scPlantDB: a comprehensive database for exploring cell types and markers of plant cell atlases.

Recent advancements in single-cell RNA sequencing (scRNA-seq) technology have enabled the comprehensive profiling of gene expression patterns at the single-cell level, offering unprecedented insights into cellular diversity and heterogeneity within plant tissues. In this study, we present a systematic approach to construct a plant single-cell database, scPlantDB, which is publicly available at https://biobigdata.nju.edu.cn/scplantdb. We integrated single-cell transcriptomic profiles from 67 high-quality datasets across 17 plant species, comprising approximately 2.5 million cells. The data underwent rigorous collection, manual curation, strict quality control and standardized processing from public databases. scPlantDB offers interactive visualization of gene expression at the single-cell level, facilitating the exploration of both single-dataset and multiple-dataset analyses. It enables systematic comparison and functional annotation of markers across diverse cell types and species while providing tools to identify and compare cell types based on these markers. In summary, scPlantDB serves as a comprehensive database for investigating cell types and markers within plant cell atlases. It is a valuable resource for the plant research community.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this meta-analysis is to assess the effect of dexmedetomidine on delirium in elderly surgical patients. DATA SOURCES: The Cochrane Library, Web of Science, PubMed, EMBASE, and Google Scholar were searched (January 1, 2000, to February 4, 2020) for randomized controlled trials (RCTs). STUDY SELECTION AND DATA EXTRACTION: RCTs without language restrictions were included if delirium incidence was assessed in elderly surgical patients receiving dexmedetomidine. Intervention and basic information were extracted. DATA SYNTHESIS: 21 studies were included. Dexmedetomidine reduced delirium occurrence (risk ratio [RR] = 0.55; 95% CI = 0.45 to 0.67) in elderly surgical patients with sufficient evidence from trial sequential analysis. Dexmedetomidine did not prevent delirium incidence for cardiac surgery (RR = 0.71; 95% CI = 0.44 to 1.15) with insufficient evidence. Dexmedetomidine decreased mortality incidence (RR = 0.47; 95% CI = 0.25 to 0.89), shortened the length of intensive care unit (ICU; standard mean difference [SMD] = -0.46) and hospital stays (SMD = -0.41), and increased bradycardia incidence (RR = 1.60). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review revealed that dexmedetomidine could reduce delirium incidence for elderly noncardiac surgical patients, and the effect of dexmedetomidine on delirium for elderly cardiac surgical patients needs further studies to guide clinicians. CONCLUSION: Dexmedetomidine reduced delirium incidence in elderly surgical patients. The efficacy of dexmedetomidine on delirium for elderly cardiac surgical patients warrants further studies. Furthermore, dexmedetomidine was associated with an increased bradycardia incidence, shorter length of ICU/hospital stays, and a lower incidence of mortality.

Transcriptional profiling of single fiber cells in a transgenic paradigm of an inherited childhood cataract reveals absence of molecular heterogeneity.

Our recent single-cell transcriptomic analysis has demonstrated that heterogeneous transcriptional activity attends molecular transition from the nascent to terminally differentiated fiber cells in the developing mouse lens. To understand the role of transcriptional heterogeneity in terminal differentiation and the functional phenotype (transparency) of this tissue, here we present a single-cell analysis of the developing lens, in a transgenic paradigm of an inherited pathology, known as the lamellar cataract. Cataracts hinder transmission of light into the eye. Lamellar cataract is the most prevalent bilateral childhood cataract. In this disease of early infancy, initially, the opacities remain confined to a few fiber cells, thus presenting an opportunity to investigate early molecular events that lead to cataractogenesis. We used a previously established paradigm that faithfully recapitulates this disease in transgenic mice. About 500 single fiber cells, manually isolated from a 2-day-old transgenic lens were interrogated individually for the expression of all known 17 crystallins and 78 other relevant genes using a Biomark HD (Fluidigm). We find that fiber cells from spatially and developmentally discrete regions of the transgenic (cataract) lens show remarkable absence of the heterogeneity of gene expression. Importantly, the molecular variability of cortical fiber cells, the hallmark of the WT lens, is absent in the transgenic cataract, suggesting absence of specific cell-type(s). Interestingly, we find a repetitive pattern of gene activity in progressive states of differentiation in the transgenic lens. This molecular dysfunction portends pathology much before the physical manifestations of the disease.

