Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells.

Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most types, the cells mapping to a t-type exhibit consistent electrophysiological and morphological properties. These properties display both discrete and continuous variation among t-types. Through multimodal integrated analysis, we define 28 met-types that have congruent morphological, electrophysiological, and transcriptomic properties and robust mutual predictability. We identify layer-specific axon innervation pattern as a defining feature distinguishing different met-types. These met-types represent a unified definition of cortical GABAergic interneuron types, providing a systematic framework to capture existing knowledge and bridge future analyses across different modalities.

A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality.

Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

Reteplase versus Alteplase for Acute Ischemic Stroke.

BACKGROUND: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. METHODS: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. RESULTS: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). CONCLUSIONS: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).

Human neocortical expansion involves glutamatergic neuron diversification.

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease.

Compulsive drug-taking is associated with habenula-frontal cortex connectivity.

As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.

Effect of Acupuncture for Methadone Reduction : A Randomized Clinical Trial.

BACKGROUND: Methadone maintenance treatment (MMT) is effective for managing opioid use disorder, but adverse effects mean that optimal therapy occurs with the lowest dose that controls opioid craving. OBJECTIVE: To assess the efficacy of acupuncture versus sham acupuncture on methadone dose reduction. DESIGN: Multicenter, 2-group, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR2200058123). SETTING: 6 MMT clinics in China. PARTICIPANTS: Adults aged 65 years or younger with opioid use disorder who attended clinic daily and had been using MMT for at least 6 weeks. INTERVENTION: Acupuncture or sham acupuncture 3 times a week for 8 weeks. MEASUREMENTS: The 2 primary outcomes were the proportion of participants who achieved a reduction in methadone dose of 20% or more compared with baseline and opioid craving, which was measured by the change from baseline on a 100-mm visual analogue scale (VAS). RESULTS: Of 118 eligible participants, 60 were randomly assigned to acupuncture and 58 were randomly assigned to sham acupuncture (2 did not receive acupuncture). At week 8, more patients reduced their methadone dose 20% or more with acupuncture than with sham acupuncture (37 [62%] vs. 16 [29%]; risk difference, 32% [97.5% CI, 13% to 52%]; P < 0.001). In addition, acupuncture was more effective in decreasing opioid craving than sham acupuncture with a mean difference of -11.7 mm VAS (CI, -18.7 to -4.8 mm; P < 0.001). No serious adverse events occurred. There were no notable differences between study groups when participants were asked which type of acupuncture they received. LIMITATION: Fixed acupuncture protocol limited personalization and only 12 weeks of follow-up after stopping acupuncture. CONCLUSION: Eight weeks of acupuncture were superior to sham acupuncture in reducing methadone dose and decreasing opioid craving. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China.

B-type natriuretic peptide levels predict long-term mortality in a large cohort of adults with congenital heart disease.

BACKGROUND AND AIMS: Many adult patients with congenital heart disease (ACHD) are still afflicted by premature death. Previous reports suggested natriuretic peptides may identify ACHD patients with adverse outcome. The study investigated prognostic power of B-type natriuretic peptide (BNP) across the spectrum of ACHD in a large contemporary cohort. METHODS: The cohort included 3392 consecutive ACHD patients under long-term follow-up at a tertiary ACHD centre between 2006 and 2019. The primary study endpoint was all-cause mortality. RESULTS: A total of 11 974 BNP measurements were analysed. The median BNP at baseline was 47 (24-107) ng/L. During a median follow-up of 8.6 years (29 115 patient-years), 615 (18.1%) patients died. On univariable and multivariable analysis, baseline BNP [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.15-1.18 and HR 1.13, 95% CI 1.08-1.18, respectively] and temporal changes in BNP levels (HR 1.22, 95% CI 1.19-1.26 and HR 1.19, 95% CI 1.12-1.26, respectively) were predictive of mortality (P < .001 for both) independently of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. Patients within the highest quartile of baseline BNP (>107 ng/L) and those within the highest quartile of temporal BNP change (>35 ng/L) had significantly increased risk of death (HR 5.8, 95% CI 4.91-6.79, P < .001, and HR 3.6, 95% CI 2.93-4.40, P < .001, respectively). CONCLUSIONS: Baseline BNP and temporal BNP changes are both significantly associated with all-cause mortality in ACHD independent of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. B-type natriuretic peptide levels represent an easy to obtain and inexpensive marker conveying prognostic information and should be used for the routine surveillance of patients with ACHD.

