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Abstract Ulcerative colitis (UC) is a significant inflammatory bowel disease caused by an abnormal immune response to gut microbes. However, there are still gaps in our understanding of how immune and metabolic changes specifically contribute to this disease. Our research aims to address this gap by examining mouse colons after inducing ulcerative colitis-like symptoms. Employing single-cell RNA-seq and 16 s rRNA amplicon sequencing to analyze distinct cell clusters and microbiomes in the mouse colon at different time points after induction with dextran sodium sulfate. We observe a significant reduction in epithelial populations during acute colitis, indicating tissue damage, with a partial recovery observed in chronic inflammation. Analyses of cell-cell interactions demonstrate shifts in networking patterns among different cell types during disease progression. Notably, macrophage phenotypes exhibit diversity, with a pronounced polarization towards the pro-inflammatory M1 phenotype in chronic conditions, suggesting the role of macrophage heterogeneity in disease severity. Increased expression of Nampt and NOX2 complex subunits in chronic UC macrophages contributes to the inflammatory processes. The chronic UC microbiome exhibits reduced taxonomic diversity compared to healthy conditions and acute UC. The study also highlights the role of T cell differentiation in the context of dysbiosis and its implications in colitis progression, emphasizing the need for targeted interventions to modulate the inflammatory response and immune balance in colitis.

Fossil resources must be replaced by renewable resources in production systems to mitigate green-house gas emissions and combat climate change. Electro-fermentation utilizes a bioelectrochemical system (BES) to valorize industrial and municipal waste. Current electro-fermentation research is mainly focused on microbial electrosynthesis using CO2 for producing commodity chemicals and replacing petroleum-based infrastructures. However, slow production rates and low titers of metabolites during CO2-based microbial electrosynthesis impede its implementation to the real application in the near future. On the other hand, CO is a highly reactive gas and an abundant feedstock discharged from fossil fuel-based industry. Here, we investigated CO and CO2 electro-fermentation, using a CO-enriched culture. Fresh cow fecal waste was enriched under an atmosphere of 50% CO and 20% CO2 in N2 using serial cultivation. The CO-enriched culture was dominated by Clostridium autoethanogenum (≥89%) and showed electro-activity in a BES reactor with CO2 sparging. When 50% CO was included in the 20% CO2 gas with 10 mA applied current, acetate and ethanol were produced up to 12.9 ± 2.7 mM and 2.7 ± 1.1 mM, respectively. The coulombic efficiency was estimated to 148% ± 8% without an electron mediator. At 25 mA, the culture showed faster initial growth and acetate production but no ethanol production, and only at 86% ± 4% coulombic efficiency. The maximum optical density (OD) of 10 mA and 25 mA reactors were 0.29 ± 0.07 and 0.41 ± 0.03, respectively, whereas it was 0.77 ± 0.19 without electric current. These results show that CO electro-fermentation at low current can be an alternative way of valorizing industrial waste gas using a bioelectrochemical system.

ABSTRACTDepressive disorders are more prevalent and severe in women; however, our knowledge of the underlying factors contributing to female vulnerability to depression remains limited. Additionally, females are notably underrepresented in studies seeking to understand the mechanisms of depression. Various animal models of depression have been devised, but only recently have females been included in research. In this comprehensive review, we aim to describe the sex differences in the prevalence, pathophysiology, and responses to drug treatment in patients with depression. Subsequently, we highlight animal models of depression in which both sexes have been studied, in the pursuit of identifying models that accurately reflect female vulnerability to depression. We also introduce explanations for the neural basis of sex differences in depression. Notably, the medial prefrontal cortex and the nucleus accumbens have exhibited sex differences in previous studies. Furthermore, other brain circuits involving the dopaminergic center (ventral tegmental area) and the serotonergic center (dorsal raphe nucleus), along with their respective projections, have shown sex differences in relation to depression. In conclusion, our review covers the critical aspects of sex differences in depression, with a specific focus on female vulnerability in humans and its representation in animal models, including the potential underlying mechanisms. Employing suitable animal models that effectively represent female vulnerability would benefit our understanding of the sex-dependent pathophysiology of depression.

Abstract In this study, we propose an optimal method for monitoring the key electrophysiological sign, the Lateral Spread Response (LSR), during microvascular decompression (MVD) surgery for hemifacial spasm (HFS). Current monitoring methods and interpretations of LSR remain unclear, leading to potential misinterpretations and undesirable outcomes." We prospectively collected data from patients undergoing MVD for HFS, including basic demographics, clinical characteristics, and surgical outcomes. Stimulation intensity was escalated by 1 mA increments to identify the optimal range for effective LSR. We designated the threshold at which we can observe LSR as THR1 and THR2 for when LSR disappears, with high-intensity stimulation (30 mA) designated as THR30. Subsequently, we compared abnormal muscle responses (AMR) between the optimal range (between THR1 and THR2) and THR30. Additionally, we conducted an analysis to identify and assess factors associated with artifacts and their potential impact on clinical outcomes. As stimulation intensity increases, the onset latency to detect AMR was shortened. The first finding of the study was high intensity stimulation caused artifact that mimic the wave of LSR. Those artifacts were observed even after decompression thus interfere interpretation of disappearance of LSR. Analyzing the factors related to the artifact, we found the AMR detected at onset latency below 9.6 ms would be the lateral spreading artifact (LSA) rather than true LSR. To avoid false positive LSR from LSA, we should stepwise increase stimulation intensity and not to surpass the intensity that cause LSR onset latency below 10 ms.