Effect of State Immunization Information System Based Reminder/Recall for Influenza Vaccinations: A Randomized Trial of Autodialer, Text, and Mailed Messages.

OBJECTIVE: To evaluate the effect of different modalities of centralized reminder/recall (autodialer, text, mailed reminders) on increasing childhood influenza vaccination. STUDY DESIGN: Two simultaneous randomized clinical trials conducted from October 2017 to April 1, 2018, in New York State and Colorado. There were 61 931 children in New York (136 practices) and 23 845 children in Colorado (42 practices) who were randomized to different centralized reminder/recall modalities-4 arms in New York (autodialer, text, mailed, and no reminder control) and 3 arms in Colorado (autodialer, mailed, and no reminder control). The message content was similar across modalities. Up to 3 reminders were sent for intervention arms. The main outcome measure was receipt of ≥1 influenza vaccine. RESULTS: In New York, compared with the control arm (26.6%), postintervention influenza vaccination rates in the autodialer arm (28.0%) were 1.4 percentage points higher (adjusted risk ratio, 1.06; 95% CI, 1.02-1.10), but the rates for text (27.6%) and mail (26.8%) arms were not different from controls. In Colorado, compared with the control arm (29.9%), postintervention influenza vaccination rates for the autodialer (32.9%) and mail (31.5%) arms were 3.0 percentage points (adjusted risk ratio, 1.08; 95% CI, 1.03-1.12) and 1.6 percentage points (adjusted risk ratio, 1.06; 95% CI, 1.02-1.10) higher, respectively. Compared with the control arm, the incremental cost per additional vaccine delivered was $20 (New York) and $16 (Colorado) for autodialer messages. CONCLUSIONS: Centralized reminder/recall for childhood influenza vaccine was most effective via autodialer, less effective via mail, and not effective via text messages. The impact of each modality was modest. Compared with no reminders, the incremental cost per additional vaccine delivered was also modest for autodialer messages. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03294473 and NCT03246100.

How Well is the Medical Home Working for Latino and Black Children?

Objective To examine the benefits of having a medical home among Latino and Black school-aged children, both with and without special health care needs (CSHCN). Methods Data from the 2011-2012 National Survey of Children's Health (NSCH) were analyzed to examine the associations of preventive dental and medical care, unmet dental or medical care, or missed school days with having a medical home among Latino and Black children compared to White children. Multivariate logistic regression with survey weights was used to adjust for child, parent, home, and geographic characteristics and an interaction term to estimate differences in outcomes among Black or Latino children receiving care in a medical home compared to White children with a medical home. Results Approximately 35% of Latino CSHCN and Latino non-CSHCN ages 6-17 years of age had a medical home. In the adjusted model comparing the effectiveness of the medical home by race and ethnicity, Latino non-CSHCN compared to White non-CSHCN were associated with lower odds of having one or more preventive dental visit in the last 12 months (OR 0.66; 95% CI 0.46-0.95) and no other associations between having a medical home and outcomes were found among Latinos compared to Whites regardless of non-CSHCN or CHSCN status. Meanwhile, having a medical home among Black non-CHSCN and CHSCN, compared to their White counterparts, showed potential benefits in regards to unmet medical care needs after adjusting for covariates, (OR 0.15; 95% CI 0.06-0.35; OR 0.16; 95% CI 0.05-0.55). Conclusions Medical homes may not be effective in delivering health services to the majority of Latino children but provide some benefit to Black children with and without CSHCN. Alternatively, the medical home may function differently for Latinos due to the specific medical home components measured by NSCH.

Trends in Cervical Cancer Screening in California's Family Planning Program.

