Differences in the DNA methylome of T cells in adults with asthma of varying severity.

BACKGROUND: DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity are less well-defined. OBJECTIVE: To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. METHODS: Peripheral blood T cells from 35 adults with asthma in Beijing, China, were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. RESULTS: Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included RUNX3, several members of the HLA family, AGT, PTPRC, PTPRJ, and several genes downstream of the JAK2 and TNF signaling pathway. CONCLUSION: These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to differences in clinical indices of asthma.

Decadal changes in microplastic accumulation in freshwater sediments: Evaluating influencing factors.

Microplastics are small plastic particles with sizes ranging between 1 µm and 5 mm. Microplastics can originate from macro plastics and degrade to a smaller size or be produced directly by manufacturers. Few studies have examined microplastic contamination in freshwater sediment cores to estimate changes in microplastic contamination over time. We present the results of a study that examined sediment cores from four watersheds, Kiskiminetas River, Blacklick Creek, Raystown Lake, and Darby Creek, in Pennsylvania, USA to reveal the history of microplastic accumulation and factors that contribute to microplastic distribution. The abundance and morphology of microplastics varied over time and between these four locations. The highest microplastic abundance was found in Raystown Lake, ranging from 704 to 5397 particles kg-1 with fiber as the dominant microplastic type, while Darby Creek (0-3000 particles kg-1), Kiskiminetas River (0-448 particles kg-1), and Blacklick Creek (0-156 particles kg-1) had lower microplastic concentration. Moreover, Darby Creek had the most diverse microplastic morphology and a trend of decreasing concentration with depth. Although the Darby Creek watershed has the most developed area and highest population density, it did not have the highest microplastic concentration. Averaged over the four cores, microplastic abundance increased as global plastics production increased from the 1950s-2010s. Our findings provide insights into the fate and transport of microplastic contamination in freshwater environments, which is vital to establishing sustainable mitigation strategies.

Evaluating Experts' Consensus on Behavioral Principles.

Over the history of our field, scholars have emphasized the critical importance that behavioral principles play in applied behavior analysis, underlining their central position as the foundation on which the field is built. Therefore, behavior analysts must have a robust comprehension of behavioral principles to be conceptually systematic, starting with understanding what constitutes a behavioral principle. Although one might assume that the behavior analytical literature clearly identifies a set of basic principles that define our field, there is no generally agreed-upon list. This study aimed to get consensus from doctoral-level behavior analysts on what they viewed as the basic principles of behavior analysis. To do so, we created a list of terms from behavior analysis texts and surveyed participants to identify whether each term constituted a basic principle or a behavioral procedure. The results suggest that there is not good consensus on what constitutes behavioral principles among doctoral-level behavior analysts who completed the survey and that there may be differences in the views of faculty and nonfaculty behavior analysts. Potential contributing factors to these results are discussed. This survey study constitutes a first step in focusing behavior analysts on this important topic and starting a discussion that could further clarify the principles that define our field.

Recruitment feasibility and dietary and behavioral patterns in toddlers with ASD: Preliminary results from the Autism Eats program.

BACKGROUND: Problematic mealtime behaviors and inadequate diet quality are pressing concerns for children with autism spectrum disorder (ASD). This study aimed to evaluate recruitment feasibility and baseline outcomes of the Autism Eats program for children under 3 years with ASD. METHODS: Recruitment feasibility was assessed through reach and participation rates. The Healthy Eating Index (HEI-2015) scores were calculated from 3-day food records. Problematic mealtime behaviors were assessed with the Brief Autism Mealtime Behavior Inventory. Parental feeding practices were assessed using the Child Feeding Questionnaire. Anthropometric measurements of children and parents were taken. Weight-for-length percentiles were calculated based on the CDC growth charts. Descriptive statistics, one-sample t-tests, and Spearman's rho correlations were used for data analysis. RESULTS: Of the contacted dyads, 74 % agreed to participate. All 51 enrolled dyads completed baseline survey (100 %), and 98 % completed 3-day food records and anthropometric measurements. Significantly higher problematic mealtime behaviors were observed, compared to the reference (e.g., Total score 55.7 vs. 32.5; p < .001). Children with ASD exhibited lower HEI-2015 scores than national data (e.g., Total score 59 vs. 62). A large proportion of the children (29 %) had a weight-for-length ≥ 95th percentile. Several significant associations were found among mealtime behaviors, diet quality, parental feeding practices, and weight status. CONCLUSION: Recruitment was highly feasible, and the findings suggest that early nutrition intervention may hold promise in addressing problematic mealtime behaviors and promoting healthier dietary habits in young children with ASD. CLINICAL TRIAL REGISTRATION: This trial has been registered at www. CLINICALTRIALS: gov (NCT05194345).

