Browse Articles

Photo-induced selective N-N bond construction via harnessing nitrene release and transfer

Analysis on hydraulic dynamic stiffness characteristics and experimental research of asymmetric valve-controlled asymmetric cylinder system

Exploring innovative G-CSF schedules in AML cytarabine-based consolidation through a digital twin study of white blood cell recovery

Patients with acute myeloid leukemia (AML) are at high risk for life-threatening infectious complications due to chemotherapy-induced leukopenia. In contrast to other malignancies, prophylactic administration of granulocyte colony-stimulating factors (G-CSF) is not routinely done in AML. However, recently, clinical trials showed that administration of G-CSF post consolidation chemotherapy leads to faster white blood cell (WBC) recovery and to fewer infections. We investigated novel G-CSF schedules using a mathematical model trained with retrospective clinical data (digital twins) consisting of high-frequency measurements of 65 patients. We evaluated 323 different treatments varying in start and duration of G-CSF administration by examining the impact on the occurrence and duration of leukopenia. For each treatment, we used the same 65 digital twins, plus an additional 100 artificial patients for uncertainty quantification, receiving 3 consolidation cycles each. We lumped the 323 treatments into 4 clusters: NO-G-CSF, PRE-G-CSF, SIM-G-CSF, and POST-G-CSF for schedules without G-CSF, that terminated G-CSF before consolidation chemotherapy started, that overlapped on at least one day, and that started post chemotherapy, respectively. The numerical simulations resulted in substantial differences in the occurrence of leukopenia: 88% of all consolidation cycles with leukopenia for NO-G-CSF, 98% for SIM-G-CSF, 45% for POST-G-CSF, and 28% for PRE-G-CSF. Administration of G-CSF before chemotherapy may thus significantly enhance the efficacy of AML consolidation therapy and, therefore, warrants clinical investigation.

Technological innovations and hafted technology in central China ~160,000–72,000 years ago

Effects of mass concentration and curing age on the mechanical properties and damage evolution of aeolian sand backfill

Effect of a hearing loss care education program for older adults targeted at visiting nurses: A cluster randomized controlled trial

Hearing loss in older adults is a risk factor for depression, cognitive decline, frailty, and other conditions, and it has various negative physical and psychological effects. Hearing loss care requires the support of medical professionals; however, most hearing care education is targeted at professionals working in hospitals and care facilities, with few interventions aimed at visiting nurses. To address this gap, we developed the “Hearing Loss Care Education Program for the Older Adults” to improve visiting nurses’ skills in managing hearing loss. This study aimed to evaluate the effectiveness of the program. This cluster randomized controlled trial was registered in the UMIN Clinical Trials Registry (UMIN000053337) and conducted across 22 visiting nursing stations: 11 in the intervention group (60 visiting nurses) and 11 in the control group (42 visiting nurses). The intervention consisted of on-demand lectures and technical exercises, followed by a 3-month follow-up period. The primary outcome was the “implementation of hearing care,” whereas the secondary outcomes were “knowledge of hearing care” and “confidence in implementing hearing care.” Between-group differences were analyzed using generalized estimating equations. As part of the primary outcome, a significant increase in the implementation of “hearing screening” was observed in the intervention group (odds ratio 8.35, 95% confidence interval 3.60–19.34, p < 0.001). Additionally, the intervention group demonstrated significantly higher “knowledge of hearing care” and “confidence in implementing hearing care.” These findings suggest that the program effectively enhanced visiting nurses’ knowledge and confidence in hearing care and supports the integration of hearing screening into their routine practice.

ZFP57 is a regulator of postnatal growth and life-long health

Abstract Early-life factors, including postnatal nutrition, shape long-term health outcomes with epigenetic effects being implicated but poorly understood in the process. Zinc-finger protein 57 (ZFP57), is an epigenetic regulator of genomic imprinting, a process controlling gene expression based on parental origin with a vital role in prenatal growth. Here, we report an imprinting-independent function of ZFP57 in postnatal resource control via the mammary gland. ZFP57 influences multiple mammary gland phenotypes, including ductal branching and cellular homeostasis with its absence leading to significant differential gene expression related to alveologenesis and lactogenesis and altered milk composition. Zfp 57 -/- dams attenuate offspring growth, with impacts on offspring metabolic health; effects exacerbated when pups are raised by a dam of a different genotype than their birth mother. The study identifies ZFP57 as a major regulator of both pre and postnatal resource control in mammals, offering new insights into early factors influencing lifelong health.