Maternal Outcomes Among Pregnant Women With Congenital Heart Disease-Associated Pulmonary Hypertension.

BACKGROUND: Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH. METHODS: Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectively from 2017 to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and moderate-to-severe PH. RESULTS: A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729 women, including 398 with mild PH (right ventricle to right atrium gradient 30-50 mm Hg) and 331 with moderate-to-severe PH (right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD-associated pulmonary arterial hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide >100 ng/L (odds ratio, 1.9 [95% CI, 1.0-3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6-5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2-0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3-0.7], P=0.001) were protective. CONCLUSIONS: Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may also help to mitigate the risk of adverse maternal cardiac events.

Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus.

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.

Artemisinin ameliorates cognitive decline by inhibiting hippocampal neuronal ferroptosis via Nrf2 activation in T2DM mice.

BACKGROUND: Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region. METHODS: STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe2+ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively. RESULTS: Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe2+, and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin. CONCLUSION: Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.

A structural variation in the promoter of the leucoanthocyanidin reductase gene AaLAR1 enhances freezing tolerance by modulating proanthocyanidin accumulation in kiwifruit (Actinidia arguta).

Proanthocyanidins (PAs) are important metabolites that enhance freezing tolerance of plants. Actinidia arguta, especially freezing-tolerant germplasms, accumulate abundant PAs in dormant shoots and thereby enhance freezing tolerance, but the underlying mechanism is unknown. In this study, we used two A. arguta with contrasting cold-resistant phenotypes, KL and RB, to explore the mechanisms in response to cold tolerance. We determined that a leucoanthocyanidin reductase gene (AaLAR1) was more highly expressed in freezing-tolerant KL than in freezing-sensitive RB. Moreover, overexpressing AaLAR1 in kiwifruit promoted PAs biosynthesis and enhanced cold tolerance. The AaLAR1 promoters of various A. arguta germplasms differ due to the presence of a 60-bp deletion in cold-tolerant genotypes that forms a functional binding site for MYC-type transcription factor. Yeast one-hybrid and two-hybrid, dual-luciferase reporter, bimolecular fluorescence complementation and coimmunoprecipitation assays indicated that the AaMYC2a binds to the MYC-core cis-element in the AaLAR1 promoter with the assistance of AaMYB5a, thereby promoting PAs accumulation in the shoots of cold-tolerant kiwifruit. We conclude that the variation in the AaLAR1 promoter and the AaMYC2a-AaMYB5a-AaLAR1 module shape freezing tolerance in A. arguta. The identification of a key structural variation in the AaLAR1 promoter offers a new target for resistance breeding of kiwifruit.

The Community Coevolution Model with Application to the Study of Evolutionary Relationships between Genes Based on Phylogenetic Profiles.

Organismal traits can evolve in a coordinated way, with correlated patterns of gains and losses reflecting important evolutionary associations. Discovering these associations can reveal important information about the functional and ecological linkages among traits. Phylogenetic profiles treat individual genes as traits distributed across sets of genomes and can provide a fine-grained view of the genetic underpinnings of evolutionary processes in a set of genomes. Phylogenetic profiling has been used to identify genes that are functionally linked and to identify common patterns of lateral gene transfer in microorganisms. However, comparative analysis of phylogenetic profiles and other trait distributions should take into account the phylogenetic relationships among the organisms under consideration. Here, we propose the Community Coevolution Model (CCM), a new coevolutionary model to analyze the evolutionary associations among traits, with a focus on phylogenetic profiles. In the CCM, traits are considered to evolve as a community with interactions, and the transition rate for each trait depends on the current states of other traits. Surpassing other comparative methods for pairwise trait analysis, CCM has the additional advantage of being able to examine multiple traits as a community to reveal more dependency relationships. We also develop a simulation procedure to generate phylogenetic profiles with correlated evolutionary patterns that can be used as benchmark data for evaluation purposes. A simulation study demonstrates that CCM is more accurate than other methods including the Jaccard Index and three tree-aware methods. The parameterization of CCM makes the interpretation of the relations between genes more direct, which leads to Darwin's scenario being identified easily based on the estimated parameters. We show that CCM is more efficient and fits real data better than other methods resulting in higher likelihood scores with fewer parameters. An examination of 3786 phylogenetic profiles across a set of 659 bacterial genomes highlights linkages between genes with common functions, including many patterns that would not have been identified under a nonphylogenetic model of common distribution. We also applied the CCM to 44 proteins in the well-studied Mitochondrial Respiratory Complex I and recovered associations that mapped well onto the structural associations that exist in the complex. [Coevolution; evolutionary rates; gene network; graphical models; phylogenetic profiles; phylogeny.].

