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“Scotty, we need more power!”

5-(3,5-Dinitrophenyl)-1,3,4-oxadiazol-2-amine derivatives, their precursors, and analogues: Synthesis and evaluation of novel highly potent antitubercular agent

Drug resistance is a growing problem for many pathogens, including mycobacteria. Small heterocyclic molecules are among the leading scaffolds for developing potential antimycobacterial agents. Therefore, based on the molecular hybridization approach, we have prepared an extensive series of N-substituted 5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2-amine derivatives. We also investigated their isosteres and acyclic synthetic precursors. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis (Mtb) H37Rv, a panel of multidrug- and extensively drug-resistant Mtb isolates and two nontuberculous mycobacterial strains (NTM; M. avium and M. kansasii). The ability to inhibit mycobacterial growth was quantified using minimum inhibitory concentration (MIC) values. Many compounds achieved MIC values ≤ 0.03 µM for NTM and Mtb, regardless of their resistance profile. The highest activity was associated with oxadiazole and thiadiazole scaffolds with benzylamino or C5-C9 alkylamino substitution. The experimentally confirmed mechanism of action of these compounds consists of disruption of mycobacterial cell wall biosynthesis via inhibition of decaprenylphosphoryl-β-D-ribose 2’-epimerase (DprE1). In vitro toxicity evaluation was performed in a hepatocyte model (HepG2), while in vivo toxicity was evaluated using Danio rerio embryos. These findings identify a promising new chemotype with potent, broad-spectrum and selective antimycobacterial activity, including efficacy against resistant strains, and support its further development as a potential therapeutic candidate.

Phonation differentiation by non-contact laryngeal magnetomyography

Abstract Phonation is important for our daily communication and requires the activation of internal and external laryngeal muscles, which can be recorded by electromyography (EMG) using surface or needle electrodes. Here we present a new noncontact method, laryngeal magnetomyography. As a proof-of-concept, we investigated the feasibility of differentiating various vocalization conditions using laryngeal MMG in two healthy subjects using optically pumped magnetometers (OPM). We recorded magnetic muscle activity of the larynx and neighboring cervical muscles using a 3 × 5 array of OPMs. Subjects vocalized an /a/ in three different conditions: loud high pitch, loud low pitch, and soft high pitch, in 90 s blocks. After removing cardiac artifacts, MMG signals were in the range of 1.5 pT with significant amplitude differences between conditions. In both subjects, Linear Discriminant Analysis (LDA) was able to significantly classify vocalization conditions based on the spatial pattern of MMG activities. In sum, we show that laryngeal MMG allows contactless differentiation of phonations based on myomagnetic signals. Our results set the stage for future studies to explore this method for clinical diagnostics and therapy. Functional, contactless muscle recordings during vocalization enable new applications for miniaturized quantum sensors, e.g. in linguistic studies and speech rehabilitation.

Ibrutinib lead-in followed by venetoclax plus ibrutinib for relapsed/refractory chronic lymphocytic leukemia: the SAKK 34/17 trial

Abstract The combination of ibrutinib plus venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment leverages their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. The Swiss Group for Clinical Cancer Research (SAKK) 34/17 study is a single-arm, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK or BCL2 inhibitors was allowed. The lead-in phase with ibrutinib was extended to 6 months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD; 10–4) rate. The primary end point was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary end points included assessing the proportion of patients transitioning to a low-risk category for TLS after receiving ibrutinib lead-in. Of the 30 enrolled patients with R/R CLL, 40.0% achieved uMRD CR/CRi by intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. After the lead-in period with ibrutinib, 57.1% of patients achieved a low risk of TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness. This trial was registered at www.clinicaltrials.gov as #NCT03708003.

Wrist-ankle acupuncture alleviates pain in the acute phase of herpes zoster: A randomized controlled trial

Alternative therapeutic strategies for herpes zoster, especially for acute phase pain relief, are still largely unexplored. This study aimed to compare the effects of wrist-ankle acupuncture combined with standard pharmacological treatment versus standard pharmacological treatment alone in relieving pain in the acute phase of herpes zoster. An open-label, randomized, controlled clinical trial was conducted, enrolling patients diagnosed with acute-phase herpes zoster with pain visual analog scale (VAS) scores greater than or equal to 2. The participants were randomly assigned to either the control group receiving standard pharmacological treatment (antiviral therapy combined with pain relievers) alone or the experimental group receiving wrist-ankle acupuncture plus standard pharmacological treatment. VAS pain scores were recorded on days 1–7 and on day 28 after treatment began. Dermatology Life Quality Index scores were assessed both during the pre-treatment phase and at hospital discharge. A total of 106 patients completed the trial protocol and were included in the analysis, with 52 and 54 patients in the control and experimental groups, respectively. The clinical cure rates of pain (the rate of complete absence of pain) in the experimental group was statistically higher than control group on days 7 after treatment began(87.04% vs 65.38%, p < 0.005). The average pain VAS scores of the experimental group were lower than the control group on days 2–6 after treatment began, and they are statistically significant (all p < 0.05). No significant difference was observed between day 7 and day 28 after treatment began (p > 0.05). The Dermatology Life Quality Index scores significantly differed at hospital discharge (p < 0.05). Side effects did not significantly differ between the two groups (all p > 0.05). Wrist-ankle acupuncture combined with standard pharmacological treatment may potentially improve the pain cure rate at 7 days post-treatment. This suggests a potential new strategy for alleviating pain in patients in the acute phase of herpes zoster. Trial registration: ChiCTR2300071795.