Over recent decades, the rural areas of Korea, including containing source waters, have become extensively developed. Combined sewer systems (CSSs) have been constructed to collect the sewage generated from these areas. Presently, it is common to experience localized heavy rain events, likely due to climate change, and sometimes, the volume of rainfall can become too high for a CSS to handle. In these cases, combined sewer overflow (CSOs) occurs, contaminating surface water, which may have been used as source water. Therefore, the Korean government will begin regulating the biochemical oxygen demand (BOD) of CSOs occurring during first flushes of less than 40 mg/L from 2024 onwards. In this study, a biofiltration-based technology was proposed to treat CSOs. Thus, this study aimed to remove BOD from CSO using this biofiltration system to contain cube-type media. For this, two different loading rates were tested on a pilot scale. Although the proposed system resulted in a footprint of only 10 % of that of a conventional activated sludge system, it was still capable of achieving efficient BOD removal. At a high loading rate, BOD removal efficiency was observed at approximately 53 %, and when this loading rate was reduced by 50 %, the removal efficiency was slightly improved to about 58 %. In both cases, the BODs of treated CSOs could be maintained below the proposed future standard: 31 mg/L and 28 mg/L for high and low loading rates, respectively. Therefore, the proposed system could potentially be preventing environmental contamination from COSs.

The high-temperature properties of titanium carbide (TiC)–reinforced stainless steel (SS) matrix composite, fabricated through infiltration process, were investigated across different temperatures. By adding highly concentrated and closely adjacent TiC particulate reinforcement, dramatic variations in the coefficient of thermal expansion (CTE) and thermal conductivity properties, which originate from the phase transformation of the SS matrix, were effectively suppressed. Moreover, the addition of TiC significantly strengthened the SS, with its strengthening effect increasing at higher temperatures and reaching its highest value after the phase transformation. Therefore, TiC–SS composite exhibit great potential for use as advanced high-temperature-resistant structural materials.

Abstract Finding d-electron heavy fermion states has been an important topic as the diversity in d-electron materials can lead to many exotic Kondo effect-related phenomena or new states of matter such as correlation-driven topological Kondo insulator. Yet, obtaining direct spectroscopic evidence for a d-electron heavy fermion system has been elusive to date. Here, we report the observation of Kondo lattice behavior in an antiferromagnetic metal, FeTe, via angle-resolved photoemission spectroscopy, scanning tunneling spectroscopy and transport property measurements. The Kondo lattice behavior is represented by the emergence of a sharp quasiparticle and Fano-type tunneling spectra at low temperatures. The transport property measurements confirm the low-temperature Fermi liquid behavior and reveal successive coherent-incoherent crossover upon increasing temperature. We interpret the Kondo lattice behavior as a result of hybridization between localized Fe 3dxy and itinerant Te 5pz orbitals. Our observations strongly suggest unusual cooperation between Kondo lattice behavior and long-range magnetic order.

Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell’s ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood–brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain–heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

Efficient screening of protein-drug interactions (PDIs) has been impeded by the limitations of current biophysical approaches. Here, the authors present a funneled YaxAB nanopore sensor which allows label-free, single-molecule detection of proteins and PDIs.

Category: Midfoot/Forefoot Introduction/Purpose: Recurrence is one of the most common complications following hallux valgus surgery. Moreover, hallux varus occurs in cases of overcorrection. We aimed to quantitatively measure, using radiographic examination, the dynamics of the soft tissues that act on deformities (recurrence of valgus and occurrence of varus) after the surgery. Methods: This retrospective single-institution study included 60 patients (98 feet) who underwent hallux valgus surgery between 2009 and 2018. According to radiographic findings of the foot under weightbearing conditions at postoperative month 1, we examined the tendons’ pathway and calculated the forces on the first metatarsophalangeal joint, which we termed the deformity force angle (DFA). We compared whether there was a significant difference in DFAs between the groups in which deformities occurred and those in which deformities did not occur after correction. In addition, the DFA was compared to known radiographic measurements of hallux valgus recurrence (hallux valgus angle, distal metatarsal articular angle, intermetatarsal angle, and sesamoid position) to assess association with recurrence. Results: We observed a significant difference in the DFA between patients with and without hallux valgus recurrence (P < .001) and between those with and without hallux varus (P < .001) based on standing radiographs taken at a minimum of 6 months postoperation. For predicting the deformities, the areas under the curve were 0.863 (hallux valgus recurrence) and 0.831 (hallux varus occurrence), respectively, which was greater than other factors evaluated. The DFA values greater than 9.5 degrees and less than 5.5 degrees were associated with the recurrence of valgus and occurrence of varus, respectively. Conclusion: In our study, DFA was associated with hallux valgus recurrence when it exceeded 9.5 degrees and hallux varus when it was less than 5.5 degrees. Moreover, in the hallux valgus surgery we performed, a DFA from 5.5 to 9.5 degrees appeared to be a “safe zone” for preventing early deformity after surgery.

