A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

A BIOCOMPATIBLE GLASS-ENCAPSULATED TRIAXIAL FORCE SENSOR FOR IMPLANTABLE TACTILE SENSING APPLICATIONS.

This paper reports a microfabricated triaxial capacitive force sensor. The sensor is fully encapsulated with inert and biocompatible glass (fused silica) material. The sensor comprises two glass plates, on which four capacitors are located. The sensor is intended for subdermal implantation in fingertips and palms and providing tactile sensing capabilities for patients with paralyzed hands. Additional electronic components, such as passives and IC chips, can also be integrated with the sensor in a hermetic glass package to achieve an implantable tactile sensing system. Through attachment to a human palm, the sensor has been shown to respond appropriately to typical hand actions, such as squeezing or picking up a bottle.

Frequency tunable magnetostatic wave filters with zero static power magnetic biasing circuitry.

A single tunable filter simplifies complexity, reduces insertion loss, and minimizes size compared to frequency switchable filter banks commonly used for radio frequency (RF) band selection. Magnetostatic wave (MSW) filters stand out for their wide, continuous frequency tuning and high-quality factor. However, MSW filters employing electromagnets for tuning consume excessive power and space, unsuitable for consumer wireless applications. Here, we demonstrate miniature and high selectivity MSW tunable filters with zero static power consumption, occupying less than 2 cc. The center frequency is continuously tunable from 3.4 GHz to 11.1 GHz via current pulses of sub-millisecond duration applied to a small and nonvolatile magnetic bias assembly. This assembly is limited in the area over which it can achieve a large and uniform magnetic field, necessitating filters realized from small resonant cavities micromachined in thin films of Yttrium Iron Garnet. Filter insertion loss of 3.2 dB to 5.1 dB and out-of-band third order input intercept point greater than 41 dBm are achieved. The filter's broad frequency range, compact size, low insertion loss, high out-of-band linearity, and zero static power consumption are essential for protecting RF transceivers from interference, thus facilitating their use in mobile applications like IoT and 6 G networks.

Optimal bilayer composites for temperature-tracking wireless electronics.

Modern silicone-based epidermal electronics engineered for body temperature sensing represent a pivotal development in the quest for advancing preventive medicine and enhancing post-surgical monitoring. While these compact and highly flexible electronics empower real-time monitoring in dynamic environments, a noteworthy limitation is the challenge in regulating the infiltration or obstruction of heat from the external environment into the surface layers of these electronics. The study presents a cost-effective temperature sensing solution by embedding wireless electronics in a multi-layered elastomeric composite to meet the dual needs of enhanced thermal insulation for encapsulation in contact with air and improved thermal conductivity for the substrate in contact with the skin. The encapsulating composite benefits from the inclusion of hollow silica microspheres, which reduce the thermal conductivity by 40%, while non-spherical aluminum nitride enhances the thermal conductivity of the substrate by 370%. The addition of particles to the respective composites inevitably leads to an increase in modulus. Two composite elements are engineered to coexist while maintaining a matching low modulus of 3.4 MPa and a stretchability exceeding 30%, all without compromising the optimized thermal properties. Consecutive thermal, electrical, and mechanical characterization confirms the sensor's capacity for precise body temperature monitoring during a single day's lifespan, while also assessing the influence of behavioral factors on body temperature.

Development of the next-generation functional neuro-cognitive imaging protocol - Part 1: A 3D sliding-window convolutional neural net for automated brain parcellation.

Functional MRI has emerged as a powerful tool to assess the severity of Post-concussion syndrome (PCS) and to provide guidance for neuro-cognitive therapists during treatment. The next-generation functional neuro-cognitive imaging protocol (fNCI2) has been developed to provide this assessment. This paper covers the first step in the analysis process, the development of a rapidly re-trainable, machine-learning, brain parcellation tool. The use of a sufficiently deep U-Net architecture encompassing a small (39 × 39 × 39 voxel input, 27 × 27 × 27 voxel output) sliding window to sample the entirety of the 3D image allows for the prediction of the entire image using only a single trained network. A large number of training, validating, and testing windows are thus generated from the 101 manually-labeled Mindboggle images, and full-image prediction is provided via a voxel-vote method using overlapping windows. Our method produces parcellated images that are highly consistent with standard atlas-based methods in under 3 min on a modern GPU, and the single network architecture allows for rapid retraining (<36 hr) as needed.

