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Correction: Genetic differentiation at extreme latitudes in the socially plastic sweat bee Halictus rubicundus
Exploring the spatiotemporal effects of urban scale and urban vitality on S&D balance in the Yangtze River Delta, China from 2015 to 2025
Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial
AbstractEarly therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7–NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10-5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes.
The involvement of Elf5 in regulating keratinocyte proliferation and differentiation processes in skin
Skin and hair development is regulated by multitude of programs of activation and silencing of gene expression to maintain normal skin and hair follicle (HF) development, homeostasis, and cycling. Here, we have identified E74-like factor 5 (Elf5) transcription factor, as a novel regulator of keratinocyte proliferation and differentiation processes in skin. Expression analysis has revealed that Elf5 expression was localised and elevated in stem/progenitor cell populations of both the epidermis (basal and suprabasal) and in HF bulge and hair germ stem cell (SCs) compartments during skin and hair development and cycling. Expressional and functional analysis using RT-qPCR, western blot and colony forming assays, revealed that Elf5 plays an important role in regulating keratinocyte proliferation and differentiation processes as well as potentially determining cell fate by regulating the stem/progenitor cell populations in skin and HFs. These data will provide a platform for pharmacological manipulation of Elf5 in skin, leading to advancements in many areas of research, including stem cell, regenerative medicine, and ageing.
Deciphering antioxidant interactions via data mining and RDKit
Long-range organization of intestinal 2D-crypts using exogenous Wnt3a micropatterning
Utilization of transitional care management services and 30-day readmission
Transitional care management (TCM) visits have been shown to reduce 30-day readmissions, but it is unclear whether the decrease arises from the TCM visit itself or from clinic-level changes to meet the requirements of the TCM visits. We conducted a cross-sectional analysis using data from Northwell Health to examine the association between the type of post-discharge follow-up visits (TCM visits versus non-TCM visits based on billing) and 30-day readmission. Furthermore, we assessed whether being seen by a provider who frequently utilizes TCM visits or the TCM visit itself was associated with 30-day readmission. We included adult patients hospitalized to Medicine service and subsequent follow-up visits within two weeks of discharge between February 24, 2018, and February 24, 2020. We examined 1) post-discharge follow-up visit type (TCM visit versus non-TCM visit) and 2) provider characteristics (frequent TCM visit utilization or not). The primary outcome was unplanned hospital readmission within 30 days following hospital discharge. After propensity matching, TCM follow-up visits were associated with decreased 30-day readmissions (hazard ratio = 0.74 [0.63–0.88]) compared to non-TCM visits. Among patients with non-TCM follow-up visits, those seen by a provider who frequently used TCM visits had decreased odds (OR = 0.84 [0.71–0.99]) of 30-day readmission compared to those seen by providers who did not use TCM visits regularly. Among patients who followed up with providers who frequently use TCM visits, TCM visits were associated with decreased 30-day readmission compared to patients with non-TCM visits (OR = 0.78 [0.62–0.98]). The study has limitations, including the health system database not capturing all out-of-network follow-up visits. The reduction in 30-day readmission associated with TCM visits likely arises from both the visit itself and being seen by a provider who frequently uses TCM visits.
Genome-wide association studies in lettuce reveal the interplay of seed age, color, and germination under high temperatures
Abstract Thermoinhibition, the suppression of seed germination by high temperatures, is an adaptive trait that ensures successful seedling establishment in natural environments. While beneficial for wild plants, thermoinhibition can adversely affect crop yields due to uneven and reduced germination rates, particularly in the face of climate change. To understand the genetic basis of thermoinhibition, we conducted a comprehensive genetic analysis of a diverse panel of Lactuca spp. accessions. Our findings revealed that L. serriola , a wild ancestor of cultivated lettuce, showed relaxed thermoinhibition response compared to cultivated lettuce, suggesting that this trait may have been positively selected during early domestication in the Mediterranean region with hot, dry summers. Additionally, we found that thermoinhibition intensified with seed age but was less pronounced in dark-colored seeds, which showed increased germination under high temperatures. Genome-wide association studies identified genomic regions associated with thermoinhibition, including genes involved in ethylene and ABA signaling. Interestingly, some of these regions were also linked to seed color, suggesting a potential genetic coupling between black seed color and reduced thermoinhibition. These results highlighted the complex interplay between thermoinhibition, seed color, and domestication in lettuce, indicating a complicated nature of thermoinhibition regulation. By elucidating the genetic architecture of thermoinhibition, our study provides a valuable foundation for breeding strategies to enhance lettuce resilience to climate change.
