Single-cell colocalization analysis using a deep generative model.

Analyzing colocalization of single cells with heterogeneous molecular phenotypes is essential for understanding cell-cell interactions, and cellular responses to external stimuli and their biological functions in diseases and tissues. However, existing computational methodologies identified the colocalization patterns between predefined cell populations, which can obscure the molecular signatures arising from intercellular communication. Here, we introduce DeepCOLOR, a computational framework based on a deep generative model that recovers intercellular colocalization networks with single-cell resolution by the integration of single-cell and spatial transcriptomes. Along with colocalized population detection accuracy that is superior to existing methods in simulated dataset, DeepCOLOR identified plausible cell-cell interaction candidates between colocalized single cells and segregated cell populations defined by the colocalization relationships in mouse brain tissues, human squamous cell carcinoma samples, and human lung tissues infected with SARS-CoV-2. DeepCOLOR is applicable to studying cell-cell interactions behind various spatial niches. A record of this paper's transparent peer review process is included in the supplemental information.

Comparison between optical coherence tomography-guided and intravascular ultrasound-guided primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

Objective: To examine the clinical outcomes of optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) in patients presenting with ST-segment elevation myocardial infarction (STEMI). Methods: We retrospectively investigated 533 consecutive patients who underwent primary PCI for STEMI between June 2016 and December 2020. The primary endpoint was a target lesion failure (TLF; defined as a composite of cardiac death, target vessel myocardial infarction, or target lesion revascularization). Propensity score (PS) matching was performed to allow direct comparison of OCT-guided and intravascular ultrasound (IVUS)-guided PCI. Results: Patients in the OCT group (n=166) were younger than those in the IVUS group (n=367) and had a significantly higher left ventricular ejection fraction and estimated glomerular filtration rate. Killip class IV and left main stem disease were more common in the IVUS group. The median peak creatine kinase level was comparable between the two groups (1953 U/L vs 1603 U/L). A significantly larger amount of contrast was used in the OCT group (200 mL vs 165 mL; p<0.001). The cumulative incidence of TLF during a median follow-up of 2.2 years did not differ significantly between OCT and IVUS groups (9.6% vs 13.6%; p=0.221) but cardiac mortality was significantly higher in the IVUS group (8.7% vs 3.6%; p=0.047). After PS matching (n=161 in each group), there was no significant between-group difference in TLF or any other clinical outcome measures. Conclusions: OCT-guided PCI demonstrated clinical outcomes in patients with STEMI that were comparable to those of IVUS-guided PCI despite considerable differences in background characteristics.

RENGE infers gene regulatory networks using time-series single-cell RNA-seq data with CRISPR perturbations.

Single-cell RNA-seq analysis coupled with CRISPR-based perturbation has enabled the inference of gene regulatory networks with causal relationships. However, a snapshot of single-cell CRISPR data may not lead to an accurate inference, since a gene knockout can influence multi-layered downstream over time. Here, we developed RENGE, a computational method that infers gene regulatory networks using a time-series single-cell CRISPR dataset. RENGE models the propagation process of the effects elicited by a gene knockout on its regulatory network. It can distinguish between direct and indirect regulations, which allows for the inference of regulations by genes that are not knocked out. RENGE therefore outperforms current methods in the accuracy of inferring gene regulatory networks. When used on a dataset we derived from human-induced pluripotent stem cells, RENGE yielded a network consistent with multiple databases and literature. Accurate inference of gene regulatory networks by RENGE would enable the identification of key factors for various biological systems.