An implantable, wireless, battery-free system for tactile pressure sensing.

The sense of touch is critical to dexterous use of the hands and thus an essential component of efforts to restore hand function after amputation or paralysis. Prosthetic systems have addressed this goal with wearable tactile sensors. However, such wearable sensors are suboptimal for neuroprosthetic systems designed to reanimate a patient's own paralyzed hand. Here, we developed an implantable tactile sensing system intended for subdermal placement. The system is composed of a microfabricated capacitive pressure sensor, a custom integrated circuit supporting wireless powering and data transmission, and a laser-fused hermetic silica package. The miniature device was validated through simulations, benchtop assessment, and testing in a primate hand. The sensor implanted in the fingertip accurately measured applied skin forces with a resolution of 4.3 mN. The output from this novel sensor could be encoded in the brain with microstimulation to provide tactile feedback. More broadly, the materials, system design, and fabrication approach establish new foundational capabilities for various applications of implantable sensing systems.

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Parent personality traits and problem behavior in adolescence: The mediating role of adolescent personality.

INTRODUCTION: Parental personality traits are predicted to influence offspring outcomes through parenting behavior and offspring personality traits. This study explored whether mother and father personality traits relate to offspring behavior problems in mid-late adolescence METHOD: In total, 3089 Australian adolescents (1576 boys, 1513 girls; Mage = 16.46 ± 0.50 years) and their parents completed questionnaires assessing personality, conduct problems, emotional and social functioning, antisocial and criminal behavior, cigarette smoking and drug use, at a single time-point. RESULTS: After controlling for sociodemographic factors, results showed that problem behaviors in adolescence were most consistently related to mothers' scores on neuroticism and conscientiousness, and fathers' scores on neuroticism. Father personality traits were most important for antisocial and criminal behavior, whereas mother personality traits were most important for social and emotional functioning. Moderation analysis showed that associations between fathers' personality traits and some adolescent outcomes (cigarette smoking and drug use) were stronger for adolescent boys than for adolescent girls. Mediation models further demonstrated that adolescent personality traits mediated associations between parent personality and adolescent outcomes in almost all cases. Indirect effects expressed as a percentage showed that between 1.4% and 33.3% of the variance in the association between parent personality and adolescent outcomes was shared with the corresponding adolescent personality trait. CONCLUSIONS: Overall, the findings of this study provide evidence that traits inherited (directly or indirectly) from parents might have an important role in shaping problem behavior in adolescence.

An implantable wireless tactile sensing system.

The sense of touch is critical to dexterous use of the hands and thus an essential component to efforts to restore hand function after amputation or paralysis. Prosthetic systems have focused on wearable tactile sensors. But wearable sensors are suboptimal for neuroprosthetic systems designed to reanimate a patient's own paralyzed hand. Here, we developed an implantable tactile sensing system intended for subdermal placement. The system is composed of a microfabricated capacitive force sensor, a custom integrated circuit supporting wireless powering and data transmission, and a laser-fused hermetic silica package. The miniature device was validated through simulations, benchtop testing, and ex vivo testing in a primate hand. The sensor implanted in the fingertip accurately measured skin forces with a resolution of 4.3 mN. The output from this novel sensor could be encoded in the brain with microstimulation to provide tactile feedback. More broadly, the materials, system design, and fabrication approach establish new foundational capabilities for various applications of implantable sensing systems.

Concentration-Dependent Inhibition of Mesophilic PETases on Poly(ethylene terephthalate) Can Be Eliminated by Enzyme Engineering.

Enzyme-based depolymerization is a viable approach for recycling of poly(ethylene terephthalate) (PET). PETase from Ideonella sakaiensis (IsPETase) is capable of PET hydrolysis under mild conditions but suffers from concentration-dependent inhibition. In this study, this inhibition is found to be dependent on incubation time, the solution conditions, and PET surface area. Furthermore, this inhibition is evident in other mesophilic PET-degrading enzymes to varying degrees, independent of the level of PET depolymerization activity. The inhibition has no clear structural basis, but moderately thermostable IsPETase variants exhibit reduced inhibition, and the property is completely absent in the highly thermostable HotPETase, previously engineered by directed evolution, which simulations suggest results from reduced flexibility around the active site. This work highlights a limitation in applying natural mesophilic hydrolases for PET hydrolysis and reveals an unexpected positive outcome of engineering these enzymes for enhanced thermostability.