Surf4 (Surfeit Locus Protein 4) Deficiency Reduces Intestinal Lipid Absorption and Secretion and Decreases Metabolism in Mice.

BACKGROUND: Postprandial dyslipidemia is a causative risk factor for cardiovascular disease. The majority of absorbed dietary lipids are packaged into chylomicron and then delivered to circulation. Previous studies showed that Surf4 (surfeit locus protein 4) mediates very low-density lipoprotein secretion from hepatocytes. Silencing hepatic Surf4 markedly reduces the development of atherosclerosis in different mouse models of atherosclerosis without causing hepatic steatosis. However, the role of Surf4 in chylomicron secretion is unknown. METHODS: We developed inducible intestinal-specific Surf4 knockdown mice (Surf4IKO) using Vil1Cre-ERT2 and Surf4flox mice. Metabolic cages were used to monitor mouse metabolism. Enzymatic kits were employed to measure serum and tissue lipid levels. The expression of target genes was detected by qRT-PCR and Western Blot. Transmission electron microscopy and radiolabeled oleic acid were used to assess the structure of enterocytes and intestinal lipid absorption and secretion, respectively. Proteomics was performed to determine changes in protein expression in serum and jejunum. RESULTS: Surf4IKO mice, especially male Surf4IKO mice, displayed significant body weight loss, increased mortality, and reduced metabolism. Surf4IKO mice exhibited lipid accumulation in enterocytes and impaired fat absorption and secretion. Lipid droplets and small lipid vacuoles were accumulated in the cytosol and the endoplasmic reticulum lumen of the enterocytes of Surf4IKO mice, respectively. Surf4 colocalized with apoB and co-immunoprecipitated with apoB48 in differentiated Caco-2 cells. Intestinal Surf4 deficiency also significantly reduced serum triglyceride, cholesterol, and free fatty acid levels in mice. Proteomics data revealed that diverse pathways were altered in Surf4IKO mice. In addition, Surf4IKO mice had mild liver damage, decreased liver size and weight, and reduced hepatic triglyceride levels. CONCLUSIONS: Our findings demonstrate that intestinal Surf4 plays an essential role in lipid absorption and chylomicron secretion and suggest that the therapeutic use of Surf4 inhibition requires highly cell/tissue-specific targeting.

Hypoxaemia risk in pediatric flexible bronchoscopy for foreign body removal: a retrospective study.

BACKGROUND: Hypoxemia represents the most prevalent adverse event during flexible bronchoscopy procedures aimed at foreign body retrieval in pediatric patients; if not expeditiously managed, it carries the potential for cardiac or respiratory arrest. The specific risk factors contributing to the occurrence of hypoxemia during foreign body FB removal via bronchoscopy have yet to be definitively established. METHODS: This retrospective study included a cohort of 266 pediatric subjects from January 1, 2015, to December 31, 2022, who underwent flexible bronchoscopy for the purpose of FB extraction. In this cohort, the supraglottic airway was used to connect the anesthesia apparatus during the removal procedure. RESULTS: In total, 45 of the pediatric patients (16.9%) experienced episodes of hypoxemia during the FB removal procedure. Multivariate analysis revealed that the following factors were significantly associated with the occurrence of hypoxemia: an operation time exceeding 60 min (odds ratio [OR] 8.55; 95% confidence interval [CI] 3.82-19.13), a maximum diameter exceeding 7 mm (OR 5.03; 95% CI, 2.24-11.29), and the presence of radiological evidence indicating pneumonia (OR 2.69; 95% CI, 1.27-5.69). CONCLUSION: During flexible bronchoscopy procedures aimed at FB removal in pediatric patients, there is an increased susceptibility to hypoxemia. Factors including extended operation duration, larger FB dimensions, and radiographic evidence suggestive of pneumonia significantly contribute to a heightened risk of hypoxemia.

A Robust Interacting Multi-Model Multi-Bernoulli Mixture Filter for Maneuvering Multitarget Tracking under Glint Noise.