Left Ventricular Hypertrophy Regression Following Transcatheter Aortic Replacement: A Comparison of Self-Expanding Versus Balloon-Expandable Prostheses.

There are limited reports on the impact of prosthesis-patient mismatch (PPM) on the regression of left ventricular hypertrophy (LVH) after transcatheter aortic valve replacement (TAVR). We compared the relative effects of supra-annular, self-expanding (SE) versus intra-annular, balloon-expandable (BE) prostheses on TAVR LVH regression. Regression of left ventricular mass index (LVMi) was evaluated in 168 consecutive TAVR patients, including 60 treated with SE valves (Evolut series) and 108 treated with BE valves (Sapien 3). All patients had LVH determined at baseline by echocardiography and had repeat LVMi measurements at a mean follow-up time of 707 ± 528 days. SE patients were more likely female (68.3% vs 46.3%, p = 0.007), but otherwise, the 2 cohorts did not differ with respect to baseline demographics and Society of Thoracic Surgeons risk score. SE patients had a higher effective orifice area indexed to body surface area after TAVR (0.98 ± 0.29 vs 0.86 ± 0.25 cm²/m², p = 0.006), with lower mean aortic valve gradients (9.9 ± 6.5 vs 12.8 ± 5.8 mm Hg, p = 0.003) and a lower prevalence of moderate/severe PPM (33.3% vs 49.1%, p = 0.049). On follow-up, changes in LVMi were similar between the SE and BE groups, with similar absolute changes in LVMi (19.2 ± 26.8 vs 21.9 ± 31.7 g/m2, p = 0.578) and relative LVMi decrease (14.0 ± 19.5 vs 16.2% ± 24.2%, p = 0.547). No difference in LVMi regression was also noted comparing combined SE/BE patients with moderate/severe PPM versus those without PPM. In conclusion, despite differences in effective orifice area indexed to body surface area, mean aortic valve gradient, and PPM after TAVR, the degree of LVH regression during intermediate follow-up did not differ between patients receiving supra-annular SE and intra-annular BE prostheses.

Community-level bystander treatment and outcomes for witnessed out-of-hospital cardiac arrest in the state of Connecticut.

Background: Prior reports have demonstrated underutilization of bystander cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) use in patients with witnessed out-of-hospital cardiac arrest (OHCA) in Connecticut. This study aimed to identify community-level risk factors that contribute to low rates of bystander intervention to improve statewide OHCA outcomes. Methods: We analyzed 2,789 adult patients with witnessed, non-traumatic OHCA submitted to the Connecticut Cardiac Arrest Registry to Enhance Survival (CARES) between 2013-2022. Patients were grouped by zip code, and associated municipal characteristics were acquired from 2022 United States Census Bureau data. Use of bystander CPR, attempted bystander AED defibrillation, and patient survival with favorable neurological function were determined for 19 of the 20 most populous cities and towns. Pearson correlation tests and linear regression were used to determine associations between OHCA treatment and outcomes with population size, racial/ethnic demographics, language use, income, and educational level. Results: Bystander CPR was lower in municipalities with population size > 100,000 and in communities where > 40% of residents are non-English-speaking. AED use was also lower in these municipalities, as well as those with per capita incomes < $40,000 or > 1/3 Hispanic residents. Communities with populations > 100,000, > 40% non-English-speaking, per capita income < $40,000, and > 1/3 Hispanic residents were all associated with lower survival rates. Conclusions: OHCA pre-hospital treatment and outcomes vary significantly by municipality in Connecticut. Community outcomes might be improved by specifically targeting urban population centers and Hispanic communities with culturally sensitive, low, or no-cost CPR and AED educational programs, using instructional languages other than English.

Spontaneous coronary artery dissection: a case series illustrating current challenges in diagnosis and treatment.

Spontaneous coronary artery dissection (SCAD) has been increasingly recognized in recent years as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, especially among young women. However, due to the lack of clinical trials on SCAD, evidence-based guidance on management is currently lacking. Presented are four case studies that illustrate the recent insights and challenges in SCAD diagnosis and treatment.

Spontaneous coronary artery dissection (SCAD) is a condition where the layers of a coronary artery tear without any apparent cause. In recent years, it has become more recognized as an important cause of chest pain, heart attacks, and sudden death, especially in younger women. However, because of the lack of clinical trials focused on SCAD, there is insufficient evidence-based guidance on managing the condition. This article shares four cases to show the current knowledge and challenges in diagnosing and treating SCAD.