Rational Design of a Bifunctional Peptide Exhibiting Lithium Titanate Oxide and Carbon Nanotube Affinities for Lithium-Ion Battery Applications.

Phage display is employed as a method for identifying polypeptides that bind to lithium-ion battery materials, specifically lithium titanate oxide (LTO) and multiwalled carbon nanotubes (MWCNTs). Output/input assays are used as a quantitative measure to narrow down the strongest binding polypeptides from several peptides selected through biopanning. Negatively stained transmission electron microscopy is used to verify that a phage presenting a particular LTO or MWCNT binding peptide sequence colocalizes with the respective material. Heterologous expression allows for ample polypeptides to be grown and purified using a peptide expression vector. Isothermal titration calorimetry in conjunction with alanine scanning enables determination of the pertinent residues involved in LTO binding and yields a dissociation constant of 3.41 µM. A rationally designed bifunctional peptide exhibiting LTO and MWCNT binding domains is subsequently validated to exhibit both LTO and MWCNT affinities and is incorporated as a binding agent in LTO coin-type electrochemical cells where the bifunctional peptide demonstrates stability at high cycle rates and potential as an alternative to non-specific binding agents for aqueous slurry processing of lithium-ion battery electrodes.

High-Energy-Density Zinc-Air Microbatteries with Lean PVA-KOH-K2CO3 Gel Electrolytes.

Small-scale, primary electrochemical energy storage devices ("microbatteries") are critical power sources for microelectromechanical system (MEMS)-based sensors and actuators. However, the achievable volumetric and gravimetric energy densities of microbatteries are typically insufficient for intermediate-term applications of MEMS-enabled distributed internet-connected devices. Further, in the increasing subset of Internet of Things (IoT) nodes, where actuation is desired, the peak power density of the microbattery must be simultaneously considered. Metal-air approaches to achieving microbatteries are attractive, as the anode and cathode are amenable to miniaturization; however, further improvements in energy density can be obtained by minimizing the electrolyte volume. To investigate these potential improvements, this work studied very lean hydrogel electrolytes based on poly(vinyl alcohol) (PVA). Integration of high potassium hydroxide (KOH) loading into the PVA hydrogel improved electrolyte performance. The addition of potassium carbonate (K2CO3) to the KOH-PVA gel decreased the carbonation consumption rate of KOH in the gel electrolyte by 23.8% compared to PVA-KOH gel alone. To assess gel performance, a microbattery was formed from a zinc (Zn) anode layer, a gel electrolyte layer, and a carbon-platinum (C-Pt) air cathode layer. Volumetric energy densities of approximately 1400 Wh L-1 and areal peak power densities of 139 mW cm-2 were achieved with a PVA-KOH-K2CO3 electrolyte. Further structural optimization, including using multilayer gel electrolytes and thinning the air cathode, resulted in volumetric and gravimetric energy densities of 1576 Wh L-1 and 420 Wh kg-1, respectively. The batteries described in this work are manufactured in an open environment and fabricated using a straightforward layer-by-layer method, enabling the potential for high fabrication throughput in a MEMS-compatible fashion.

Preoperative Type and Screen Before General Thoracic Surgery: A Nomogram to Reduce Unnecessary Tests.