In practical radar systems, changes in the target aspect toward the radar will result in glint noise disturbances in the measurement data. The glint noise has heavy-tailed characteristics and cannot be perfectly modeled by the Gaussian distribution widely used in conventional tracking algorithms. In this article, we investigate the challenging problem of tracking a time-varying number of maneuvering targets in the context of glint noise with unknown statistics. By assuming a set of models for the possible motion modes of each single-target hypothesis and leveraging the multivariate Laplace distribution to model measurement noise, we propose a robust interacting multi-model multi-Bernoulli mixture filter based on the variational Bayesian method. Within this filter, the unknown noise statistics are adaptively learned while filtering and the predictive likelihood is approximately calculated by means of the variational lower bound. The effectiveness and superiority of our proposed filter is verified via computer simulations.

A Sparse Recovery Algorithm for Suppressing Multiple Linear Frequency Modulation Interference in the Synthetic Aperture Radar Image Domain.

In synthetic aperture radar (SAR) signal processing, compared with the raw data of level-0, level-1 SAR images are more readily accessible and available in larger quantities. However, an amount of level-1 images are affected by radio frequency interference (RFI), which typically originates from Linear Frequency Modulation (LFM) signals emitted by ground-based radars. Existing research on interference suppression in level-1 data has primarily focused on two methods: transforming SAR images into simulated echo data for interference suppression, or focusing interference in the frequency domain and applying notching filters to reduce interference energy. However, these methods overlook the effective utilization of the interference parameters or are confined to suppressing only one type of LFM interference at a time. In certain SAR images, multiple types of LFM interference manifest bright radiation artifacts that exhibit varying lengths along the range direction while remaining constant in the azimuth direction. It is necessary to suppress multiple LFM interference on SAR images when original echo data are unavailable. This article proposes a joint sparse recovery algorithm for interference suppression in the SAR image domain. In the SAR image domain, two-dimensional LFM interference typically exhibits differences in parameters such as frequency modulation rate and pulse width in the range direction, while maintaining consistency in the azimuth direction. Based on this observation, this article constructs a series of focusing operators for LFM interference in SAR images. These operators enable the sparse representation of dispersed LFM interference. Subsequently, an optimization model is developed that can effectively suppress multi-LFM interference and reduce image loss with the assistance of a regularization term in the image domain. Simulation experiments conducted in various scenarios validate the superior performance of the proposed method.

Cross-study analyses of microbial abundance using generalized common factor methods.

BACKGROUND: By creating networks of biochemical pathways, communities of micro-organisms are able to modulate the properties of their environment and even the metabolic processes within their hosts. Next-generation high-throughput sequencing has led to a new frontier in microbial ecology, promising the ability to leverage the microbiome to make crucial advancements in the environmental and biomedical sciences. However, this is challenging, as genomic data are high-dimensional, sparse, and noisy. Much of this noise reflects the exact conditions under which sequencing took place, and is so significant that it limits consensus-based validation of study results. RESULTS: We propose an ensemble approach for cross-study exploratory analyses of microbial abundance data in which we first estimate the variance-covariance matrix of the underlying abundances from each dataset on the log scale assuming Poisson sampling, and subsequently model these covariances jointly so as to find a shared low-dimensional subspace of the feature space. CONCLUSIONS: By viewing the projection of the latent true abundances onto this common structure, the variation is pared down to that which is shared among all datasets, and is likely to reflect more generalizable biological signal than can be inferred from individual datasets. We investigate several ways of achieving this, demonstrate that they work well on simulated and real metagenomic data in terms of signal retention and interpretability, and recommend a particular implementation.

Development of a 135K SNP genotyping array for Actinidia arguta and its applications for genetic mapping and QTL analysis in kiwifruit.