OBJECTIVE: Guidelines recommend 3-year cervical cancer screening intervals to avoid unnecessary invasive procedures; however, regular testing remains critical. We evaluated trends in cervical cancer screening among low-income women receiving family planning-related services and their association with patient and provider characteristics. MATERIALS AND METHODS: Using claims and enrollment data from California's publicly funded family planning program, we identified 540,026 women with a clinician visit at 216 sites between 2011 and 2015. We calculated guideline adherent cervical cancer testing rates for 6-month periods among women aged 21 to 24, 25 to 29, and 30 to 64 years. We also calculated guideline adherent chlamydia testing for women aged 21 to 24 years. RESULTS: Having a 3-year cervical cancer screening test declined for all age groups. The odds of cervical cancer screening declined for women aged 21 to 24 years by an estimated 11% every 6 months (odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.89-0.90), a significantly greater decline than for the other age groups. Among women aged 21 to 29 years, the decrease was significantly larger for Latina (ratio of ORs = 0.95, 95% CI = 0.95-0.96) and Spanish-speaking (ratio of ORs = 0.95, 95% CI = 0.95-0.96) women compared with non-Latina and non-Spanish-speaking women. A smaller decline was seen for chlamydia screening. CONCLUSIONS: Changes in screening interval guidelines are associated with overall decreased screening. This trend was strongest among women aged 21 to 24 years, even as they continued to be screened appropriately for chlamydia, suggesting many missed opportunities. Efforts to reduce unnecessary cervical cancer screening should be monitored to maintain appropriate screening rates to avoid advanced-stage diagnoses and higher health care costs.

Validity of Forced Eyelid Closure Test: A Novel Clinical Screening Test for Ocular Myasthenia Gravis.

BACKGROUND: Forced eyelid closure test (FECT) is a clinical screening test developed from the original Cogan lid twitch (CLT) sign to assist in the diagnosis of ocular myasthenia gravis (OMG), We evaluated the sensitivity and specificity of FECT compared with CLT and benchmarked to standard diagnostic tests. METHODS: This study was a retrospective chart review of 48 patients using electronic medical records of those that presented with ptosis and/or diplopia at Doheny Eye Institute, University of California, Los Angeles between February 2015 and April 2016. Patients without FECT testing were excluded. FECT and CLT results, and final diagnosis were recorded. To perform FECT, the patient was asked to squeeze his or her eyelids shut for 5-10 seconds then open quickly and fixate in primary position. The excessive upward overshoot of eyelids movement indicated a positive FECT. The test was performed by a neuro-ophthalmologist before establishing the diagnosis. Patients who had equivocal test results and/or inconclusive final diagnosis were excluded. RESULTS: Of the 48 patients studied, 18 patients (37.5%) had positive FECT; 15 of whom had a final diagnosis of OMG (83.3%). Of the 30 patients with negative FECT, 1 had OMG (3.3%). Of the 48 patients, 35 patients also had a documented CLT result (72.9%). CLT was positive in 11 of these 35 patients (31.4%), and 9 of these 11 had OMG (81.8%). Of the 24 patients with negative CLT, 2 of them had OMG (8.3%). Sensitivity and specificity of FECT were 94% and 91% (joint 95% confidence region: sensitivity × specificity = [0.70, 1] × [0.75, 1]). The relative true-positive fraction (rTPF) between FECT and CLT was 1.15; the relative false-positive fraction was 1.31. CONCLUSIONS: FECT is a simple clinical screening test with good sensitivity and specificity for OMG.

Comprehensive integration of single-cell transcriptomic data illuminates the regulatory network architecture of plant cell fate specification.

Plant morphogenesis relies on precise gene expression programs at the proper time and position which is orchestrated by transcription factors (TFs) in intricate regulatory networks in a cell-type specific manner. Here we introduced a comprehensive single-cell transcriptomic atlas of Arabidopsis seedlings. This atlas is the result of meticulous integration of 63 previously published scRNA-seq datasets, addressing batch effects and conserving biological variance. This integration spans a broad spectrum of tissues, including both below- and above-ground parts. Utilizing a rigorous approach for cell type annotation, we identified 47 distinct cell types or states, largely expanding our current view of plant cell compositions. We systematically constructed cell-type specific gene regulatory networks and uncovered key regulators that act in a coordinated manner to control cell-type specific gene expression. Taken together, our study not only offers extensive plant cell atlas exploration that serves as a valuable resource, but also provides molecular insights into gene-regulatory programs that varies from different cell types.