BACKGROUND: A preoperative type and screen (T&S) is traditionally routinely obtained before noncardiac thoracic surgery; however an intraoperative blood transfusion is rare. This practice is overly cautious and expensive. METHODS: We included adult patients undergoing major thoracic surgery at the Mayo Clinic from 2007 to 2016. Patients receiving a T&S blood test ≤72 hours of surgery was the main exposure. We randomly split the cohort into derivation and validation datasets. We used multiple logistic regression to create a parsimonious nomogram predicting the need for a T&S in relation to the likelihood of intraoperative blood transfusion. We validated the nomogram in terms of discrimination, calibration, and negative predictive value. RESULTS: Of 6280 patients 46.1% had a preoperative T&S, but only 7.1% received intraoperative transfusions. The derivation dataset had 4196 patients. Patients who had a T&S were more likely to have baseline hemoglobin level <10 g/dL (7.9% vs 3.6%, P < .001) and less likely to have minimally invasive operations (36.1% vs 43.5%, P < .001) but were otherwise similar in baseline age and comorbidities. A transfusion threshold of 5% was selected a priori. The nomogram included age, planned operation, approach, body mass index, and preoperative hemoglobin. The nomogram was validated with a c-statistic of 86% and a negative predictive value of 97.9%. Patients who needed a blood transfusion but who did not have a preoperative T&S did not have a higher rate of mortality (P = .121). CONCLUSIONS: An intraoperative blood transfusion during major thoracic surgery is a rare event. Patient who required transfusion but did not have a T&S did not have worse outcomes. A simple nomogram can aid in the selective use of T&S orders preoperatively.

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital.

PURPOSE: To describe the tolerability and efficacy of neratinib as a monotherapy and in combination with capecitabine in advanced HER2-positive breast cancer in a real-world setting. METHODS: Patients who received neratinib for advanced HER2-positive at the Royal Marsden Hospital NHS Trust between August 2016 and May 2020 were identified from electronic patient records and baseline characteristics, previous treatment and response to treatment were recorded. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. RESULTS: Seventy-two patients were eligible for the analysis. Forty-five patients received neratinib in combination with capecitabine and 27 patients received monotherapy. After a median duration of follow-up of 38.5 months, the median PFS for all patients was 5.9 months (95% confidence interval (CI) 4.9-7.4 months) and median OS was 15.0 months (95% Cl 10.4-22.2 months). Amongst the 52.7% (38/72) patients with confirmed brain metastases at baseline, median PFS was 5.7 months (95% CI 2.9-7.4 months) and median OS was 12.5 months (95% CI 7.7-21.4 months). Despite anti-diarrhoeal prophylaxis, diarrhoea was the most frequent adverse event, reported in 64% of patients which was grade 3 in 10%. There were no grade 4 or 5 toxicities. Seven patients discontinued neratinib due to toxicity. CONCLUSIONS: Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases. PFS and OS were found to be similar as previous trial data. Routine anti-diarrhoeal prophylaxis allows this combination to be safely delivered to patients in a real-world setting.

Hydrological control of river and seawater lithium isotopes.

Seawater lithium isotopes (δ7Li) record changes over Earth history, including a ∼9‰ increase during the Cenozoic interpreted as reflecting either a change in continental silicate weathering rate or weathering feedback strength, associated with tectonic uplift. However, mechanisms controlling the dissolved δ7Li remain debated. Here we report time-series δ7Li measurements from Tibetan and Pamir rivers, and combine them with published seasonal data, covering small (<102 km2) to large rivers (>106 km2). We find seasonal changes in δ7Li across all latitudes: dry seasons consistently have higher δ7Li than wet seasons, by -0.3‰ to 16.4‰ (mean 5.0 ± 2.5‰). A globally negative correlation between δ7Li and annual runoff reflects the hydrological intensity operating in catchments, regulating water residence time and δ7Li values. This hydrological control on δ7Li is consistent across climate events back to ~445 Ma. We propose that hydrological changes result in shifts in river δ7Li and urge reconsideration of its use to examine past weathering intensity and flux, opening a new window to reconstruct hydrological conditions.

Episodic back-arc spreading centre jumps controlled by transform fault to overriding plate strength ratio.

Spreading centre jumps are a common feature of oceanic back-arc basins. Jumps are conventionally suggested to be triggered by plate velocity changes, pre-existing weaknesses, or punctuated events such as the opening of slab windows. Here, we present 3D numerical models of back-arc spreading centre jumps evolving naturally in a homogeneous subduction system surrounded by continents without a trigger event. Spreading centres jump towards their subduction zone if the distance from trench to spreading centre becomes too long. In particular, jumps to a new spreading centre occur when the resistance on the boundary transform faults enabling relative motion of back-arc and neighbouring plates is larger than the resistance to break the overriding plate closer to trench. Time and distance of spreading centres jumps are, thus, controlled by the ratio between the transform fault and overriding plate strengths. Despite being less complex than natural systems, our models explain why narrow subducting plates (e.g. Calabrian slab), have more frequent and closely-spaced spreading jumps than wider subduction zones (e.g. Scotia). It also explains why wide back-arc basins undergo no spreading centre jumps in their life cycle.