Quantum-limited stochastic optical neural networks operating at a few quanta per activation
Abstract Energy efficiency in computation is ultimately limited by noise, with quantum limits setting the fundamental noise floor. Analog physical neural networks hold promise for improved energy efficiency compared to digital electronic neural networks. However, they are typically operated in a relatively high-power regime so that the signal-to-noise ratio (SNR) is large (>10), and the noise can be treated as a perturbation. We study optical neural networks where all layers except the last are operated in the limit that each neuron can be activated by just a single photon, and as a result the noise on neuron activations is no longer merely perturbative. We show that by using a physics-based probabilistic model of the neuron activations in training, it is possible to perform accurate machine-learning inference in spite of the extremely high shot noise (SNR ~ 1). We experimentally demonstrated MNIST handwritten-digit classification with a test accuracy of 98% using an optical neural network with a hidden layer operating in the single-photon regime; the optical energy used to perform the classification corresponds to just 0.038 photons per multiply-accumulate (MAC) operation. Our physics-aware stochastic training approach might also prove useful with non-optical ultra-low-power hardware.
A NOTCH3 pathogenic variant influences osteogenesis and can be targeted by antisense oligonucleotides in induced pluripotent stem cells
Lateral Meningocele Syndrome (LMS), a disorder associated with NOTCH3 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia that is ameliorated by the administration of Notch3 antisense oligonucleotides (ASO) targeting either Notch3 or the Notch3 mutation. To determine the consequences of LMS pathogenic variants in human cells and whether they can be targeted by ASOs, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH36692-93insC insertion were created. Parental iPSCs, NOTCH36692-93insC and isogenic controls, free of chromosomal aberrations as determined by human CytoSNP850 array, were cultured under conditions of neural crest, mesenchymal and osteogenic cell differentiation. The expected cell phenotype was confirmed by surface markers and a decline in OCT3/4 and NANOG mRNA. NOTCH36692-93insC cells displayed enhanced expression of Notch target genes HES1, HEY1, 2 and L demonstrating a NOTCH3 gain-of-function. There was enhanced osteogenesis in NOTCH36692-93insC cells as evidenced by increased mineralized nodule formation and ALPL, BGLAP and BSP expression. ASOs targeting NOTCH3 decreased both NOTCH3 wild type and NOTCH36692-93insC mutant mRNA by 40% in mesenchymal and 90% in osteogenic cells. ASOs targeting the NOTCH3 insertion decreased NOTCH36692-93insC by 70–80% in mesenchymal cells and by 45–55% in osteogenic cells and NOTCH3 mRNA by 15–30% and 20–40%, respectively. In conclusion, a NOTCH3 pathogenic variant causes a modest increase in osteoblastogenesis in human iPS cells in vitro and NOTCH3 and NOTCH3 mutant specific ASOs downregulate NOTCH3 transcripts associated with LMS.
Flow prediction in sound-based uroflowmetry
Genomic and phenotypic stability of fusion-driven pediatric sarcoma cell lines
AbstractHuman cancer cell lines are the mainstay of cancer research. Recent reports showed that highly mutated adult carcinoma cell lines (mainly HeLa and MCF-7) present striking diversity across laboratories and that long-term continuous culturing results in genomic/transcriptomic heterogeneity with strong phenotypical implications. Here, we hypothesize that oligomutated pediatric sarcoma cell lines mainly driven by a fusion transcription factor, such as Ewing sarcoma (EwS), are genetically and phenotypically more stable than the previously investigated adult carcinoma cell lines. A comprehensive molecular and phenotypic characterization of multiple EwS cell line strains, together with a simultaneous analysis during 12 months of continuous cell culture show that fusion-driven pediatric sarcoma cell line strains are genomically more stable than adult carcinoma strains, display remarkably stable and homogenous transcriptomes, and exhibit uniform and stable drug response. Additionally, the analysis of multiple EwS cell lines subjected to long-term continuous culture reveals that variable degrees of genomic/transcriptomic/phenotypic changes among fusion-driven cell lines, further exemplifying that the potential for reproducibility of in vitro scientific results may be rather understood as a spectrum, even within the same tumor entity.
