation towards granules and myeloid lineages after cytosine arabinoside (Ara-C) treatment. Mechanistically, FOXO3 is identified as a downstream target of FTO, the hypomethylation of FOXO3 mRNA affects its RNA degradation and further reduces its own expression, which ultimately result in attenuated cell differentiation. Collectively, these results demonstrate that FTO-m6A-FOXO3 is the main regulatory axis to affect the chemotherapy resistance of AML cells and FTO is a potential therapeutic target of chemotherapy resistance in AML.

Sources of Heterogeneity in Functional Connectivity During English Word Processing in Bilingual and Monolingual Children.

Diversity and variation in language experiences, such as bilingualism, contribute to heterogeneity in children's neural organization for language and brain development. To uncover sources of such heterogeneity in children's neural language networks, the present study examined the effects of bilingual proficiency on children's neural organization for language function. To do so, we took an innovative person-specific analytical approach to investigate young Chinese-English and Spanish-English bilingual learners of structurally distinct languages. Bilingual and English monolingual children (N = 152, M(SD)age = 7.71(1.32)) completed an English word recognition task during functional near-infrared spectroscopy neuroimaging, along with language and literacy tasks in each of their languages. Two key findings emerged. First, bilinguals' heritage language proficiency (Chinese or Spanish) made a unique contribution to children's language network density. Second, the findings reveal common and unique patterns in children's patterns of task-related functional connectivity. Common across all participants were short-distance neural connections within left hemisphere regions associated with semantic processes (within middle temporal and frontal regions). Unique to more proficient language users were additional long-distance connections between frontal, temporal, and bilateral regions within the broader language network. The study informs neurodevelopmental theories of language by revealing the effects of heterogeneity in language proficiency and experiences on the structure and quality of emerging language neural networks in linguistically diverse learners.

CSRP2 transcript levels after consolidation therapy increase prognostic prediction ability in B-cell acute lymphoblastic leukaemia.

Quantification of measurable residual disease (MRD) correlates with the risk of leukemia recurrence in adults with B-cell acute lymphoblastic leukemia (ALL). However, it remains unknown whether collecting data on cysteine and glycine-rich protein 2 (CSRP2) transcript levels, after completing the second course of consolidation, improves prognosis prediction accuracy. A total of 204 subjects with B-cell ALL were tested for CSPR2 transcripts after completing the second course of consolidation using quantitative real-time polymerase chain reaction (qRT-PCR) and divided into high (N = 32) and low (N = 172) CSRP2 expression cohorts. In multivariable analyses, subjects with high expression of CSRP2 had a higher 5-year cumulative incidence of relapse (CIR) (hazard ratio [HR] = 2.57, 95% confidence interval [CI] 1.38-4.76; P = 0.003), lower 5-year relapse-free survival (RFS) (HR = 3.22, 95% CI 1.75-5.93; P < 0.001), and overall survival (OS) (HR = 4.59, 95% CI 2.64-7.99; P < 0.001) in the whole cohort, as well as in the multi-parameter flow cytometry (MPFC) MRD-negative cohort (for CIR, HR = 2.70, 95% CI 1.19-6.12; for RFS, HR = 4.37, 95% CI 1.94-9.85; for OS, HR = 4.90, 95% CI 2.43-9.90; all P < 0.05). Prognostic analysis showed that allogeneic hematopoietic stem cell transplantation (allo-HSCT) could significantly improve the prognosis of patients with high CSRP2 expression (allo-HSCT vs chemotherapy: 5-year CIR, 52% vs 91%; RFS, 41% vs 9%; OS, 38% vs 20%; all P < 0.05). Our data indicate that incorporating data from CSPR2 transcript levels to the MRD-testing at the end of the second course of consolidation therapy enhances prognosis prediction accuracy in adults with B-cell ALL.

Integration of Metabolomics and Transcriptomics to Reveal the Metabolic Characteristics of Exercise-Improved Bone Mass.

(1) Background: Exercise is effective in promoting and maintaining bone mass. The aim of this study was to detect the exercise-induced metabolic changes in bone tissue of zebrafish. (2) Methods: Thirty-eight zebrafish (Danio rerio, six months old) were analyzed. The exercise group (n = 19) received 8 weeks of counter-current swimming training. The control group (n = 19) was not subjected to exercise. Mineralization was quantified, and alkaline phosphatase (Alp) and anti-tartrate acid phosphatase (Trap) activities were estimated (n = 12). The metabolomics (n = 12) and transcriptomics (n = 14) data of bone tissue were used for the integration analyses. (3) Results: The results showed that the exercise training improved the bone mineralization of zebrafish, e.g., the exercise group (5.74 × 104 ± 7.63 × 103) had a higher mean optical density than the control group (5.26 × 104 ± 8.56 × 103, p = 0.046) for the caudal vertebrae. The amount of mineralized matrix in scales of the exercised zebrafish was also higher (0.156 ± 0.012 vs. 0.102 ± 0.003, p = 0.005). Both histological staining and biochemical analysis revealed increased Alp activity (0.81 ± 0.26 vs. 0.76 ± 0.01, p = 0.002) and decreased Trap activity (1.34 ± 0.01 vs. 1.36 ± 0.01, p = 0.005) in the exercise group. A total of 103 different metabolites (DMs, VIP ≥ 1, fold change (FC) ≥ 1.20 or ≤0.83, p < 0.050) were identified. Alanine, aspartate and glutamate metabolism, ß-alanine metabolism, pyrimidine metabolism, and pantothenate and CoA biosynthesis were the significantly enriched metabolic pathways (p < 0.050). A total of 35 genes (q ≤ 0.050 (BH), |Log2FC| ≥ 0.5) were coenriched with the 103 DMs in the four identified pathways. Protein-protein interaction network analysis of the 35 genes showed that entpd3, entpd1, and cmpk2 were the core genes. (4) Conclusions: The results of this study suggest that alanine, aspartate and glutamate metabolism, ß-alanine metabolism, pyrimidine metabolism, and pantothenate and CoA biosynthesis contributed to exercise-induced improvements in bone mass.

Stellate ganglion block alleviates postoperative cognitive dysfunction via inhibiting TLR4/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1ß, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients.