A 38-Year-Old Woman With REM Predominant Central Sleep Apnea After Bulbar Infarction.

CASE PRESENTATION: A 38-year-old previously healthy woman was referred to our sleep center for recurrent witnessed breathing arrest during sleep. She had been brought to the ED 3 months earlier because of sudden onset of dizziness with nausea and vomiting, numbness and weakness of the left limb, less clear speech, double vision, dysphagia, and choking cough while drinking water. Brain MRI showed an acute cerebral infarction in the left medulla oblongata (Fig 1). High-resolution MRI showed vertebral artery dissection (Fig 2). Antiplatelet aggregation, lipid reduction, plaque stabilization, and trophic nerve treatments were administered, and the left limb strength, speech, and swallowing function improved. She complained of poor sleep and difficulties with memory.

Exploring Bimanual Haptic Feedback for Spatial Search in Virtual Reality.

Spatial search tasks are common and crucial in many Virtual Reality (VR) applications. Traditional methods to enhance the performance of spatial search often employ sensory cues such as visual, auditory, or haptic feedback. However, the design and use of bimanual haptic feedback with two VR controllers for spatial search in VR remains largely unexplored. In this work, we explored bimanual haptic feedback with various combinations of haptic properties, where four types of bimanual haptic feedback were designed, for spatial search tasks in VR. Two experiments were designed to evaluate the effectiveness of bimanual haptic feedback on spatial direction guidance and search in VR. The results from the first experiment reveal that our proposed bimanual haptic schemes significantly enhanced the recognition of spatial directions in terms of accuracy and speed compared to spatial audio feedback. The second experiment's findings suggest that the performance of bimanual haptic feedback was comparable to or even better than the visual arrow, especially in reducing the angle of head movement and enhancing searching targets behind the participants, which was supported by subjective feedback as well. Based on these findings, we have derived a set of design recommendations for spatial search using bimanual haptic feedback in VR.

Perovskite-based photodetector for real-time and quantitative monitoring of sports motion.

Reliable monitoring the movement amplitude and dynamics during sports exercise is significant for improving training results and preventing training wound. Here, we present a printed perovskite-based photodetector for real-time and quantitative monitoring of sports motion. The ordered nucleation and growth of perovskite crystals are regulated by the 4-acetamidothiophenol (AMTP) at the interface, which promotes the size of perovskite crystals into the micrometer. Benefiting from the uniformity of the AMTP-regulated MAPbI3, the as-prepared photodetector gives great photocurrent response under indoor light or outdoor light. During the exercise, real-time monitoring sports motion is achieved through detecting the illumination changing of photodetectors attaching on the wrist and ankles. Moreover, twelve kinds of common sports can be quantitatively analyzed with the detection of illumination changing on the photodetector. Such photodetector provides an efficient measurement method of wearable electronics for sports monitoring.

The Relationship Among Nurse Leaders' Humanistic Care Behavior, Nurses' Professional Identity, and Psychological Security.

Objectives: We investigated the relationship among humanistic care behavior, nurses' professional identity, and psychological security among nurse leaders in tertiary hospitals in Beijing, China. Methods: We conducted a cross-sectional survey using convenience sampling to select 1600 clinical nurses from 5 general tertiary hospitals. Participants were surveyed electronically using the Socio-Demographic Profile Questionnaire, the Scale of Humanistic Care Behavior Shown by Nurse Leaders to Nurses, the Nurses' Professional Identity Scale, and the Psychological Security Scale. Results: A total of 1600 questionnaires were distributed, and 1526 valid questionnaires were collected. There was a significant positive correlation between nurse leaders' humanistic care behavior and nurses' professional identity (r=0.66, p<.001). There was also a significant positive correlation between nurse leaders' humanistic care behavior and psychological security (r=0.45, p<.001) and between psychological security and nurses' professional identity (r=0.64, p<.001). A multiple regression analysis showed that the humanistic care behavior of nurse leaders and the psychological security of nurses influenced nurses' professional identity. Structural equation modelling analysis showed that psychological security played a mediating role in the humanistic care behavior of nurses and nurses' professional identity (ß=0.210, p<.001). Conclusions: The humanistic care behavior of nurse leaders significantly affects nurses' professional identity and psychological security scores. Nurse leaders' humanistic care can also indirectly affect professional identity through psychological security as a mediator; therefore, in nursing management, improving nurse leaders' humanistic care behavior can improve nurses' professional identity.

Wearable perovskite solar cells by aligned liquid crystal elastomers.

In a flexible perovskite solar cell, the bottom interface between perovskite and the electron-transporting layer is critical in determining its efficiency and reliability. High defect concentrations and crystalline film fracturing at the bottom interface substantially reduce the efficiency and operational stability. In this work, a liquid crystal elastomer interlayer is intercalated into a flexible device with the charge transfer channel toughened by the aligned mesogenic assembly. The molecular ordering is instantly locked upon photopolymerization of liquid crystalline diacrylate monomers and dithiol-terminated oligomers. The optimized charge collection and the minimized charge recombination at the interface boost the efficiency up to 23.26% and 22.10% for rigid and flexible devices, respectively. The liquid crystal elastomer-induced suppression of phase segregation endows the unencapsulated device maintaining >80% of the initial efficiency for 1570 h. Moreover, the aligned elastomer interlayer preserves the configuration integrity with remarkable repeatability and mechanical robustness, which enables the flexible device to retain 86% of its original efficiency after 5000 bending cycles. The flexible solar cell chips are further integrated into a wearable haptic device with microneedle-based arrays of sensors to demonstrate a pain sensation system in virtual reality.

Construction of a constitutively active type III secretion system for heterologous protein secretion.

Proteins comprise a multibillion-dollar industry in enzymes and therapeutics, but bacterial protein production can be costly and inefficient. Proteins of interest (POIs) must be extracted from lysed cells and inclusion bodies, purified, and resolubilized, which adds significant time and cost to the protein-manufacturing process. The Salmonella pathogenicity island 1 (SPI-1) type III secretion system (T3SS) has been engineered to address these problems by secreting soluble, active proteins directly into the culture media, reducing the number of purification steps. However, the current best practices method of T3SS pathway activation is not ideal for industrial scaleup. Previously, the T3SS was activated by plasmid-based overexpression of the T3SS transcriptional regulator, hilA, which requires the addition of a small molecule inducer (IPTG) to the culture media. IPTG adds significant cost to production and plasmid-based expression is subject to instability in large-scale fermentation. Here, we modulate the upstream transcriptional regulator, hilD, to activate the T3SS via three distinct methods. In doing so, we develop a toolbox of T3SS activation methods and construct constitutively active T3SS strains capable of secreting a range of heterologous proteins at titers comparable to plasmid-based hilA overexpression. We also explore how each activation method in our toolbox impacts the SPI-1 regulatory cascade and discover an epistatic relationship between T3SS regulators, hilE and the hilD 3' untranslated region (hilD 3'UTR). Together, these findings further our goal of making an industrially competitive protein production strain that reduces the challenges associated with plasmid induction and maintenance. KEY POINTS: • Characterized 3 new type III secretion system (T3SS) activation methods for heterologous protein secretion, including 2 constitutive activation methods. • Eliminated the need for a second plasmid and a small molecule inducer to activate the system, making it more suitable for industrial production. • Discovered new regulatory insights into the SPI-1 T3SS, including an epistatic relationship between regulators hilE and the hilD 3' untranslated region.

Comprehensive microRNA analysis across genome-edited colorectal cancer organoid models reveals miR-24 as a candidate regulator of cell survival.

Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect microRNAs. Here, using genetically-modified mouse intestinal organoid (enteroid) models, we identify 12 different modules of microRNA expression patterns across different combinations of mutations common in CRC. We also show that miR-24-3p is aberrantly upregulated in genetically-modified mouse enteroids irrespective of mutational context. Furthermore, we identify an enrichment of miR-24-3p predicted targets in downregulated gene lists from various mutational contexts compared to WT. In follow-up experiments, we demonstrate that miR-24-3p promotes CRC cell survival in multiple cell contexts. Our novel characterization of genotype-specific patterns of miRNA expression offer insight into the mechanisms that drive inter-tumor heterogeneity and highlight candidate microRNA therapeutic targets for the advancement of precision medicine for CRC.

Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets.

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Multidimensional assessment and cluster analysis for OSA phenotyping.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a heterogeneous disease with varying phenotype. A cluster analysis based on multidimensional disease characteristics, including symptoms, anthropometry, polysomnography, and craniofacial morphology, in combination with auto-continuous positive airway pressure titration response and comorbidity profiles, was conducted within a well-characterized cohort of patients with OSA, with the aim to refine the current phenotypic expressions of OSA with clinical implications. METHODS: Two hundred ninety-one patients with a new diagnosis of moderate to severe OSA referred for auto-continuous positive airway pressure titration to the sleep center were included for analysis. In-laboratory polysomnography and craniofacial computed tomography scanning were performed, followed by an auto-continuous positive airway pressure titration. The symptom of excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale. RESULTS: Three patient phenotypes-normal weight, nonsleepy, moderate OSA; obese, nonsleepy, severe OSA; and obese, sleepy, very severe OSA with craniofacial limitation-were identified. Among the polysomnography parameters, only percentage of N3 time of total sleep time (N3%) and mean pulse oxygen saturation were found to be associated with the Epworth Sleepiness Scale score, and they only explained a small fraction of the variation (R2 = .136). Neck circumference and craniofacial limitation were associated with the more severe phenotype, which had a higher prevalence of hypertension and metabolic syndrome, greater diurnal blood gas abnormalities, and worse positive airway pressure titration response. CONCLUSIONS: Three OSA phenotypes were identified according to multiple aspects of clinical features in patients with moderate to severe OSA, who differed in their prevalence of hypertension, metabolic syndrome, diurnal blood gas parameters, and continuous positive airway pressure titration response. Self-reported excessive daytime sleepiness was not related with the severity of sleep breathing disturbance, and craniofacial limitation was associated with the more severe phenotype. These findings highlight the necessity of integrating multiple disease characteristics into phenotyping to achieve a better understanding of the clinical features of OSA. CITATION: Zhang XL, Zhang L, Li YM, et al. Multidimensional assessment and cluster analysis for OSA phenotyping. J Clin Sleep Med. 2022;18(7):1779-1788.

Association of Craniofacial and Upper Airway Morphology with Cardiovascular Risk in Adults with OSA.

BACKGROUND AND OBJECTIVE: Clinical and population-based studies have demonstrated a strong association between obstructive sleep apnea (OSA) and cardiovascular disease (CVD). Anatomical abnormalities of the craniofacial region and upper airway are important risk factors for OSA. The objective of this study was to investigate the association of craniofacial and upper airway morphology with CVD risk biomarkers. METHODS: One hundred and sixty-nine male patients with OSA underwent in-laboratory polysomnography (PSG) and upper airway computed tomography (CT) scanning. Ten-year Framingham CVD risk score (FRS) was calculated and categorized into low- and moderate-to-high-risk groups. N-terminal pro B-type natriuretic peptide (NT-proBNP) was measured as a biomarker of increased myocardial wall stress. RESULTS: Compared to the low-risk group, total sleep time (TST), the proportion of N3 (N3%) and mean oxygen saturation (SpO2mean) were lower, while the arousal index of non-rapid eye movement (NREM) sleep, apnea index (AI) of NREM sleep, apnea hypopnea index (AHI) of NREM sleep, oxygen desaturation index (ODI) and percentage of total sleep time spent with oxyhemoglobin saturation below 90% (TST90) were higher in the moderate-to-high risk group. The corrected upper airway length (UAL), ANB angle and gonion-gnathion-hyoid angle were larger for subjects in the moderate-to-high risk group than those in the low-risk group. In multiple regression analysis, TST, AINREM and adjusted UAL were independently associated with moderate-to-high CVD risk. Plasma NT-proBNP levels were higher in patients in the moderate- to high-risk group, and among the PSG and CT scan parameters, only SPO2mean was marginally associated with NT-proBNP (r=0.183, P=0.054). CONCLUSION: Craniofacial and upper airway features may contain valid cues about CVD risk, and sleep duration, obstructive event type and occurrence phase may be closely related to CVD risk for patients with OSA.

Rapid interrogation of cancer cell of origin through CRISPR editing.

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

An optimized growth medium for increased recombinant protein secretion titer via the type III secretion system.

BACKGROUND: Protein secretion in bacteria is an attractive strategy for heterologous protein production because it retains the high titers and tractability of bacterial hosts while simplifying downstream processing. Traditional intracellular production strategies require cell lysis and separation of the protein product from the chemically similar cellular contents, often a multi-step process that can include an expensive refolding step. The type III secretion system of Salmonella enterica Typhimurium transports proteins from the cytoplasm to the extracellular environment in a single step and is thus a promising solution for protein secretion in bacteria. Product titer is sensitive to extracellular environmental conditions, however, and T3SS regulation is integrated with essential cellular functions. Instead of attempting to untangle a complex web of regulatory input, we took an "outside-in" approach to elucidate the effect of growth medium components on secretion titer. RESULTS: We dissected the individual and combined effects of carbon sources, buffers, and salts in a rich nutrient base on secretion titer. Carbon sources alone decreased secretion titer, secretion titer increased with salt concentration, and the combination of a carbon source, buffer, and high salt concentration had a synergistic effect on secretion titer. Transcriptional activity measured by flow cytometry showed that medium composition affected secretion system activity, and prolonged secretion system activation correlated strongly with increased secretion titer. We found that an optimal combination of glycerol, phosphate, and sodium chloride provided at least a fourfold increase in secretion titer for a variety of proteins. Further, the increase in secretion titer provided by the optimized medium was additive with strain enhancements. CONCLUSIONS: We leveraged the sensitivity of the type III secretion system to the extracellular environment to increase heterologous protein secretion titer. Our results suggest that maximizing secretion titer via the type III secretion system is not as simple as maximizing secreted protein expression-one must also optimize secretion system activity. This work advances the type III secretion system as a platform for heterologous protein secretion in bacteria and will form a basis for future engineering efforts.

Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage.

The anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.

Acceptance of and six-month adherence to continuous positive airway pressure in patients with moderate to severe obstructive sleep apnea.

BACKGROUND: Continuous positive airway pressure (CPAP) is the most effective treatment for moderate to severe obstructive sleep apnea (OSA). Acceptance of and adherence to CPAP are crucial for optimal treatment outcomes. The aim of this study was to investigate the factors influencing patients' acceptance of and adherence to CPAP treatment. METHODS: One hundred eighty-eight patients with moderate to severe OSA who had received CPAP titration from October 2017 to September 2018 were recruited. They were interviewed at 2 weeks and at 6 months to assess CPAP use and barriers to acceptance and adherence. RESULTS: One hundred fourteen patients (60.6%) accepted CPAP treatment. Disease severity, assessed by apnea-hypopnea index (AHI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.08), subjective satisfaction of titration (OR, 12.83; 95% CI, 3.83-42.99), initial intention of CPAP therapy (OR, 3.33; 95% CI, 1.05-10.51) and short-term home CPAP trial (OR, 9.40; 95% CI, 2.85-31.08) were associated with acceptance of CPAP treatment. Two-third of the 98 CPAP acceptors reported good CPAP adherence at 6 months follow-up. Average hours of CPAP use per day for the first 2 weeks (OR, 1.88; 95% CI, 1.28-3.04) and the global problems associated with CPAP use (OR, 0.82; 95% CI, 0.73-0.91) were independent predictors of the six-month CPAP adherence. CONCLUSIONS: Nearly 40% of patients with moderate to severe OSA did not accept CPAP treatment, and one-third of those CPAP acceptors had poor adherence to CPAP treatment. Improvement in disease awareness, comfortable titration experience, short-term home CPAP trial may be of help to increase CPAP acceptance and early experience with CPAP is important for long-term adherence. The differences in predicting factors for CPAP acceptance and adherence highlight the importance of focusing on specific aspects during the whole process management of OSA.

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify new Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-κB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-κB activation.

Copula-Based Uncertainty Quantification (Copula-UQ) for Multi-Sensor Data in Structural Health Monitoring.

The problem of uncertainty quantification (UQ) for multi-sensor data is one of the main concerns in structural health monitoring (SHM). One important task is multivariate joint probability density function (PDF) modelling. Copula-based statistical inference has attracted significant attention due to the fact that it decouples inferences on the univariate marginal PDF of each random variable and the statistical dependence structure (called copula) among the random variables. This paper proposes the Copula-UQ, composing multivariate joint PDF modelling, inference on model class selection and parameter identification, and probabilistic prediction using incomplete information, for multi-sensor data measured from a SHM system. Multivariate joint PDF is modeled based on the univariate marginal PDFs and the copula. Inference is made by combing the idea of the inference functions for margins and the maximum likelihood estimate. Prediction on the PDF of the target variable, using the complete (from normal sensors) or incomplete information (due to missing data caused by sensor fault issue) of the predictor variable, are made based on the multivariate joint PDF. One example using simulated data and one example using temperature data of a multi-sensor of a monitored bridge are presented to illustrate the capability of the Copula-UQ in joint PDF modelling and target variable prediction.

Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.

Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.

Ventilatory response to exercise is preserved in patients with obesity hypoventilation syndrome.

STUDY OBJECTIVES: Blunted ventilatory responses to hypoxia and hypercapnia during resting conditions are common findings in patients with obesity hypoventilation syndrome (OHS). Exercise increases the work and oxygen cost of breathing and produces excessive carbon dioxide (CO2). The aim of this investigation was to study ventilatory responses to incremental exercise in patients with OHS. METHODS: Sixty-eight obese adults with OHS (n = 15), eucapnic obstructive sleep apnea (n = 26), or simple obesity (n = 27) participated in an incremental exercise test on a cycle ergometer and an in-laboratory sleep study. RESULTS: The peak oxygen uptake (peak VO2) and peak pulse oxygen was decreased in patients with OHS compared with patients with either obstructive sleep apnea or simple obesity. The ventilatory response to exertional metabolic demand (nadir VE/VCO2, ∆VE/∆VCO2 slope, and VE/VCO2 at peak exercise) did not significantly differ among the 3 groups. Minute ventilation, tidal volume, respiratory frequency, tidal volume/respiratory frequency, and inspiratory time/total time ratio at a given work rate were comparable among the 3 groups. Among the whole cohort, apnea-hypopnea index was not independently associated with peak VO2, and no association was found between the ∆VE/∆VCO2 slope and resting arterial partial pressure of CO2. CONCLUSIONS: The ventilatory response to incremental exercise is preserved in patients with OHS compared with patients with obstructive sleep apnea and simple obesity who were matched for age and body mass index. This result highlights the complexity of the respiratory control system during exercise for patients with OHS, which may be uncoupled with the ventilatory response during sleep and resting conditions.

An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants.

KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. SIGNIFICANCE: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents.See related commentary by Kostyrko and Sweet-Cordero, p. 1626.This article is highlighted in the In This Issue feature, p. 1611.