Study of distribution and morphological characteristics of the trabecular bone in the uncinate process of the cervical spine using micro-computed tomography
The cervical uncinate process is a unique structure of the cervical spine that undergoes significant changes in its morphological characteristics with age, and these changes may be related to osteoporosis. This study aimed to observe the distribution of cancellous bone in the cervical uncinate process and its morphological features using micro-computed tomography (Micro-CT) to gain a deeper understanding of the morphological characteristics of the uncinate microstructure. We performed Micro-CT scans on 31 sets of C3-C7 vertebrae, a total of 155 intact bone samples, and subsequently used the measurement software with the Micro-CT system to obtain parameters related to the cancellous bone of the uncinate process. We found that the cancellous bone of the uncinate process was predominantly longitudinally cross-aligned and continuous with the cancellous bone within the vertebral body. Comparisons between the left and right sides of each parameter showed significant differences only in the bone surface area, and the peaks of each parameter were primarily concentrated in C4-C6. In this study, we found that the C5 uncinate process is the site of most significant stress in the cervical vertebrae, which leads to the earliest occurrence of osteoporosis, and this study provides experimental, theoretical bases for the prevention of cervical spondylosis and osteoporosis, and the diagnosis and treatment of related diseases.
Viral nucleic acid load in the milk of lactating mothers with COVID-19 and the prognosis of infants
Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)
Recovery time and predictors of severe acute malnutrition in children aged 6–59 months via an outpatient therapeutic program in Borena zone: A prospective cohort study
Background Severe acute malnutrition (SAM) is a severe condition causing bilateral pitting edema or signs of wasting in children, with a high mortality risk. An outpatient therapeutic program is recommended for managing SAM children without complications, but there is limited information on recovery time and its determinants. Objective This study aims to assess the time to recovery and its predictors among children aged 6–59 months with SAM admitted to the Outpatient therapeutic program in the Borena zone, Oromia region, Southern Ethiopia in 2023. Methods A prospective follow-up study was carried out from March 1–30, 2023, on 322 children aged 6–59 months in health facilities in the Borena zone. After being collected using a structured questionnaire, the data was imported into Epi Data Manager version 3.1 and exported to SPSS version 26 for analysis. Model fitness was assessed using the log rank test, and time-to-recovery from SAM was found to be predicted by Cox regression analysis. Lastly, the study used the Adjusted Hazard Ratio with a p-value < 0.05 and a 95% confidence interval to describe the connection. Results The median duration for recovery was found to be 42 days with an interquartile range of 35 to 49. Children who received Amoxicillin had a four-times higher recovery rate (AHR = 4.09; 95% CI: 2.75, 6.07). The presence of diarrhea prolonged the recovery time by 53.0% (AHR = 0.47; 95% CI: 0.36, 0.62), while vomiting prolonged the recovery time by 58.0% (AHR = 0.42; 95% CI: 0.32, 0.55). Edema reduced the chances of recovery by 48% (AHR = 0.52; 95% CI: 0.36, 0.62). Conclusion The study found that recovery time for children with severe acute malnutrition is consistent with prior research. Key factors influencing recovery duration include the prompt administration of Amoxicillin upon admission and the presence of symptoms like diarrhea, vomiting, and edema. The findings emphasize the critical role of specific symptoms in predicting recovery times for children with SAM. By understanding these relationships, healthcare providers can enhance treatment strategies, improve resource management, and ultimately contribute to better health outcomes for affected children.