Emotional labor is typically conceptualized as a process in which individuals regulate their emotions in response to display rules. Most research on emotional labor has focused on the influence of display rules at individual-level perceptions but is rarely examined at the team level. We examine the influence of the shared display rules in teams as emotional display norms. This study considers emotional dissonance as the difference between the positive emotional display norm at the team level and positive emotion at the individual level. To examine the purpose of this study, data were collected from leader-follower pairs within teams and based on a three-wave design. Thus, this study conducted a multi-level polynomial regression analysis and used the response surface methodology to interpret the incongruence effect. The results show that the incongruence effect of emotional dissonance is positively related to surface acting. In addition, the moderating effect of regulatory focus significantly strengthens the positive relationship between emotional dissonance and emotion regulation strategies. The results also show that surface acting strategy is negatively related to selfless Organizational citizenship behaviors (OCB). These findings highlight that emotional display norms play an important role as the standard for emotional experience in teams, and especially with the moderating effect of self-regulatory focus, emotion regulation strategies affect the selfless OCB rating of observers.

Abstract Background Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9–12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms. Results While C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9–10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia. Conclusions Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.

Connexin 36 (Cx36) gap junction channel is responsible for signal transmission in electrical synapses. Here, the authors determine cryo-EM structures of Cx36, providing insights into a potential role of lipids in the channel gating.

Minimally invasive surgeries call for surgical tools that can work at the mesoscale. Here, Gu et al. present a class of magnetic soft robotic chains that can self fold into large assemblies with stable configurations using a combination of elastic and magnetic energies stored in printed chain material.

Gap junction intercellular channels (GJIChs) facilitate direct communication between adjacent cells. Here, authors provide high-resolution information on dynamic structural changes in Cx43 GJICh that are necessary to understand the gating mechanism.

Shape-memory materials are promising actuation sources for small-scale machines. The authors demonstrate that domain switching in twisted ferroic nanocomposites enables a giant shape-memory effect and superelasticity in the nanoscale structure.

Background: Childhood sleep problems are common and among the most frequent and impairing comorbidities of childhood psychiatric disorders. In adults, sleep disturbances are heritable and show strong genetic associations with brain morphology; however, little is known about the genetic architecture of childhood sleep and potential etiological links between sleep, brain development, and pediatric-onset psychiatric symptoms. Methods: Using data from the Adolescent Brain Cognitive Development Study (nPhenotype = 4428 for discovery/replication, nGenetics = 4728; age 9–10 years), we assessed phenotypic relationships, heritability, and genetic correlations between childhood sleep disturbances (insomnia, arousal, breathing, somnolence, hyperhidrosis, sleep-wake transitions), brain size (surface area, cortical thickness, volume), and dimensional psychopathology. Results: Sleep disturbances showed widespread positive associations with multiple domains of childhood psychopathology; however, only insomnia showed replicable associations with smaller brain surface area. Among the sleep disturbances assessed, only insomnia showed significant heritability (h2SNP = 0.15, p < .05) and showed substantial genetic correlations with externalizing and attention-deficit/hyperactivity disorder symptomatology (rGs > 0.80, ps < .05). We found no evidence of genetic correlation between childhood insomnia and brain size. Furthermore, polygenic risk scores calculated from genome-wide association studies of adult insomnia and adult brain size did not predict childhood insomnia; instead, polygenic risk scores trained using attention-deficit/hyperactivity disorder genome-wide association studies predicted decreased surface area at baseline as well as insomnia and externalizing symptoms longitudinally. Conclusions: Findings demonstrate a distinct genetic architecture underlying childhood insomnia and brain size and suggest genetic overlap between childhood insomnia and attention-deficit/hyperactivity disorder symptomatology. Additional research is needed to examine how genetic risk manifests in altered developmental trajectories and comorbid sleep/psychiatric symptoms across adolescence.

Triple-negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive nature and limited treatment options. In search of new treatment targets, not only single genes but also gene pairs involved in protein interactions, we explored the tumor microenvironment (TME) of TNBC from a retrospective point of view, using public single-cell RNA sequencing datasets. A High-resolution Cell type Annotation Tool, HiCAT, was used first to identify the cell type in 3-level taxonomies. Tumor cells were then identified based on the estimates of copy number variation. With the annotation results, differentially expressed genes were analyzed to find subtype-specific markers for each cell type, including tumor cells, fibroblast, and macrophage. Cell–cell interactions were also inferred for each cell type pair. Through integrative analysis, we could find unique TNBC markers not only for tumor cells but also for various TME components, including fibroblasts and macrophages. Specifically, twelve marker genes, including DSC2 and CDKN2A, were identified for TNBC tumor cells. Another key finding of our study was the interaction between the DSC2 and DSG2 genes among TNBC tumor cells, suggesting that they are more tightly aggregated with each other than those of other subtypes, including normal epithelial cells. The overexpression of DSC2 in TNBC and its prognostic power were verified by using METABRIC, a large bulk RNA-seq dataset with clinical information. These findings not only corroborate previous hypotheses but also lay the foundation for a new structural understanding of TNBC, as revealed through our single-cell analysis workflow.

Abstract Semi-structured environments are difficult for autonomous driving because there are numerous unknown obstacles in drivable area without lanes, and its width and curvature considerably change. In such environments, searching for a path on a real-time is difficult, and localization data are inaccurate, reducing path tracking accuracy. Instead, alternative methods that reactively avoid obstacles in real-time using candidate paths or an artificial potential field have been studied. However, these require heuristics to identify specific parameters for handling various environments and are vulnerable to inaccurate input data. To address these limitations, this study proposes a method in which a vehicle drives toward drivable area using vision and deep learning. The proposed imitation learning method learns the look-ahead point where the vehicle should reach on a vision-based occupancy grid map to obtain a safe policy with a clear state action pattern relationship. Furthermore, using this point, the data aggregation (DAgger) algorithm with weighted loss function is proposed, which imitates expert behavior more accurately, especially in unsafe or near-collision situations. Experimental results in actual semi-structured environments demonstrated the limitations of general model-based methods and the effectiveness of the proposed imitation learning method. Moreover, simulation experiments showed that DAgger with the weight obtains a safer policy than existing DAgger algorithms.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. Despite a successful vaccination programme, the emergence of mutated variants that can escape current levels of immunity mean infections continue. Herein, we report the development of CT-P63, a broad-spectrum neutralizing monoclonal antibody. In vitro studies demonstrated potent neutralizing activity against the most prevalent variants, including Delta and the BA.1 and BA.2 sub-lineages of Omicron. In a transgenic mouse model, prophylactic CT-P63 significantly reduced wild-type viral titres in the respiratory tract and CT-P63 treatment proved efficacious against infection with Beta, Delta, and Omicron variants of SARS-CoV-2 with no detectable infectious virus in the lungs of treated animals. A randomized, double-blind, parallel-group, placebo-controlled, Phase I, single ascending dose study in healthy volunteers (NCT05017168) confirmed the safety, tolerability, and pharmacokinetics of CT-P63. Twenty-four participants were randomized and received the planned dose of CT-P63 or placebo. The safety and tolerability of CT-P63 were evaluated as primary objectives. Eight participants (33.3%) experienced a treatment-emergent adverse event (TEAE), including one grade ≥3 (blood creatine phosphokinase increased). There were no deaths, treatment-emergent serious adverse events, TEAEs of special interest, or TEAEs leading to study drug discontinuation in the CT-P63 groups. Serum CT-P63 concentrations rapidly peaked before declining in a biphasic manner and systemic exposure was dose proportional. Overall, CT-P63 was clinically safe and showed broad-spectrum neutralizing activity against SARS-CoV-2 variants in vitro and in vivo.

Abstract Background In cell signaling pathways, proteins interact with each other to determine cell fate in response to either cell-extrinsic (micro-environmental) or intrinsic cues. One of the well-studied pathways, the mitogen-activated protein kinase (MAPK) signaling pathway, regulates cell processes such as differentiation, proliferation, apoptosis, and survival in response to various micro-environmental stimuli in eukaryotes. Upon micro-environmental stimulus, receptors on the cell membrane become activated. Activated receptors initiate a cascade of protein activation in the MAPK pathway. This activation involves protein binding, creating scaffold proteins, which are known to facilitate effective MAPK signaling transduction. Results This paper presents a novel mathematical model of a cell signaling pathway coordinated by protein scaffolding. The model is based on the extended Boolean network approach with stochastic processes. Protein production or decay in a cell was modeled considering the stochastic process, whereas the protein–protein interactions were modeled based on the extended Boolean network approach. Our model fills a gap in the binary set applied to previous models. The model simultaneously considers the stochastic process directly. Using the model, we simulated a simplified mitogen-activated protein kinase (MAPK) signaling pathway upon stimulation of both a single receptor at the initial time and multiple receptors at several time points. Our simulations showed that the signal is amplified as it travels down to the pathway from the receptor, generating substantially amplified downstream ERK activity. The noise generated by the stochastic process of protein self-activity in the model was also amplified as the signaling propagated through the pathway. Conclusions The signaling transduction in a simplified MAPK signaling pathway could be explained by a mathematical model based on the extended Boolean network model with a stochastic process. The model simulations demonstrated signaling amplifications when it travels downstream, which was already observed in experimental settings. We also highlight the importance of stochastic activity in regulating protein inactivation.

Background Long thoracic nerve (LTN) neuropathy occasionally occurs in young people who engage in various sports. It may have a traumatic or non-traumatic etiology. The landmark manifestation of LTN neuropathy is scapular winging; however, it can also occur without scapular winging and specific magnetic resonance imaging findings. Case An 18-year-old male complained of right-sided lateral chest pain for 7 months. He was treated with medication, trigger point injection, and physical therapy but showed no improvement. Electromyelogram findings suggested LTN neuropathy in the right lateral chest. We performed a serratus anterior (SA) plane block with ultrasound (US)-guided hydrodissection and achieved pain relief. Conclusions We report the successful treatment of LTN neuropathy with an SA plane block and US-guided hydrodissection.

2D nanoporous membranes are predicted to provide highly selective gas transport in combination with extreme permeance. Here authors demonstrate gas separation performance and transport mechanisms through membranes of graphdiyne, a quasi 2D material with a graphene-like structure.

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment option for several hematologic cancers. However, efforts to achieve the same level of therapeutic success in solid tumors have largely failed mainly due to CAR-T cell exhaustion and poor persistence at the tumor site. Although immunosuppression mediated by augmented programmed cell death protein-1 (PD-1) expression has been proposed to cause CAR-T cell hypofunction and limited clinical efficacy, little is known about the underlying mechanisms and immunological consequences of PD-1 expression on CAR-T cells. With flow cytometry analyses and in vitro and in vivo anti-cancer T cell function assays, we found that both manufactured murine and human CAR-T cell products displayed phenotypic signs of T cell exhaustion and heterogeneous expression levels of PD-1. Unexpectedly, PD-1high CAR-T cells outperformed PD-1low CAR-T cells in multiple T cell functions both in vitro and in vivo. Despite the achievement of superior persistence at the tumor site in vivo, adoptive transfer of PD-1high CAR-T cells alone failed to control tumor growth. Instead, a PD-1 blockade combination therapy significantly delayed tumor progression in mice infused with PD-1high CAR-T cells. Therefore, our data demonstrate that robust T cell activation during the ex vivo CAR-T cell manufacturing process generates a PD-1high CAR-T cell subset with improved persistence and enhanced anti-cancer functions. However, these cells may be vulnerable to the immunosuppressive microenvironment and require combination with PD-1 inhibition to maximize therapeutic functions in solid tumors.

The deformability of leukocytes is relevant to a wide array of physiological and pathophysiological behaviors. The goal of this study is to provide a detailed, quantitative characterization of the mechanical properties of T cells and how those properties change with activation. We tested T cells and CD8+ cells isolated from peripheral blood samples of healthy donors either immediately (naïve population) or after 7 days of activation in vitro. Single-cell micropipette aspiration was used to test the mechanical properties. T cells exhibit the general characteristics of a highly viscous liquid drop with a cortical “surface” tension, Tcort. The time course of each cell entry into the micropipette was measured at two different aspiration pressures to test for shear thinning behavior. The data were analyzed in the framework of an approximate mechanical model of the cell deformation to determine the cortical tension, the cell volume, the magnitude of the initial cell entry, the characteristic viscosity μo, and the shear thinning coefficient, b. Activation generally caused increases in cellular resistance to deformation and a broadening of the distribution of cell properties. The cell volume increased substantially upon cell activation from ∼200 μm3 to ∼650 μm3. Naive and activated T cells had similar mean cortical tension (∼150 pN/μm). However, compared to naïve CD8+ cells, the cortical tension of activated CD8+ cells increased significantly to ∼250 pN/μm. Dynamic resistance of naive CD8+ T cells, as reflected in their characteristic viscosity, was ∼870 Pa and significantly increased to 1,180 Pa after in vitro activation. The magnitude of the instantaneous projection length as the cell enters the pipette (Linit) was more than doubled for activated vs. naive cells. All cell types exhibited shear thinning behavior with coefficients b in the range 0.5–0.65. Increased cell size, cortical tension, and characteristic viscosity all point to increased resistance of activated T cells to passage through the microvasculature, likely contributing to cell trapping. The increased initial elastic response of cells after activation was unexpected and could point to instability in the cell that might contribute to spontaneous cell motility.

Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed that knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrate that SLC38A5 could be a novel target to overcome gemcitabine resistance in PDAC therapy.

The purpose of this study was to investigate the outcome of microvascular decompression (MVD) in patients with hemifacial spasm (HFS) who have no definite radiological neurovascular compression (NVC). Sixteen HFS patients without radiological NVC on preoperative MRI underwent MVD surgery. The symptoms were left-sided in fourteen (87.5%) and right-sided in two patients (12.5%). Intraoperatively, the most common vessel compressing the facial nerve was the AICA (8, 44.4%), followed by arterioles (5, 27.8%), veins (4, 22.2%), and the PICA (1, 5.6%). The most common compression site was the cisternal portion (13, 76.5%) of the facial nerve, followed by the REZ (4, 23.5%). One patient (6.3%) was found to have multiple NVC sites. Arachnoid type (7, 50%) was the most common compressive pattern, followed by perforator type (4, 28.6%), sandwich type (2, 14.3%), and loop type (1, 7.1%). A pure venous compression was seen in two patients, while a combined venous-arterial “sandwich” compression was detected in two patients. Symptom improvement was observed in all of the patients. Only one patient experienced recurrence after improvement. Based on our experience, MVD surgery can be effective for primary HFS patients with no definite radiological NVC. MVD can be considered if the patient shows typical HFS features, although NVC is not evident on MRI.