Behavioral skills training produces acquisition and generalization of run-blocking skills of high school football players.

Behavioral skills training (BST) has been used to improve football players' performance in one prior study, but limited data were collected on how the skill generalized from the training environment to the natural environment. The purpose of this study was to further evaluate the effects of BST in enhancing football players' performance while also evaluating the generalization of a skill taught in a training environment (i.e., practice) to the natural environment (i.e., game-simulated scrimmage). This study included five high school offensive line football players and recorded their run-blocking skills in the training context and a game context in baseline and following BST. The results showed that BST improved performance in the training environment, with run-blocking skills slightly generalizing from the training environment to game-simulated scrimmages. When BST was conducted in the natural environment, it further improved the participants' run-blocking skills.

HER2 antibody-drug conjugates are active against desmoplastic small round cell tumor.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation with very poor outcomes. Herein, we leveraged ERBB2/HER2 expression in DSRCT as a therapeutic target. EXPERIMENTAL DESIGN: ERBB2/HER2 expression was evaluated in clinical samples and patient-derived xenografts (PDX) using RNA-seq, RT-qPCR, and a newly developed HER2 IHC assay (Clone 29D8). Responses to HER2 antibody-drug conjugates (ADC) -trastuzumab deruxtecan (DS-8201, T-DXd) and trastuzumab emtansine (T-DM1)- were evaluated in DSRCT-PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays. RESULTS: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity of RNA assays and improved IHC detectability using Clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or T-DM1 resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2-ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status. Conclusions ERBB2/HER2 is a therapeutic target for DSRCT. HER2-ADCs are novel options for managing this exceptionally aggressive sarcoma and may fulfill its urgent and historically unmet need for more effective clinical therapy.

PpIX-enabled fluorescence-based detection and photodynamic priming of platinum-resistant ovarian cancer cells under fluid shear stress.

Over 75% percent of ovarian cancer patients are diagnosed with advanced-stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build-up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi-line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced-stage ovarian cancer will relapse and succumb to platinum-resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial-to-mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS-induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro-drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence-based biomarker of FSS-induced platinum resistance. Additionally, this study investigates the efficacy of PpIX-enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov-3 and NIH:OVCAR-3 cells, two representative cell lines for high-grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA-PpIX-mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX-mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence-based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.

Impact of Small Aortic Annuli on the Performance of Transcatheter Aortic Valve Replacement Bioprostheses: An Updated Meta-Analysis of Recent Studies.

A metanalysis of available randomized controlled trials and observational studies comparing self-expanding (SE) and balloon-expandable (BE) bioprostheses in patients with small aortic annulus and aortic stenosis for short- and midterm hemodynamic and clinical outcomes was performed. A total of 21 studies with a total 8,647 patients (SE: n = 4,336 patients vs BE: n = 4,311 patients) were included. SE bioprostheses had a lower postoperative mean gradient at 30 days (Mean Difference [MD] -5.16, 95% confidence interval [CI] 4.7 to 5.5, p <0.001) and at 1 year (MD -6.6, 95%CI 6.1 to 7.03, p <0.001), with a larger indexed effective orifice area (0.17, 95% CI 0.13 to 0.22, p <0.001 and 0.17, 95% CI 0.08 to 0.27, p <0.001) at both time intervals. BE bioprostheses had a higher risk of 30-day and 1-year severe prosthesis-patient mismatch (risk ratio [RR] 1.07, 95% CI 1.04 to 1.09, p <0.001; RR 1.07, 95% CI 1.04 to 1.11, p <0.001). The 30-day and 1 year paravalvular leaks (RR 0.99, 95% CI 0.98 to 0.99, p <0.001; RR 0.89, 95% CI 0.82 to 0.95, p <0.001) and permanent pacemaker implantation (RR 0.97, 95% CI 0.94 to 0.99, p 0.01, I2 = 40%,) were lower in the BE group. BE bioprostheses were associated with a lower risk of in-hospital stroke (RR 0.99, 95% CI 0.98 to 1, p = 0.01). In conclusion, in patients with small aortic annulus and aortic stenosis, SE bioprostheses have superior hemodynamic performance but higher rates of paravalvular leak, permanent pacemaker implantation, and in-hospital stroke. BE bioprostheses were associated with a higher risk of severe prosthesis-patient mismatch.

Comparing video feedback and video modeling plus video feedback for improving soccer skills.