Robust consensus ordinal priority approach for improvisational emergency supplier selection under expert consensus ambiguity

The impact of multimorbidity on the occurrence of depression among middle-aged and elderly people in China

Objective This study aims to investigate the association between multimorbidity and the incidence of depression in the middle-aged and elderly populations in China, focusing on the impact of multiple chronic diseases on mental health outcomes. Methods This research comprises a rigorous retrospective cohort study utilizing the esteemed China Health and Retirement Longitudinal Study (CHARLS) data. Follow-up data were meticulously analyzed from 2013 (Wave 2) to 2020 (Wave 5), with data from 2015 serving as the essential baseline for examining multimorbidity and depression. We employed Directed Acyclic Graphs (DAGs) to identify potential confounding factors, applying overlap weighting to effectively mitigate their influence, thus ensuring that intergroup comparisons mirror the integrity of a randomized trial. The association between multimorbidity and depression was systematically evaluated through Cox regression models, supplemented by thorough subgroup analyses and sensitivity analyses to confirm the robustness of our findings. Results Our analysis included 3,495 participants aged 45 and older. Multimorbidity was found to significantly elevate the risk of depression (Hazard Ratio [HR] = 1.431, 95% Confidence Interval [CI] 1.202–1.703). This risk was particularly pronounced in women (HR = 1.617, 95% CI: 1.290–2.027) and older adults (HR = 1.482, 95% CI: 1.221–1.799). The risk of depression increased with the number of chronic diseases, particularly with two (HR = 1.423, 95% CI: 1.192–1.701) or three (HR = 2.045, 95% CI: 1.503–2.784) chronic conditions. However, this association diminished in significance when four chronic conditions were present (HR = 0.815, 95% CI: 0.444–1.497). Conclusion The pronounced association between multimorbidity and depression in middle-aged and elderly individuals highlights an urgent public health issue, particularly for women and older adults. This study’s use of overlap weighting provides strong evidence of the substantial impact of multimorbidity on mental health. It underscores the immediate need for targeted interventions to improve mental well-being in these vulnerable groups.

Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial

Abstract CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2– BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 > 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67 C1D15  ≤ 2.7% at cycle 1, day 15), was achieved in 57.6% of patients (95%CI: 39.2–74.5%). Resistance to ANA/PAL (Ki67 C1D15  > 10%) was associated with higher pre-treatment tumor grade, Ki67, and specific PAM50 subtypes. Resistant tumors demonstrated reduced ER signaling and upregulation of cell cycle, mTOR, interferon, JAK/STAT, and immune checkpoints. Additionally, a 33-gene signature that predicted neoadjuvant Ki67 response to ANA/PAL was prognostic in a metastatic validation cohort. These findings underscore dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6i.

NEK7 phosphorylation of cortactin modulates the migratory capacity of cells expressing EML4-ALK V3

Abstract EML4-ALK is a common oncogenic driver of non-small cell lung cancer. Distinct EML4-ALK variants cause different rates of disease progression, with patients expressing variant 3 (V3) exhibiting accelerated metastasis. Cells expressing EML4-ALK V3 develop a mesenchymal-like morphology and enhanced migration that is dependent on the NEK9 and NEK7 kinases. However, downstream substrates of these kinases relevant to these phenotypes are largely unknown. Here, we show that the actin-binding protein cortactin is phosphorylated by NEK7 within the F-actin-binding region (ABR) and that depletion of cortactin abrogates the morphological and migration phenotypes induced by EML4-ALK V3. Expression of constitutively active mutants of NEK9 or NEK7 causes similar cortactin-dependent morphological and migration changes. Cortactin co-localises with NEK7 and EML4-ALK V3 at branched filopodia-like extensions that are also generated upon expression of a cortactin protein with phospho-mimetic mutations in the ABR. In contrast, phospho-null mutations dissociate cortactin from F-actin. We propose that EML4-ALK V3 alters cell morphology and promotes directed cell migration by modulating the actin cytoskeleton via NEK7-mediated phosphorylation of cortactin within its ABR.

Output stream analysis in a queueing model with working vacation mechanism as a power reduction strategy

The aim of this paper is to analyze the departure process of a queueing model with general independent input stream, exponentially distributed service time, finite buffer and working vacation mechanism. The explicit solution for a Laplace transform of generating function of this characteristic is determined. Utilizing numerical Laplace transform inversion, the time-dependent mean number of jobs served in a time interval is computed. The numerical examples show the behavior of the output stream in dependence on the model parameters, such as interarrival distribution, mean working vacation period duration, the workload in normal and in working vacation mode.

Abiotic sugar enantiomers in the CI carbonaceous chondrite Orgueil

Efficient feature ranked hybrid framework for android Iot malware detection

Abstract Android-based IoT devices are still exposed to increasing sophistication in malware; therefore, detecting this malware using lightweight and accurate approaches is very important. This paper presents a hybrid malware detection framework, incorporating static and dynamic analysis with a dual feature-ranking mechanism based on Information Gain and Gini Index, for selecting the most relevant features. The framework uses a Random Forest classifier optimized via systematic hyperparameter tuning and is evaluated on four benchmark datasets: Drebin, CCCS-CIC-AndMal-2020, TUANDROMD, and CIMD-2024. It showed very consistent performance across all four datasets, yielding accuracy in the range of 99.03% to 100% with corresponding F1-scores in the range of 0.98 to 1.00. On the contrary, the highly imbalanced nature of the CIMD-2024 dataset essentially requires imbalance-handling strategies to effectively detect both majority and minority classes. Experiments on cross-validation confirm the model’s stability and generalizability, while the interpretability analysis pinpoints the most influential behavioral and static features that drive such classification. The results ensured that the proposed approach provided an efficient, interpretable, and resource-friendly solution for malware detection within Android-IoT environments.