Abstract Cytotoxic lymphocytes fight pathogens and cancer by forming immune synapses with infected or transformed target cells and then secreting cytotoxic perforin and granzyme into the synaptic space, with potent and specific killing achieved by this focused delivery. The mechanisms that establish the precise location of secretory events, however, remain poorly understood. Here we use single cell biophysical measurements, micropatterning, and functional assays to demonstrate that localized mechanotransduction helps define the position of secretory events within the synapse. Ligand-bound integrins, predominantly the αLβ2 isoform LFA-1, function as spatial cues to attract lytic granules containing perforin and granzyme and induce their fusion with the plasma membrane for content release. LFA-1 is subjected to pulling forces within secretory domains, and disruption of these forces via depletion of the adaptor molecule talin abrogates cytotoxicity. We thus conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance their cytotoxic power and fidelity.

Abstract The heavy fermion state with Kondo-hybridisation (KH), usually manifested in f-electron systems with lanthanide or actinide elements, was recently discovered in several 3d transition metal compounds without f-electrons. However, KH has not yet been observed in 4d/5d transition metal compounds, since more extended 4d/5d orbitals do not usually form flat bands that supply localised electrons appropriate for Kondo pairing. Here, we report a substitution- and temperature-dependent angle-resolved photoemission study on 4d Ca2−xSrxRuO4, which shows the signature of KH. We observed a spectral weight transfer in the γ-band, reminiscent of an orbital-selective Mott phase (OSMP). The Mott localised γ-band induces the KH with an itinerant β-band, resulting in spectral weight suppression around the Fermi level. Our work demonstrates the evolution of the OSMP with possible KH among 4d electrons, and thereby expands the material boundary of Kondo physics to 4d multi-orbital systems.

Abstract Background The efficacy and safety of high-power, short-duration (HPSD) radiofrequency catheter ablation for atrial fibrillation (AF) have been demonstrated in several studies. We aimed to evaluate and compare the effects of the conventional method and the HPSD method for AF ablation on the sinus and AV node function in patients with paroxysmal AF. Methods The medical records of patients with paroxysmal AF who underwent pulmonary vein isolation (PVI) were retrieved from a prospectively collected AF ablation registry at a large-sized tertiary center. The HPSD group (n = 41) was distinguished from the conventional ablation group (n = 198) in terms of the power (50 W vs. 20–40 W) and duration (6–10 s vs. 20–30 s) of radiofrequency energy delivery during PVI. Peri-procedural changes in cardiac autonomy were assessed in terms of the changes in sinus cycle length (SCL), block cycle length (BCL), and effective refractory period (ERP) of the atrioventricular node (AVN). Results The SCL, BCL, and ERP of the AVN at baseline and post-ablation were not significantly different between the conventional ablation group and the HPSD group. Shortening of the SCL, BCL, and ERP of the AVN was observed immediately after AF ablation in both groups. One-year recurrence of AF/atrial flutter (35.1% vs. 20.3%; P = 0.011) and atrial flutter (13.8% vs. 4.7%; P = 0.015) were higher in the HPSD group than in the conventional ablation group. Conclusion Both the HPSD and the conventional ablation method resulted in post-ablation vagal modification as evidenced by the shortening of SCL, BCL, and ERP of the AVN. One-year recurrence of atrial flutter and AF/atrial flutter was higher in patients who underwent the HPSD method.

IntroductionDespite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. MethodsHere, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. ResultsDifferential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. DiscussionAberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

Background The GlideScope® videolaryngoscope (GVL) is widely used in patients with difficult airways and provides a good glottic view. However, the acute angle of the blade can make insertion and advancement of an endotracheal tube (ETT) more difficult than direct laryngoscopy, and the use of a stylet is recommended. This randomized controlled trial compared Parker Flex-It™ stylet (PFS) with GlideRite® rigid stylet (GRS) to facilitate intubation with the GVL in simulated difficult intubations. Methods Fifty-four patients were randomly allocated to undergo GVL intubation using either GRS (GRS group) or PFS (PFS group). The total intubation time (TIT), 100-mm visual analog scale (VAS) for ease of intubation, success rate at the first attempt, use of laryngeal manipulation, tube advancement rate by assistant, and complications were recorded. Results There was no significant difference between the GRS and PFS groups regarding TIT (50.3 ± 12.0 s in the GRS group and 57.8 ± 18.8 s in the PFS group, P = 0.108). However, intubation was more difficult in the PFS group than in the GRS group according to VAS score (P = 0.011). Cases in which the ETT was advanced from the stylet by an assistant, were more frequent in the GRS group than in the PFS group (P = 0.002). The overall incidence of possible complications was not significantly different. Conclusions In patients with a simulated difficult airway, there was no difference in TIT using either the PFS or GRS. However, endotracheal intubation with PFS is more difficult to perform than GRS.