A novel interval valued bipolar fuzzy hypersoft topological structures for multi-attribute decision making in the renewable energy sector

Are you ready for it? VEN-HMA for younger patients with AML

Cell death and iron deposition in the liver in two murine models of acute radiation syndrome

Different tissues exhibit differential sensitivity to ionizing radiation exposure and display different time courses of pathologies that are not well understood. Ionizing radiation causes hemolysis of red blood cells, causing the release of iron that is taken up by a variety of tissues. The increased iron has been associated with altered expression of iron binding proteins and, in some cases, markers of ferroptosis. Here we examined the time course of iron uptake in murine liver following 60Co total body irradiation (TBI) at 7.9 Gy (LD90/30) and 6.85 Gy (LD0/30). 7.9 Gy induced hydropic degeneration, micro-vesicular steatosis, and inflammatory cell infiltration, whereas at 6.85 Gy the livers displayed only inflammatory cell infiltration. In both cases, iron levels increased significantly, maximal at ~21 days post-TBI. Increased iron was associated with altered expression of ferritin, heme oxygenase, an enzyme required for iron recycling, and the pro-inflammatory cytokine serum amyloid A, maximal ~16–21 days. 7.9 Gy induced liver caspase-3 activation consistent with apoptosis. In contrast, 6.85 Gy induced markers of ferroptosis but not of apoptosis. Our data indicate that iron is deposited in the liver at a delayed time point following radiation and is associated with increased ferritin, HO-1, and inflammatory cytokine production.

Stratification of G2 pancreatic neuroendocrine tumors using a Ten Percent Ki-67 index cut-off based on clinicopathological and molecular analyses

A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia

Abstract Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19) T-cell therapy, >50% of patients relapse within a year. Both leukemia cell–intrinsic factors favoring immune escape and poor CAR T-cell persistence contribute to clinical failure. Moreover, the expression of immune checkpoint receptors (ICRs) and their ligands within the bone marrow (BM) microenvironment may contribute to leukemia progression and therapy resistance. Here, we characterized the expression of ICRs and their ligands in leukemic blasts, T cells, and mesenchymal stromal cells (MSCs) from B-ALL BM samples at diagnosis and relapse, comparing them with age-matched healthy BM controls. Our findings reveal a significantly upregulated expression of TIM-3 in T cells and its ligand, galectin-9, in both blasts and MSCs throughout disease progression. The expression of galectin-9 in B-ALL blasts and TIM-3 in CAR19 T cells negatively correlates with clinical outcome. Furthermore, we demonstrate that galectin-9 impairs CAR19 T-cell homeostasis and cytotoxicity. Notably, an engineered TIM-3–Fc decoy receptor, delivered either by primary T cells coadministered with CAR19 T cells or via a bicistronic all-in-one CAR19–TIM-3–Fc construct, improved the antileukemia efficacy and persistence of CAR19 T cells in B-ALL xenograft models. Mechanistically, CAR19–TIM-3–Fc T-cell treatment promotes the in vivo expansion of transduced and bystander effector and memory T cells, as determined by spectral flow cytometry. Collectively, these TIM-3–Fc decoy–armored CAR19 T cells offer a promising therapeutic strategy for patients with R/R B-ALL.

Postpartum hemorrhage incidence and risk factors: Evidence from a multicenter study in Zhejiang Province, China

Objective Postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide, and its risk factors vary regionally. This study assessed the incidence and determinants of PPH in Zhejiang Province, China. Methods We conducted a cross-sectional study using data from the Maternity Near Miss Surveillance System in Zhejiang Province, collected from January to December 2020. The cohort included 56,014 pregnant women at a gestational age of 28 weeks or more. PPH was defined as blood loss of ≥500 mL for vaginal deliveries and ≥1,000 mL for cesarean sections within 24 h of delivery. Logistic regression analyzed the risk factors for PPH. Results Of the pregnant women, 2,016 (3.60%) experienced PPH. The mortality rate associated with PPH was 1.74 per 100,000 live births. Significant independent risk factors included multiple births (OR 3.10; 95% CI 2.42–3.98; P < 0.01), vaginal delivery (OR 3.00; 95% CI 2.62–3.42; P < 0.01), macrosomia (OR 2.30; 95% CI 1.97–2.68; P < 0.01), hypertensive disorders of pregnancy (OR 1.79; 95% CI 1.50–2.13; P < 0.01), and a lower educational level (OR 1.20; 95% CI 1.07–1.36; P < 0.01). Conclusion The incidence and mortality rates of PPH in Zhejiang Province are low. Identified risk factors such as multiple births, vaginal delivery, macrosomia, hypertensive disorders, and lower education level can guide interventions to mitigate PPH risk.