This study compared the effects of video feedback (VF) as a stand-alone intervention and video modeling plus video feedback (VMVF) for improving soccer players' static ball control skills. Research has suggested that VF alone and VMVF produce substantial improvements for young athlete's skills, though no studies have compared the two. Therefore, we used a multiple-baseline-across-participants design with embedded alternating treatments to compare VF and VMVF. Two 10-year-old female soccer players and one 9-year-old male soccer player participated. The first author implemented the VF and VMVF training procedures and assessed the same three target behaviors across participants. The results suggested that VF and VMVF produced similar increases in performance for two of three participants and that VMVF produced slightly greater increases for one participant. In addition, both interventions were effective at substantially improving ball control skills from baseline levels and relative to a control skill.

Response of hypoxia to future climate change is sensitive to methodological assumptions.

Climate-induced changes in hypoxia are among the most serious threats facing estuaries, which are among the most productive ecosystems on Earth. Future projections of estuarine hypoxia typically involve long-term multi-decadal continuous simulations or more computationally efficient time slice and delta methods that are restricted to short historical and future periods. We make a first comparison of these three methods by applying a linked terrestrial-estuarine model to the Chesapeake Bay, a large coastal-plain estuary in the eastern United States. Results show that the time slice approach accurately captures the behavior of the continuous approach, indicating a minimal impact of model memory. However, increases in mean annual hypoxic volume by the mid-twenty-first century simulated by the delta approach (+ 19%) are approximately twice as large as the time slice and continuous experiments (+ 9% and + 11%, respectively), indicating an important impact of changes in climate variability. Our findings suggest that system memory and projected changes in climate variability, as well as simulation length and natural variability of system hypoxia, should be considered when deciding to apply the more computationally efficient delta and time slice methods.

CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/ß-Catenin Signaling to Inhibit EZH2-Driven EMT.

Metaplastic breast carcinomas (mBrCA) are a highly aggressive subtype of triple-negative breast cancer with histologic evidence of epithelial-to-mesenchymal transition and aberrant differentiation. Inactivation of the tumor suppressor gene cellular communication network factor 6 (CCN6; also known as Wnt1-induced secreted protein 3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with epithelial-to-mesenchymal transition. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. In this study, we showed that CCN6 interacts with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of ß-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a ß-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/ß-catenin/TCF signaling in Ccn6-KO mBrCA cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacologic inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated ß-catenin and high EZH2 in human spindle mBrCAs compared with other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a ß-catenin/TCF/EZH2 axis and highlight the inhibition of ß-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs. Significance: CCN6 deficiency drives metaplastic breast carcinoma growth and metastasis by increasing Wnt/ß-catenin activation to upregulate EZH2, identifying EZH2 inhibition as a mechanistically guided treatment strategy for this deadly form of breast cancer.

Impact of Persistent Versus Paroxysmal Preoperative Atrial Fibrillation on In-Hospital, One-Year, and Late Clinical Outcomes Following Transcatheter Aortic Valve Implantation.

Previous reports on the impact of preexisting atrial fibrillation (AF) on clinical outcomes after transcatheter aortic valve implantation (TAVI) have presented limited data on the relative impact of paroxysmal versus persistent AF subtypes. We compared in-hospital, 1-year, and late clinical outcomes in 1,098 patients who underwent TAVI with preoperative AF (556 paroxysmal, 542 persistent) versus 1,787 patients without AF. The propensity-matched cohorts with AF (n = 643) and without AF (n = 686) did not differ with respect to baseline clinical characteristics, operative technique, or in-hospital TAVI complications. At 1-year, patients with AF had higher all-cause mortality (9.0% vs 6.1%, p = 0.046) and readmission rates (13.1 vs 8.8%, p = 0.014), with lower Kansas City cardiomyopathy questionnaire scores (77.8 ± 21.8 vs 84.3 ± 17.1, p <0.001). Echocardiographic follow-up (mean time 455 ± 285 days) demonstrated no significant intergroup differences in hemodynamic findings other than a progressive increase in left atrial volume index in patient subgroups (without AF: 37.4 ± 14.7 ml/m2 vs paroxysmal AF: 46.4 ± 21.4 ml/m2 vs persistent AF: 60.5 ± 26.3 ml/m2, p <0.001). On late follow-up (mean time 49.0 [45.1 to 52.9] months), patients with persistent AF had worse all-cause mortality than patients without AF (hazard ratio 1.55, 95% confidence interval 1.17 to 2.06, p = 0.003), with no significant survival differences between the paroxysmal AF and without AF subgroups. In conclusion, patients with preexisting AF and patients without AF who underwent TAVI had similar in-hospital outcomes but worse 1-year mortality, hospital readmission, and quality of life outcomes. Compared with patients without AF, patients with persistent but not paroxysmal preexisting AF have higher late all-cause mortality at a mean follow-up of 49 months. Patients with persistent AF have higher levels of left atrial volume index than patients with paroxysmal AF and patients without AF on intermediate echocardiographic follow-up.