In recent times, the production of multidimensional data in various domains and their storage in array databases has witnessed a sharp increase; this rapid growth in data volumes necessitates compression in array databases. However, existing compression schemes used in array databases are general-purpose and not designed specifically for the databases. They could degrade query performance with complex analytical tasks, which incur huge computing costs. Thus, a compression scheme that considers the workflow of array databases is required. This study presents a compression scheme, SEACOW, for storing and querying multidimensional array data. The scheme is specially designed to be efficient for both dimension-based and value-based exploration. It considers data access patterns for exploration queries and embeds a synopsis, which can be utilized as an index, in the compressed array. In addition, we implement an array storage system, namely MSDB, to perform experiments. We evaluate query performance on real scientific datasets and compared it with those of existing compression schemes. Finally, our experiments demonstrate that SEACOW provides high compression rates compared to existing compression schemes, and the synopsis improves analytical query processing performance.

Abstract Purpose We aimed to compare the outcomes and complications of anatomical shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) for primary glenohumeral osteoarthritis with intact cuff tissue. Materials and methods The MEDLINE, Embase, and Cochrane Library databases were systematically searched for studies published before March 2, 2021 using the PRISMA guidelines. Studies were included if they directly compared aTSA and rTSA for treating primary glenohumeral arthritis. A meta-analysis was performed using six studies that compared radiologic outcomes, functional scores, and range of motion (ROM). All the data were pooled using a random-effects model. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated as dichotomous data, while continuous data were analyzed using mean differences with 95% CIs. Results Two independent researchers reviewed 1,061 studies. Six studies met the inclusion criteria. The range of motion, especially external rotation, was better for aTSA than for rTSA (MD = − 10.28, 95% CI: − 16.69 to − 3.88, P = 0.002). Functional scores showed no difference between aTSA and rTSA. Glenoid loosening (OR = 0.17, 95% CI: 0.06–0.50, P = 0.001) was more common with aTSA, and scapula notching (OR = 10.63, 95% CI: 1.73–65.27, P = 0.01) with rTSA. In the mid-term follow-up, the overall revision rate showed no difference between aTSA and rTSA, with a pooled OR of 0.33 (95% CI: 0.07–1.57, P = 0.16). Conclusion A better ROM was achieved after aTSA than after rTSA. There was no difference in the revision rate at mid-term follow-up between aTSA and rTSA. Glenoid loosening was more common with aTSA, and scapula notching with rTSA. Level of evidence: Level IV, Meta-analysis.

Accurately estimating the pose of a vehicle is important for autonomous parking. The study of around view monitor (AVM)-based visual Simultaneous Localization and Mapping (SLAM) has gained attention due to its affordability, commercial availability, and suitability for parking scenarios characterized by rapid rotations and back-and-forth movements of the vehicle. In real-world environments, however, the performance of AVM-based visual SLAM is degraded by AVM distortion errors resulting from an inaccurate camera calibration. Therefore, this paper presents an AVM-based visual SLAM for autonomous parking which is robust against AVM distortion errors. A deep learning network is employed to assign weights to parking line features based on the extent of the AVM distortion error. To obtain training data while minimizing human effort, three-dimensional (3D) Light Detection and Ranging (LiDAR) data and official parking lot guidelines are utilized. The output of the trained network model is incorporated into weighted Generalized Iterative Closest Point (GICP) for vehicle localization under distortion error conditions. The experimental results demonstrate that the proposed method reduces localization errors by an average of 39% compared with previous AVM-based visual SLAM approaches.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer with a poor prognosis and low survival rates. The prognostic and predictive biomarkers of PDAC are still largely unknown. The receptor CD74 was recently identified as a regulator of oncogenic properties in various cancers. However, the precise molecular mechanism of CD74 action in PDAC remains little understood. We investigated the role of CD74 by silencing CD74 in the pancreatic cancer cell line Capan-1. CD74 knockdown led to reductions in cell proliferation, migration, and invasion and increased apoptosis. Moreover, silencing CD74 resulted in the decreased expression and secretion of S100A8 and S100A9. An indirect co-culture of fibroblasts and tumor cells revealed that fibroblasts exposed to conditioned media from CD74 knockdown cells exhibited a reduced expression of inflammatory cytokines, suggesting a role of CD74 in influencing cytokine secretion in the tumor microenvironment. Overall, our study provides valuable insights into the critical role of CD74 in regulating the oncogenic properties of pancreatic cancer cells and its influence on the expression and secretion of S100A8 and S100A9. Taken together, these findings indicate CD74 as a potential diagnostic biomarker and therapeutic target for pancreatic cancer.