Correction: Prenatal exposure to extreme ambient heat may amplify the adverse impact of Superstorm Sandy on basal ganglia volume among school-aged children

Author Correction: A streamlined base editor engineering strategy to reduce bystander editing

Benchmarking the geographic generalization of deep learning models for precipitation downscaling

Abstract Earth System Models (ESM) are our main tool for projecting the impacts of climate change. However, running these models at sufficient resolution for local-scale risk-assessments is not computationally feasible. Deep learning-based super-resolution models offer a promising solution to downscale ESM outputs to higher resolutions by learning from data. Yet, due to regional variations in climatic processes, these models typically require retraining for each geographical area–demanding high-resolution observational data, which is unevenly available across the globe. This highlights the need to assess how well these models generalize across geographic regions. To address this, we introduce RainShift, a dataset and benchmark for evaluating downscaling under geographic distribution shifts. We evaluate state-of-the-art downscaling approaches including GANs and diffusion models in generalizing across data gaps between the Global North and Global South. Our findings reveal substantial performance drops in out-of-distribution regions, depending on model and geographic area. While expanding the training domain generally improves generalization, it is insufficient to overcome shifts between geographically distinct regions. We show that addressing these shifts through, for example, domain adaptation can improve spatial generalization. Our work advances the global applicability of downscaling methods and represents a step toward reducing inequities in access to high-resolution climate information.

Neurochemical imaging reveals changes in dopamine dynamics with photoperiod in a seasonally social vole species

Studying dopamine signaling in nonmodel organisms is crucial for understanding the broad range of behaviors not represented in traditional model systems. However, exploring new species is often hindered by a scarcity of tools suitable for nongenetic models. In this work, we introduce near-infrared catecholamine nanosensors (nIRCats) to investigate dopamine dynamics in meadow voles, a rodent species that exhibits distinct changes in social behavior and neurobiology across photoperiods. We observe increased dopamine release and release site density in voles housed in short photoperiods (which induce a social phenotype), suggesting adaptations linked to environmental changes. Moreover, pharmacological and extracellular manipulations demonstrate that short photoperiod/social voles exhibit heightened responsiveness to dopamine-increasing interventions and resilience against suppressive conditions. These findings highlight a significant association between dopamine signaling and photoperiod-driven changes in social behavior and establish nIRCats as an effective tool for expanding our understanding of dopamine dynamics across nonmodel organisms.

Effect of thermoformed tray architecture on transfer accuracy of lingual brackets: A prospective clinical study

Introduction This prospective clinical study assessed whether thermoformed transfer tray architecture influences in-vivo positional fidelity of lingual brackets during indirect bonding, and whether the resulting deviations remain within clinically acceptable limits. Methods A fully digital indirect bonding workflow was used. Bracket positions were planned on a virtual setup, and transfer trays were fabricated by thermoforming on 3D-printed models. Four tray designs were tested clinically under routine full-arch lingual bonding: a single-layer rigid tray (SR1) and three bilayer trays with a flexible inner liner of increasing thickness (BL1, BL2, BL3). After bonding, each bracket was digitized and superimposed onto the planned position using a local bracket-based coordinate system. Linear (mesiodistal, buccolingual, vertical) and angular (rotation, crown angulation, torque) deviations were calculated at the tooth level and compared across tray designs. Results All trays achieved clinically acceptable transfer accuracy. All linear deviations remained below 0.5 mm at the group level, and rotation and angulation were generally within 2.0°. SR1 showed the most favorable buccolingual and rotational control but required the longest chairside delivery time. BL1 achieved acceptable accuracy with a shorter delivery time. Increasing liner thickness (BL2, BL3) did not improve precision and was associated with greater deviation in several dimensions. Conclusion Tray architecture affected which axes were most vulnerable to error. Torque remained the least predictable dimension across all designs. Clinically, SR1 may be preferred in cases requiring strict control of rotation and buccolingual position, whereas BL1 offers a faster alternative for straightforward alignment without routine escalation to thicker bilayer trays.

Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota

Abstract Chemotherapy-induced intestinal toxicity is a major dose-limiting complication, but the underlying mechanisms linking systemic metabolism to localized gut damage are poorly understood. Here we show that serum L-kynurenine, a tryptophan metabolite, is elevated in patients with severe oxaliplatin-induced intestinal toxicity. Accumulation of L-kynurenine is driven by IFNγ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) in myeloid cells. Using scRNA-seq and myeloid cell-specific knockout models, we confirm that myeloid cell-derived L-kynurenine exacerbates toxicity. Critically, L-kynurenine accumulation drives gut dysbiosis, characterized by the loss of Lactobacillus johnsonii , and subsequently activates the TNFα/JNK pathway, leading to intestinal epithelial apoptosis. Pharmacological inhibition or engineered reduction of L-kynurenine mitigates chemotherapy-induced intestinal injury. Our findings reveal an important role of L-kynurenine from myeloid cells in chemotherapy tolerance and propose its targeting as a potential therapeutic strategy.