A Wirelessly Powered Scattered Neural Recording Wearable System.

This paper introduces a wirelessly powered scattered neural recording wearable system that can facilitate continuous, untethered, and long-term electroencephalogram (EEG) recording. The proposed system, including 32 standalone EEG recording devices and a central controller, is incorporated in a wearable form factor. The standalone devices are sparsely distributed on the scalp, allowing for flexible placement and varying quantities to provide extensive spatial coverage and scalability. Each standalone device featuring a low-power EEG recording application-specific integrated circuit (ASIC) wirelessly receives power through a 60 MHz inductive link. The low-power ASIC design (84.6 µW) ensures sufficient wireless power reception through a small receiver (Rx) coil. The 60 MHz inductive link also serves as the data carrier for wireless communication between standalone devices and the central controller, eliminating the need for additional data antennas. All these efforts contribute to the miniaturization of standalone devices with dimensions of 12 × 12 × 5 mm3, enhancing device wearability. The central controller applies the pulse width modulation (PWM) scheme on the 60 MHz carrier, transmitting user commands at 4 Mbps to EEG recording ASICs. The ASIC employs a novel synchronized PWM demodulator to extract user commands, operating signal digitization and data transmission. The analog frontend (AFE) amplifies the EEG signal with a gain of 45 dB and applies band-pass filtering from 0.03 Hz to 400 Hz, with an input-referred noise (IRN) of 3.62 µVRMS. The amplified EEG signal is then digitized by a 10-bit successive approximation register (SAR) analog-to-digital converter (ADC) with a peak signal-to-noise and distortion ratio (SNDR) of 55.4 dB. The resulting EEG data is transmitted to an external software-defined radio (SDR) Rx through load-shift-keying (LSK) backscatter at 3.75 Mbps. The system's functionality is fully evaluated in human experiments.

Comparing stimulus preference and response force in a conjugate preparation: A replication with auditory stimulation.

This study examined a conjugate approach for evaluating auditory stimulus preference for 81 participants using force as a continuous response dimension. First, the researchers used a verbal preference assessment to evaluate each participant's preference for listening to five genres of music. This process identified high-preference and low-preference music for each participant. Thereafter, the researchers exposed each participant to the five music genres in a randomized order while using a hand dynamometer to measure their response force to increase the auditory clarity of the music. The results indicate (a) 63% of the participants' high-preference music genres corresponded to the genre for which they exerted the highest mean force and (b) most participants' low-preference music genres corresponded to the genre for which they exerted the lowest mean force. These findings are consistent with those from Davis et al. (2021) and further support using conjugate preparations for measuring the relative value of some stimulus events.

A Wireless Multimodal Physiological Monitoring ASIC for Animal Health Monitoring Injectable Devices.

Utilizing injectable devices for monitoring animal health offers several advantages over traditional wearable devices, including improved signal-to-noise ratio (SNR) and enhanced immunity to motion artifacts. We present a wireless application-specific integrated circuit (ASIC) for injectable devices. The ASIC has multiple physiological sensing modalities including body temperature monitoring, electrocardiography (ECG), and photoplethysmography (PPG). The ASIC fabricated using the CMOS 180 nm process is sized to fit into an injectable microchip implant. The ASIC features a low-power design, drawing an average DC power of 155.3 µW, enabling the ASIC to be wirelessly powered through an inductive link. To capture the ECG signal, we designed the ECG analog frontend (AFE) with 0.3 Hz low cut-off frequency and 45-79 dB adjustable midband gain. To measure PPG, we employ an energy-efficient and safe switched-capacitor-based (SC) light emitting diode (LED) driver to illuminate an LED with milliampere-level current pulses. A SC integrator-based AFE converts the current of photodiode with a programmable transimpedance gain. A resistor-based Wheatstone Bridge (WhB) temperature sensor followed by an instrumentation amplifier (IA) provides 27-47 °C sensing range with 0.02 °C inaccuracy. Recorded physiological signals are sequentially sampled and quantized by a 10-bit analog-to-digital converter (ADC) with the successive approximation register (SAR) architecture. The SAR ADC features an energy-efficient switching scheme and achieves a 57.5 dB signal-to-noise-and-distortion ratio (SNDR) within 1 kHz bandwidth. Then, a back data telemetry transmits the baseband data via a backscatter scheme with intermediate-frequency assistance. The ASIC's overall functionality and performance has been evaluated through an in vivo experiment.

Illumination of understudied ciliary kinases.

Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography.

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.