Neutrophil extracellular traps formation in the lesional skin of various types of pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is a chronic neutrophilic disorder characterized by recurrent painful ulcers. Aseptic inflammation by neutrophils plays an essential role, and neutrophil extracellular traps (NETs) formation can contribute to the pathogenesis of PG. Seventy-five patients were diagnosed as having PG in our department, among which 58 ulcerative, 4 bullous, 3 pustular and 10 vegetative type. We examined the 20 skin biopsy specimens (11 ulcerative, 3 bullous, 2 pustular and 4 vegetative type), and local NETs formation in various types of PG was compared among each type. The biopsied specimens were double labelled for myeloperoxidase, citrullinated histone H3. Immunofluorescent images indicated that the histopathologic location and depth of NETs formation in PG varied by the clinical subtypes. In ulcerative PG, NETs formation was observed in the upper to deep dermis. In bullous PG, NETs formation was mainly observed in the epidermis. Pustular type showed NETs formation in the epidermis near the pustules, and in vegetative type, showed NETs formation mainly in the upper dermis. These results indicate that NETting neutrophils play an important role in the pathogenesis of various forms of PG, although the location and depth of NETs formation in the skin lesion of PG differ depending on each type. Further studies are necessary to examine what factors identify different clinical features of PG.

Efficacy of Intravascular Ultrasound-Based 3D Wiring Using the Tip Detection Method for CTO Intervention.

To perform intravascular ultrasound (IVUS)-based real-time 3-dimensional wiring in chronic total occlusion percutaneous coronary intervention, we devised a tip detection method and developed AnteOwl WR (AO)-IVUS, which is an upgraded version of Navifocus WR (Navi)-IVUS with an added pull back transducer system. We compared the procedural outcomes of AO-IVUS-based 3-dimensional wiring using the tip detection method (n = 30) and Navi-IVUS-based conventional wiring (n = 17) in chronic total occlusion percutaneous coronary intervention. The success rate of IVUS-guided wiring was markedly improved in the AO-IVUS group compared with the Navi-IVUS group (93% vs 59% of cases, respectively; P = 0.007). In cases of successful IVUS-guided wiring, the IVUS-guided wiring time was markedly improved in the AO-IVUS group compared with the Navi-IVUS group (9 ± 8 minutes vs 24 ± 26 minutes, respectively; P = 0.001). There were 2 successful cases of tip detection-antegrade dissection and re-entry in the AO-IVUS group.

Erythema nodosum-like sarcoid lesion: a specific skin manifestation occasionally seen in Japanese sarcoidosis patients.

Background: Erythema nodosum-like sarcoid lesion is a specific form of cutaneous sarcoidosis sometimes observed in Japanese patients, with a female predominance, involving the lower extremities. By contrast, erythema nodosum as a non-specific cutaneous manifestation associated with sarcoidosis is rare in Japan. Erythema nodosum-like sarcoid lesion resembles erythema nodosum only in appearance, but histologically shows sarcoid granulomas. Objectives: To determine the clinical characteristics of erythema nodosum-like sarcoid lesion. Methods: We examined the clinical characteristics of erythema nodosum-like sarcoid lesion in our patients with sarcoidosis. Clinical charts were retrospectively examined from 2000 to 2019. The patients' data, such as age, gender, types of cutaneous lesion, serum levels of angiotensin-converting enzyme, and extracutaneous organ involvement, were evaluated. We also reviewed cases of erythema nodosum-like sarcoid lesion reported in previous literature. Results: Among 101 cutaneous sarcoidosis patients, eight were diagnosed as having erythema nodosum-like sarcoid lesion in our department. The patients were one male and seven females, and their ages ranged from 30 to 74 years old. All cases involved the lower extremities. The serum angiotensin-converting enzyme level was elevated in five cases. Lung sarcoidosis was observed in all cases, and ocular sarcoidosis was observed in six cases, whereas no patients had cardiac sarcoidosis. Conclusions: Although erythema nodosum-like sarcoid lesion may not be major skin manifestation of sarcoidosis, erythema nodosum-like sarcoid lesion frequently accompanies lung and ocular sarcoidosis. Thus, we should pay much attention to erythema nodosum-like sarcoid lesion for early identification of patients needing workup for systemic illness.

Eruptive superficial porokeratosis in a patient with nephrotic syndrome.