Psychophysiological effects of slow-paced breathing at six cycles per minute with or without heart rate variability biofeedback.

Heart rate variability (HRV) biofeedback, referring to slow-paced breathing (SPB) realized while visualizing a heart rate, HRV, and/or respiratory signal, has become an adjunct treatment for a large range of psychologic and medical conditions. However, the underlying mechanisms explaining the effectiveness of HRV biofeedback still need to be uncovered. This study aimed to disentangle the specific effects of HRV biofeedback from the effects of SPB realized alone. In total, 112 participants took part in the study. The parameters assessed were emotional (valence, arousal, and control) and perceived stress intensity as self-report variables and the root mean square of the successive differences (RMSSD) as a physiologic variable. A main effect of condition was found for emotional valence only, valence being more positive overall in the SPB-HRVB condition. A main effect of time was observed for all dependent variables. However, no main effects for the condition or time x condition interaction effects were observed. Results showed that for PRE and POST comparisons (referring, respectively, to before and after SPB), both SPB-HRVB and SPB-NoHRVB conditions resulted in a more negative emotional valence, lower emotional arousal, higher emotional control, and higher RMSSD. Future research might investigate psychophysiological differences between SPB-HRVB and SPB-NoHRVB across different time periods (e.g., long-term interventions), and in response to diverse psychophysiological stressors.

A microwell-based impedance sensor on an insertable microneedle for real-time in vivo cytokine detection.

Impedance-based protein detection sensors for point-of-care diagnostics require quantitative specificity, as well as rapid or real-time operation. Furthermore, microfabrication of these sensors can lead to the formation of factors suitable for in vivo operation. Herein, we present microfabricated needle-shaped microwell impedance sensors for rapid-sample-to-answer, label-free detection of cytokines, and other biomarkers. The microneedle form factor allows sensors to be utilized in transcutaneous or transvascular sensing applications. In vitro, experimental characterization confirmed sensor specificity and sensitivity to multiple proteins of interest. Mechanical characterization demonstrated sufficient microneedle robustness for transcutaneous insertion, as well as preserved sensor function postinsertion. We further utilized these sensors to carry out real-time in vivo quantification of human interleukin 8 (hIL8) concentration levels in the blood of transgenic mice that endogenously express hIL8. To assess sensor functionality, hIL8 concentration levels in serum samples from the same mice were quantified by ELISA. Excellent agreement between real-time in vivo sensor readings in blood and subsequent ELISA serum assays was observed over multiple transgenic mice expressing hIL8 concentrations from 62 pg/mL to 539 ng/mL.

Engineering a Cytochrome P450 for Demethylation of Lignin-Derived Aromatic Aldehydes.

Biological funneling of lignin-derived aromatic compounds is a promising approach for valorizing its catalytic depolymerization products. Industrial processes for aromatic bioconversion will require efficient enzymes for key reactions, including demethylation of O-methoxy-aryl groups, an essential and often rate-limiting step. The recently characterized GcoAB cytochrome P450 system comprises a coupled monoxygenase (GcoA) and reductase (GcoB) that catalyzes oxidative demethylation of the O-methoxy-aryl group in guaiacol. Here, we evaluate a series of engineered GcoA variants for their ability to demethylate o-and p-vanillin, which are abundant lignin depolymerization products. Two rationally designed, single amino acid substitutions, F169S and T296S, are required to convert GcoA into an efficient catalyst toward the o- and p-isomers of vanillin, respectively. Gain-of-function in each case is explained in light of an extensive series of enzyme-ligand structures, kinetic data, and molecular dynamics simulations. Using strains of Pseudomonas putida KT2440 already optimized for p-vanillin production from ferulate, we demonstrate demethylation by the T296S variant in vivo. This work expands the known aromatic O-demethylation capacity of cytochrome P450 enzymes toward important lignin-derived aromatic monomers.