Single-cell transcriptome analysis dissects lncRNA-associated gene networks in Arabidopsis.

The plant genome produces an extremely large collection of long noncoding RNAs (lncRNAs) that are generally expressed in a context-specific manner and have pivotal roles in regulation of diverse biological processes. Here, we mapped the transcriptional heterogeneity of lncRNAs and their associated gene regulatory networks at single-cell resolution. We generated a comprehensive cell atlas at the whole-organism level by integrative analysis of 28 published single-cell RNA sequencing (scRNA-seq) datasets from juvenile Arabidopsis seedlings. We then provided an in-depth analysis of cell-type-related lncRNA signatures that show expression patterns consistent with canonical protein-coding gene markers. We further demonstrated that the cell-type-specific expression of lncRNAs largely explains their tissue specificity. In addition, we predicted gene regulatory networks on the basis of motif enrichment and co-expression analysis of lncRNAs and mRNAs, and we identified putative transcription factors orchestrating cell-type-specific expression of lncRNAs. The analysis results are available at the single-cell-based plant lncRNA atlas database (scPLAD; https://biobigdata.nju.edu.cn/scPLAD/). Overall, this work demonstrates the power of integrative single-cell data analysis applied to plant lncRNA biology and provides fundamental insights into lncRNA expression specificity and associated gene regulation.

Asymptomatic Gouty Tophi in Thyroid Cartilage: A Case Report and Literature Review.

Gouty tophi is a disease characterized by the long-term deposition of monosodium urate crystals in joints or cartilages. The most commonly affected site is the first metatarsophalangeal joint, and gouty tophi in the head and neck region are relatively rare. This article reports a case involving an elderly male with asymptomatic gouty tophi in the thyroid cartilage. The patient had a history of gout for over 10 years and presented with a painless thyroid mass that had been present for at least 3 years. He had not received systemic treatment. Preoperative contrast-enhanced cervical CT results indicated a high likelihood of gouty tophi. Postoperative pathology confirmed the mass to be consistent with gouty nodules. Following the procedure, the patient was treated symptomatically with non-busulfan tablets and colchicine. No recurrence was observed at the 1-year follow-up. This report highlights the need to consider gouty tophi in cases of prolonged gout history and abnormal imaging findings in the head and neck region. Appropriate management, including urate-lowering therapy and surgery, if necessary, can lead to optimal outcomes and prevent recurrences. Further research is warranted to enhance understanding and clinical management of this uncommon regional manifestation of gout.

cisDynet: An integrated platform for modeling gene-regulatory dynamics and networks.

Chromatin accessibility sequencing has been widely used for uncovering genetic regulatory mechanisms and inferring gene regulatory networks. However, effectively integrating large-scale chromatin accessibility datasets has posed a significant challenge. This is due to the lack of a comprehensive end-to-end solution, as many existing tools primarily emphasize data preprocessing and overlook downstream analyses. To bridge this gap, we have introduced cisDynet, a holistic solution that combines streamlined data preprocessing using Snakemake and R functions with advanced downstream analysis capabilities. cisDynet excels in conventional data analyses, encompassing peak statistics, peak annotation, differential analysis, motif enrichment analysis, and more. Additionally, it allows to perform sophisticated data exploration, such as tissue-specific peak identification, time course data modeling, integration of RNA-seq data to establish peak-to-gene associations, constructing regulatory networks, and conducting enrichment analysis of genome-wide association study (GWAS) variants. As a proof of concept, we applied cisDynet to reanalyze comprehensive ATAC-seq datasets across various tissues from the Encyclopedia of DNA Elements (ENCODE) project. The analysis successfully delineated tissue-specific open chromatin regions (OCRs), established connections between OCRs and target genes, and effectively linked these discoveries with 1861 GWAS variants. Furthermore, cisDynet was instrumental in dissecting the time course open chromatin data of mouse embryonic development, revealing the dynamic behavior of OCRs over developmental stages and identifying key transcription factors governing differentiation trajectories. In summary, cisDynet offers researchers a user-friendly solution that minimizes the need for extensive coding, ensures the reproducibility of results, and greatly simplifies the exploration of epigenomic data.