A 34-year-old female was referred to our department, complaining of multiple asymptomatic lesions that appeared two weeks previously. The patient had active nephritis with nephrotic syndrome and was treated with immunosuppressive therapies. Physical examination revealed multiple well-circumscribed rounds of flat brownish plaques with slightly elevated borders, some of which were covered by scales. The number of lesions was nine in total. Skin biopsy specimens showed dyskeratotic cells in the thinned epidermis with cornoid lamella, and the absence of a granular cell layer. The development of porokeratosis was considered to be related to immunosuppressive therapy or the activity of nephritis.

Six Cases of Erythrodermic Pemphigus Foliaceus: A Case Report.

Pemphigus foliaceus (PF) is one of the causes of erythroderma; however, to date, there have been relatively few reported cases. We herein describe 6 cases of erythrodermic PF. In all 6 cases, PF was a direct cause of erythroderma because the patients had not undergone any medical treatments and neither had any other skin diseases nor were taking any drugs that typically cause erythroderma. Serum levels of IgE and thymus and activation-regulated chemokine were elevated in 5 of the 6 cases, whereas soluble interleukin-2 receptor and squamous cell carcinoma-related antigen were markedly increased in all cases, suggesting that those markers are strong indicators of skin surface damage. All patients were treated with predonisolon (PSL), of which PSL pulse was added in 4 patients and intravenous immunoglobulin was added in 4 patients. Furthermore, all patients except for one were older adults, among whom 2 cases developed Kaposi's varicelliform eruption, and died, and another 2 patients, respectively, died of gastrointestinal bleeding and sepsis. Kaposi's varicelliform eruption is a complication of erythrodermic PF associated with poor prognosis, and thus caution is necessary when considering the diagnosis. Furthermore, elderly people are more likely to have complications due to PSL, which may result in death. Inappropriate treatment and delay in treatment may cause erythroderma, so early diagnosis and treatment are necessary.

Brainless Walking: Animal Gaits Emerge From an Actuator Characteristic.

In this study, we discovered a phenomenon in which a quadruped robot without any sensors or microprocessor can autonomously generate the various gait patterns of animals using actuator characteristics and select the gaits according to the speed. The robot has one DC motor on each limb and a slider-crank mechanism connected to the motor shaft. Since each motor is directly connected to a power supply, the robot only moves its foot on an elliptical trajectory under a constant voltage. Although this robot does not have any computational equipment such as sensors or microprocessors, when we applied a voltage to the motor, each limb begins to adjust its gait autonomously and finally converged to a steady gait pattern. Furthermore, by raising the input voltage from the power supply, the gait changed from a pace to a half-bound, according to the speed, and also we observed various gait patterns, such as a bound or a rotary gallop. We investigated the convergence property of the gaits for several initial states and input voltages and have described detailed experimental results of each gait observed.

A Reciprocal Excitatory Reflex Between Extensors Reproduces the Prolongation of Stance Phase in Walking Cats: Analysis on a Robotic Platform.

Spinal reflex is essential to the robust locomotion of quadruped animals. To investigate the reflex mechanisms, we developed a quadruped robot platform that emulates the neuromuscular dynamics of animals. The leg is designed to be highly back-drivable, and four Hill-type muscles and neuronal pathways are simulated on each leg using software. By searching for the reflex circuit that contributes to the generation of steady gait in cats through robotic experiments, we found a simple reflex circuit that could produce leg trajectories and a steady gait. In addition, this circuit can reproduce the experimental behavior observed in cats. As a major contribution of this study, we show that the underlying structure of the reflex circuit is the reciprocal coupling between extensor muscles via excitatory neural pathways. In the walking experiments on the robot, a steady gait and experimental behaviors of walking cats emerged from the reflex circuit without any central pattern generators. Furthermore, to take advantage of walking experiments using a neurophysiological robotic platform, we conducted experiments in which a part of the proposed reflex circuit was disconnected for a certain period of time during walking. The results showed that the prolongation of the stance phase caused by the reciprocal excitatory reflex contributed greatly to the generation of a steady gait.