Optimising the mechanical properties of concrete for non-structural applications through partial replacement of fine aggregates with wastewater sludge

One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them

Abstract Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B-cell and dendritic-cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency was recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss-of-function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of individuals harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and noninfectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic-cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks.

A foundation model for the Earth system

An improved modeling approach to investigate biases in human random number generation

Recently, a novel computational model was proposed to investigate the processes and biases involved in human random number generation (RNG). This two-parameter model includes a repetition parameter and a side-switching parameter representing influences of the immediately preceding number on the choice of the next number. We propose two changes to the model. First, we replace the side-switching parameter with a more general and less task-dependent distance parameter, which accounts for the tendency to select subsequent numbers that tend to be either closer to or further away from the previous number on the selected response pad. Second, we extend the computational model by adding a third parameter to account for the human tendency to select subsequent numbers with greater probability the longer the respective number has not been previously selected, following the pattern of the well-known gambler’s fallacy. This new “cycling” parameter takes into account the most recent and all previous selections. The generalized distance parameter, and particularly the new cycling parameter, improved the fit of the model to human-generated sequences and the rate of successful predictions of the next choice from 14.09% to 26.48%, significantly exceeding the expected chance value of 1/9 = 11.1%. Model-driven simulations also showed that the extended three-parameter model could better account for systematic patterns that can be observed in human RNG tasks. The improved model could be useful in many contexts where human biases in RNG tasks are analyzed.

Unveiling Isorhapontigenin’s therapeutic potential in lung cancer via integrated network pharmacology, molecular docking, and experimental validation

SPI-ing on human B-cell development

Research on identity authentication and data security of photovoltaic power generation management personnel based on blockchain technology

As high-frequency technological developments happen and the variety of Microgrids (MG) grows, microgrids are going to be able to secure their own usage while competing in the electricity sector. To optimize each individual’s earnings, the most efficient bidding approach for the transaction process is determined using a novel customized hunter prey optimization (CHPO), it has been established with blockchain technology and shown as a MG transactional framework in this research. To address the issue of energy underuse in a MG gaming competition, research have developed the CHPO, an innovative technique in the most effective bidding approach for the transaction process. Two market participants such as Major Users (MU) and Users of Microgrid (UoM) were explored for the performance in energy transactions. The market participants performance was creating various methods for buying and selling power at various locations in the MG framework to enhance the participant’s desires and power developments in the market. In addition, the main market participants are employed as study subjects to develop a distributed energy resources (DERs) integration system that addresses the issue of real-time power pricing. The design comparison is analyzed with an authentication paradigm to demonstrate its applicability to microwave, optical, and radio frequency (RF) technologies. In addition, the main market participants are employed as research subjects to develop a DERs integration system that addresses the issue of real-time power pricing. The design comparison is analyzed with an authentication paradigm to demonstrate its applicability to microwave, optical, and RF technologies. The CHPO method demonstrated high efficiency with a mean convergence time of 54 iterations and an interval of 240, which makes it scalable. It ensures low latency at 45ms, and the unit operation metrics (UoM) range from 2,402,077–2,935,889, which is quite robust. The CHPO method also performed better in RMSE at 4.75, MAPE at 10.12, MAE at 2.31.

Uncovering the molecular mechanisms of tonifying kidney and activating blood Decoction against myocardial fibrosis using network Pharmacology and experimental validation

Evaluating the impact of <i>CRBN</i> mutations on response to immunomodulatory drugs and novel cereblon E3 ligase modulators in myeloma

Abstract Immunomodulatory drug (IMiD) resistance is a key clinical challenge in myeloma treatment. Previous data suggest almost one-third of myeloma patients acquire genetic alteration of the key IMiD effector cereblon (CRBN) by the time they are pomalidomide refractory. Some events, including stop codons/frameshift mutations and copy loss, have clearly explicable effects on CRBN protein function. Missense mutations have also been reported throughout the length of CRBN but their functional impact has not been systematically studied. This study modeled selected missense mutations and examined their effect on CRBN function also analyzing whether any mutations deleterious to IMiD action could be overcome using the novel cereblon E3 ligase modulators (CELMoDs). Three patterns of response to missense mutations were apparent: mutations that led to complete loss of CRBN function for all agents, those that had no effect on CRBN function, and those with agent-dependent effect on CRBN function. The latter group of 4 mutations were profiled in more detail with confirmatory experiments demonstrating an ability of the more potent CELMoDs to lead to neosubstrate degradation and cell death even though IMiDs were not active. Dynamic modeling based on a newly generated crystal structure of the DDB1/CRBN/lenalidomide complex, with greater resolution than those published to date, helped to understand the impact of these mutations. These results have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of CELMoD agents.