Initiation of Continuous Glucose Monitoring Is Linked to Improved Glycemic Control and Fewer Clinical Events in Type 1 and Type 2 Diabetes in the Veterans Health Administration.

OBJECTIVE: To determine the benefit of starting continuous glucose monitoring (CGM) in adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) with regard to longer-term glucose control and serious clinical events. RESEARCH DESIGN AND METHODS: A retrospective observational cohort study within the Veterans Affairs Health Care System was used to compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization between propensity score overlap weighted initiators of CGM and nonusers over 12 months. RESULTS: CGM users receiving insulin (n = 5,015 with T1D and n = 15,706 with T2D) and similar numbers of nonusers were identified from 1 January 2015 to 31 December 2020. Declines in HbA1c were significantly greater in CGM users with T1D (-0.26%; 95% CI -0.33, -0.19%) and T2D (-0.35%; 95% CI -0.40, -0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c <8 and <9% after 12 months were greater in CGM users. In T1D, CGM initiation was associated with significantly reduced risk of hypoglycemia (hazard ratio [HR] 0.69; 95% CI 0.48, 0.98) and all-cause hospitalization (HR 0.75; 95% CI 0.63, 0.90). In patients with T2D, there was a reduction in risk of hyperglycemia in CGM users (HR 0.87; 95% CI 0.77, 0.99) and all-cause hospitalization (HR 0.89; 95% CI 0.83, 0.97). Several subgroups (based on baseline age, HbA1c, hypoglycemic risk, or follow-up CGM use) had even greater responses. CONCLUSIONS: In a large national cohort, initiation of CGM was associated with sustained improvement in HbA1c in patients with later-onset T1D and patients with T2D using insulin. This was accompanied by a clear pattern of reduced risk of admission to an emergency room or hospital for hypoglycemia or hyperglycemia and of all-cause hospitalization.

Review of recent advances in frequency-domain near-infrared spectroscopy technologies [Invited].

Over the past several decades, near-infrared spectroscopy (NIRS) has become a popular research and clinical tool for non-invasively measuring the oxygenation of biological tissues, with particular emphasis on applications to the human brain. In most cases, NIRS studies are performed using continuous-wave NIRS (CW-NIRS), which can only provide information on relative changes in chromophore concentrations, such as oxygenated and deoxygenated hemoglobin, as well as estimates of tissue oxygen saturation. Another type of NIRS known as frequency-domain NIRS (FD-NIRS) has significant advantages: it can directly measure optical pathlength and thus quantify the scattering and absorption coefficients of sampled tissues and provide direct measurements of absolute chromophore concentrations. This review describes the current status of FD-NIRS technologies, their performance, their advantages, and their limitations as compared to other NIRS methods. Significant landmarks of technological progress include the development of both benchtop and portable/wearable FD-NIRS technologies, sensitive front-end photonic components, and high-frequency phase measurements. Clinical applications of FD-NIRS technologies are discussed to provide context on current applications and needed areas of improvement. The review concludes by providing a roadmap toward the next generation of fully wearable, low-cost FD-NIRS systems.

scPlant: A versatile framework for single-cell transcriptomic data analysis in plants.