Kiwifruit (Actinidia spp) is a woody, perennial and deciduous vine. In this genus, there are multiple ploidy levels but the main cultivated cultivars are polyploid. Despite the availability of many genomic resources in kiwifruit, SNP genotyping is still a challenge given these different levels of polyploidy. Recent advances in SNP array technologies have offered a high-throughput genotyping platform for genome-wide DNA polymorphisms. In this study, we developed a high-density SNP genotyping array to facilitate genetic studies and breeding applications in kiwifruit. SNP discovery was performed by genome-wide DNA sequencing of 40 kiwifruit genotypes. The identified SNPs were stringently filtered for sequence quality, predicted conversion performance and distribution over the available Actinidia chinensis genome. A total of 134 729 unique SNPs were put on the array. The array was evaluated by genotyping 400 kiwifruit individuals. We performed a multidimensional scaling analysis to assess the diversity of kiwifruit germplasm, showing that the array was effective to distinguish kiwifruit accessions. Using a tetraploid F1 population, we constructed an integrated linkage map covering 3060.9 cM across 29 linkage groups and performed QTL analysis for the sex locus that has been identified on Linkage Group 3 (LG3) in Actinidia arguta. Finally, our dataset presented evidence of tetrasomic inheritance with partial preferential pairing in A. arguta. In conclusion, we developed and evaluated a 135K SNP genotyping array for kiwifruit. It has the advantage of a comprehensive design that can be an effective tool in genetic studies and breeding applications in this high-value crop.

Atf4 regulates angiogenic differences between alveolar bone and long bone macrophages by regulating M1 polarization, based on single-cell RNA sequencing, RNA-seq and ATAC-seq analysis.

In the repair of maxillofacial bone defects, autogenous craniofacial bone can often provide superior clinical results over long bone grafts. Most current studies have focused on the osteogenic differences between alveolar bone marrow (ABM) and long bone marrow (LBM), however, studies about the angiogenic differences between the two are currently lacking. We downloaded single-cell RNA sequencing (scRNA-seq) of mouse ABM and LBM respectively from the public database, and the data were processed by using Seurat package. CellphoneDB2 results showed that macrophages had the strongest interaction with mesenchymal stem cells (MSCs) and endothelial cells (ECs). ELISA results confirmed that ABM macrophages secreted a higher level of vascular endothelial growth factor A (Vegfa) compared to LBM macrophages, which further promoted angiogenesis of ECs and MSCs. Using SCENIC package, six key transcription factors (TFs) were identified to regulate the difference between ABM and LBM macrophages, and activating transcription factor 4 (Atf4) was confirmed to be more expressed in ABM macrophages by polymerase chain reaction (PCR) and western blot (WB), with predicted target genes including Vegfa. Besides, the result of scRNA-seq implied ABM macrophages more in M1 status than LBM macrophages, which was confirmed by the following experiments. From the results of another assay for transposase accessible chromatin sequencing (ATAC-seq) and RNA-seq about M1 macrophages, Atf4 was also confirmed to regulate the M1 polarization. So, we suspected that Atf4 regulated the different expression of Vegfa between ABM and LBM macrophages by activating M1 polarization. After knocking down Atf4, the expression of M1 polarization markers and Vegfa were downregulated and vasculogenic differences were eliminated, which were subsequently reversed by the addition of LPS/IFN-γ. Our study might provide a new idea to improve the success rate of autologous bone grafting and treatment of oral diseases.

Long Noncoding RNA MIAT Modulates Chronic Retinal Ischemia-Reperfusion Injury in Mice via the microRNA-203-3p/SNAI2 Axis.

Retinal ischemia-reperfusion injury (RIRI) is a vital pathological process of multiple ocular diseases. This study aimed at investigating the effects of the MIAT/miR-203-3p/SNAI2 axis on RIRI. RIRI was produced by inducing an exceedingly high intraocular pressure (IOP) in mice. Mouse retinal ganglion cells (RGCs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic in vitro models. Relevant oligonucleotides or plasmids were transfected into OGD/R-induced RGCs in vitro or injected into RIRI mice models in vivo via a vitreous cavity. The findings of our paper indicated that MIAT and SNAI2 were highly expressed and miR-203-3p was lowly expressed in mouse RIRI tissues and OGD/R-induced RGCs. Interfering MIAT promoted the viability of OGD/R-induced RGCs, decreased apoptosis, and reduced oxidative stress in vitro. Silencing MIAT increased retinal neuronal cell numbers and decreased retinal neuronal cell apoptosis in mouse RIRI tissues in vivo. MIAT sponged miR-203-3p, and miR-203-3p targeted and inhibited SNAI2 expression. SNAI2 up-regulation or miR-203-3p down-regulation reversed the protective effects of MIAT down-regulation on RIRI in mice and OGD/R-induced RGCs. MIAT sponges miR-203-3p upregulated the expression of SNAI2, thereby promoting RIRI in mice. In summary, MIAT may be a therapeutic target for the treatment of chronic RIRI.