This review article discusses the clinical significance of intraoperative neurophysiological monitoring (IONM), provides recommendations for monitoring protocols, and considers the interpretation of results in microvascular decompression (MVD) for hemifacial spasm (HFS). The lateral spread response (LSR) is an important monitoring parameter during MVD. It helps to identify the responsible blood vessel and confirms its thorough decompression from the facial nerve. The disappearance of the LSR during surgery is associated with favorable clinical outcomes. Standard and revised monitoring protocols and the confirmation of LSR persistence and disappearance are also discussed. The blink reflex and other facial nerve monitoring modalities, such as free-running electromyography, facial motor evoked potentials, F-waves, and the Z-L response, are further considered.

Transition metal oxides exhibit a variety of correlated phases in their bulk form; however, they typically become insulators in the monolayer limit. Here, the authors report a correlated metallic state in a single-atomic layer of epitaxial SrRuO3, realized in epitaxial oxide heterostructure.

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.

Sepsis is a life-threatening systemic inflammatory condition causing approximately 11 million annual deaths worldwide. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been recognized, our understanding of the factors that predispose patients to septic mortality is limited. Due to the lack of reliable prognostic measures, the development of appropriate clinical management that improves patient survival remains challenging. Here, we discovered that a subpopulation of CD49chigh neutrophils with dramatic upregulation of the complement component 1q (C1q) gene expression arises during severe sepsis. We further found that deceased septic patients failed to maintain C1q protein expression in their neutrophils, whereas septic survivors expressed higher levels of C1q. In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. Apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis; thus, treatment of septic mice with C1q drastically increased survival. These results suggest that neutrophil C1q is a reliable prognostic biomarker of septic mortality and a potential novel therapeutic target for the treatment of sepsis.

Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.

Abstract Background Spontaneous subdural hematoma rarely presents with a hypervascular or malignant tumor but even less frequently in a benign tumor like meningioma. We encountered a patient with acute subdural hematoma associated with benign meningioma. Here, we report this case along with a review of previous reports, especially focusing on their clinical features and possible bleeding mechanisms. Case presentation A 53-year-old Asian woman presented with severe headache and progressive neurologic deterioration due to cerebral edema. The patient was submitted to open surgery for evacuation of the subdural hematoma and concurrent tumor removal on the ipsilateral parietal convexity. A hypervascular, encapsulated mass was identified during surgery and completely removed including the adjacent dura mater (Simpson grade 0). The tumor was histologically confirmed as an angiomatous meningioma (World Health Organization grade I). Her clinical course was uneventful after surgery. Conclusions Although meningiomas are commonly benign according to their histological traits, they can lead to spontaneous bleeding and cause neurologically unstable condition. Therefore, meningiomas need to be considered as a cause of spontaneous subdural hematoma if radiologically suspicious, which should be reflected by proper management for a positive outcome.

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.

Abstract. Lumbar spinal stenosis is a common degenerative disorder that is characterized by pain and neurogenic claudication. Previous studies have evaluated the effects of an epidural steroid injection (ESI) on spinal stenosis, based on changes to the spinal canal diameter. This study aimed to examine the impact of the ESI on pain scores and walking distance in patients with lumbar central spinal stenosis, stratified based on disease severity, which was graded according to the degree of cauda equina separation. We reviewed the medical records of patients who received the ESI for lumbar spinal central canal stenosis. A total of 128 patients were divided into moderate and severe groups, based on the degree of cauda equina separation. Relative to baseline values, 2 weeks after the ESI, the moderate group showed a significant decrease in the numeric rating scale (NRS) scores and an increase in walking distance. Meanwhile, the severe group showed a significant decrease in the NRS scores and no significant change in walking distance. The moderate group had lower NRS scores and a longer walking distance than did the severe group 2 weeks after the ESI. The proportion of patients with improved levels of satisfaction was higher in the moderate group than in the severe group. Lumbar interlaminar ESI may reduce pain scores and increase walking distance in patients with moderate lumbar spinal central canal stenosis. Patients with moderate spinal stenosis achieved better outcomes than did patients with severe stenosis.

This paper proposes an algorithm for path-following and collision avoidance of an autonomous vehicle based on model predictive control (MPC) using time-varying and non-uniformly spaced horizon. The MPC based on non-uniformly spaced horizon approach uses the time intervals that are small for the near future, and time intervals that are large for the distant future, to extend the length of the whole prediction horizon with a fixed number of prediction steps. This MPC has the advantage of being able to detect obstacles in advance because it can see the distant future. However, the presence of longer time interval samples may lead to poor path-following performance, especially for paths with high curvature. The proposed algorithm performs proper adjustment of the prediction interval according to a given situation. For sections with large curvature, it uses the short prediction intervals to increase the path-following performance; further, to consider obstacles over a wider range, it uses the long prediction intervals. This technique allows simultaneous improvement of the path-following performance and the range of obstacle avoidance with fixed computational complexity. The effectiveness of the proposed method is verified through an open-source simulator, CARLA and real-time experiments.

Therapies and vaccines for COVID-19, caused by the SARS-CoV-2 viral pandemic, are urgently needed. Here the authors establish and screen an antibody library from a convalescent COVID-19 patient to isolate a neutralizing antibody with the ability to reduce viral titer and alleviate symptoms in ferret, hamster, and rhesus monkey infection models.