Single-cell transcriptomics has been fully embraced in plant biological research and is revolutionizing our understanding of plant growth, development, and responses to external stimuli. However, single-cell transcriptomic data analysis in plants is not trivial, given that there is currently no end-to-end solution and that integration of various bioinformatics tools involves a large number of required dependencies. Here, we present scPlant, a versatile framework for exploring plant single-cell atlases with minimum input data provided by users. The scPlant pipeline is implemented with numerous functions for diverse analytical tasks, ranging from basic data processing to advanced demands such as cell-type annotation and deconvolution, trajectory inference, cross-species data integration, and cell-type-specific gene regulatory network construction. In addition, a variety of visualization tools are bundled in a built-in Shiny application, enabling exploration of single-cell transcriptomic data on the fly.

fNIRS-EEG BCIs for Motor Rehabilitation: A Review.

Motor impairment has a profound impact on a significant number of individuals, leading to a substantial demand for rehabilitation services. Through brain-computer interfaces (BCIs), people with severe motor disabilities could have improved communication with others and control appropriately designed robotic prosthetics, so as to (at least partially) restore their motor abilities. BCI plays a pivotal role in promoting smoother communication and interactions between individuals with motor impairments and others. Moreover, they enable the direct control of assistive devices through brain signals. In particular, their most significant potential lies in the realm of motor rehabilitation, where BCIs can offer real-time feedback to assist users in their training and continuously monitor the brain's state throughout the entire rehabilitation process. Hybridization of different brain-sensing modalities, especially functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), has shown great potential in the creation of BCIs for rehabilitating the motor-impaired populations. EEG, as a well-established methodology, can be combined with fNIRS to compensate for the inherent disadvantages and achieve higher temporal and spatial resolution. This paper reviews the recent works in hybrid fNIRS-EEG BCIs for motor rehabilitation, emphasizing the methodologies that utilized motor imagery. An overview of the BCI system and its key components was introduced, followed by an introduction to various devices, strengths and weaknesses of different signal processing techniques, and applications in neuroscience and clinical contexts. The review concludes by discussing the possible challenges and opportunities for future development.

GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown activity in treating relapsed or refractory multiple myeloma; however, relapse is still common, and new targets are needed. We aimed to assess the activity and safety profile of G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. METHODS: POLARIS was a first-in-human, single-centre, single-arm, phase 1 trial of GPRC5D-targeted CAR T cells (OriCAR-017) done at the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Eligible patients were adults aged 18-75 years with a diagnosis of relapsed or refractory multiple myeloma and an ECOG performance status of 0-2, had GPRC5D expression in bone marrow plasma cells greater than 20% or were positive for GPRC5D by immunohistochemistry, and had received at least three previous lines of treatment including proteasome inhibitors, immunomodulatory drugs, and chemotherapy. Patients were consecutively assigned to receive a single dose of intravenous OriCAR-017 at 1 × 106 CAR T cells per kg, 3 × 106 CAR T cells per kg, or 6 × 106 CAR T cells per kg in the dose-escalation phase. In the expansion phase, patients received the recommended phase 2 dose. Recruitment to the expansion phase terminated early due to the COVID-19 pandemic on May 1, 2022. The primary endpoints were safety, the maximum tolerated dose and the recommended phase 2 dose. Safety and activity analyses included all patients who received OriCAR-017. This trial is registered with ClinicalTrials.gov, NCT05016778. This trial has been completed and is entering long-term follow-up. FINDINGS: Between June 9, 2021, and Feb 28, 2022, we recruited 13 patients for inclusion into the study. One patient was excluded because of GPRC5D negativity and two patients discontinued after apheresis because of rapid progression. Nine patients were assigned to the dose escalation phase (three received 1 × 106 CAR T cells per kg, three received 3 × 106 CAR T cells per kg, and three received 6 × 106 CAR T cells per kg). The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 106 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. Five patients (50%) were female, five (50%) were male, and all were Chinese. Five patients (50%) were previously treated with BCMA-targeted CAR T-cell therapy. Median follow-up was 238 days (IQR 182-307). There were no serious adverse events and no treatment-related deaths. The most common grade 3 or worse adverse events were haematological, including neutropenia (ten [100%] of ten patients), thrombocytopenia (nine [90%]), leukopenia (nine [90%]), and anaemia (seven [70%]). All patients had cytokine release syndrome (nine [90%] grade 1 and one [10%] grade 2). No neurological toxic effects were reported. Ten (100%) of ten patients had an overall response, of whom six (60%) had a stringent complete response and four (40%) had very good partial response. Two patients discontinued due to disease progression (one GPRC5D-positive patient in the middle-dose group and one GPRC5D-negative patient in the low-dose group). INTERPRETATION: The results of this study suggest that GPRC5D is an active target for immunotherapy in multiple myeloma. GPRC5D-targeted CAR T-cell therapy is a promising treatment modality for patients with relapsed or refractory multiple myeloma and deserves further testing. FUNDING: OriCell Therapeutics.

A chromosome-level genome assembly provides insights into Cornus wilsoniana evolution, oil biosynthesis, and floral bud development.

Cornus wilsoniana W. is a woody oil plant with high oil content and strong hypolipidemic effects, making it a valuable species for medicinal, landscaping, and ecological purposes in China. To advance genetic research on this species, we employed PacBio together with Hi-C data to create a draft genome assembly for C. wilsoniana. Based on an 11-chromosome anchored chromosome-level assembly, the estimated genome size was determined to be 843.51 Mb. The N50 contig size and N50 scaffold size were calculated to be 4.49 and 78.00 Mb, respectively. Furthermore, 30 474 protein-coding genes were annotated. Comparative genomics analysis revealed that C. wilsoniana diverged from its closest species ~12.46 million years ago (Mya). Furthermore, the divergence between Cornaceae and Nyssaceae occurred >62.22 Mya. We also found evidence of whole-genome duplication events and whole-genome triplication γ, occurring at ~44.90 and 115.86 Mya. We further inferred the origins of chromosomes, which sheds light on the complex evolutionary history of the karyotype of C. wilsoniana. Through transcriptional and metabolic analysis, we identified two FAD2 homologous genes that may play a crucial role in controlling the oleic to linoleic acid ratio. We further investigated the correlation between metabolites and genes and identified 33 MADS-TF homologous genes that may affect flower morphology in C. wilsoniana. Overall, this study lays the groundwork for future research aimed at identifying the genetic basis of crucial traits in C. wilsoniana.

Bag of little bootstraps for massive and distributed longitudinal data.

Linear mixed models are widely used for analyzing longitudinal datasets, and the inference for variance component parameters relies on the bootstrap method. However, health systems and technology companies routinely generate massive longitudinal datasets that make the traditional bootstrap method infeasible. To solve this problem, we extend the highly scalable bag of little bootstraps method for independent data to longitudinal data and develop a highly efficient Julia package MixedModelsBLB.jl. Simulation experiments and real data analysis demonstrate the favorable statistical performance and computational advantages of our method compared to the traditional bootstrap method. For the statistical inference of variance components, it achieves 200 times speedup on the scale of 1 million subjects (20 million total observations), and is the only currently available tool that can handle more than 10 million subjects (200 million total observations) using desktop computers.

Systematic annotation of conservation states provides insights into regulatory regions in rice.

Plant genomes contain a large fraction of noncoding sequences. The discovery and annotation of conserved noncoding sequences (CNSs) in plants is an ongoing challenge. Here we report the application of comparative genomics to systematically identify CNSs in 50 well-annotated Gramineae genomes using rice (Oryza sativa) as the reference. We conduct multiple-way whole-genome alignments to the rice genome. The rice genome is annotated as 20 conservation states (CSs) at single-nucleotide resolution using a multivariate hidden Markov model (ConsHMM) based on the multiple-genome alignments. Different states show distinct enrichments for various genomic features, and the conservation scores of CSs are highly correlated with the level of associated chromatin accessibility. We find that at least 33.5% of the rice genome is highly under selection, with more than 70% of the sequence lying outside of coding regions. A catalog of 855,366 regulatory CNSs is generated, and they significantly overlapped with putative active regulatory elements such as promoters, enhancers, and transcription factor binding sites. Collectively, our study provides a resource for elucidating functional noncoding regions of the rice genome and an evolutionary aspect of regulatory sequences in higher plants.