Rapid spread, slow evaporation: a long-lasting water film on hydrogel nanowire arrays for continuous wearables.

A successful flexible wearable not only has to fulfill its function, but also has to ensure long-term wettability and comfort during wearing. In biological systems, tears spread rapidly across the cornea to ensure clear imaging while slowly evaporating to maintain moisture in the eyes. This dynamic behavior of 'rapid spread, slow evaporation' ensures durative humidity and comfort, which can provide design guidelines for continuous wearable devices. However, realizing this dynamic process in vitro remains a challenge. Herein, inspired by a healthy ocular surface, we biomimetically construct a hybrid surface featuring mucin-like hydrophilic layer@hydrogel nanowire arrays (HL@HNWs). A droplet (2 µL) rapidly spreads into a thin film, stabilizing for ∼10 minutes, whereas the contrast sample rapidly ruptures and dewets within 1 minute. We demonstrate that enhancing the proportion of hydrated water (HW), which includes intermediate water (IW) and bound water (BW), and introducing the capillary resistance of the nanowire arrays could synergistically stabilize the water film and improve the wettability. Hydrogel-based nanowire array contact lenses can ensure wettability during continuous wear, and a stable water film can substantially improve comfort and provide superior visual quality.

Wafer-level heterogeneous integration of electrochemical devices and semiconductors for a monolithic chip.

Micro-scale electrochemical devices, despite their wide applications and unique potential to achieve 'More than Moore's law', face significant limitations in constructing functional chips due to their inability to integrate with semiconductors. In this study, we propose an electrochemical gating effect and material work function matching criteria, and thus establish the first heterogeneous integration theory for electrochemical devices and semiconductors. Accordingly, we create a novel 3D integration architecture and CMOS-compatible fabrication methodology, including optimizing individual devices, electron/ionic isolation, interconnection, and encapsulation. As a demonstration, we integrate electrochemical micro supercapacitors with a P-N junction diode rectifier bridge circuit and successfully obtain the first monolithic rectifier-filter chip, which shows a revolutionary volume reduction of 98% compared to non-integrateable commercial products. The chip can provide a stable output with a tiny ripple factor of 0.23% in typical conditions, surpassing the requirements of most applications by more than one order of magnitude. More importantly, all the processes are suitable for mass production in standard foundries, allowing ubiquitous applications of electrochemistry in integrated electronics.

Human activities reshape the spatial overlap between North Chinese leopard and its wild ungulate prey.

BACKGROUND: Rapidly expanding human activities have profoundly changed the habitat use of both large carnivores and their prey, but whether and how human activities affect the interactions between them has received relatively less attention. In this study, we conducted a systematically designed camera-trapping survey on an endangered large carnivore (North Chinese leopard Panthera pardus japonensis) and its wild ungulate prey (Siberian roe deer Capreolus pygargus and wild boar Sus scrofa) in the Taihang Mountains of central North China. Using conditional two-species occupancy model based on data derived from the extensive sampling effort (15,654 camera-days at 102 camera sites), we examined the relationship of spatial use between leopards and each prey species under the effects of human presence, free-ranging cattle, roads and settlements. RESULTS: Humans and cattle had contrasting effects on the relationship of spatial use between leopard and roe deer, with higher and lower spatial segregation between them at human and cattle-frequented sites, respectively. Roads might create a shelter for wild boar from leopard predation, with less spatial segregation between them at sites close to the roads. CONCLUSIONS: Our findings demonstrate that human activities are reshaping the spatial overlap between large carnivores and their prey, and have non-equivalent effects among different types of human activity. Such effects may further alter the strength of interspecific interactions between predator and prey, with far-reaching influences on the community and ecosystem that require more research.

Precise control of transmembrane current via regulating bionic lipid membrane composition.

The transport of ions through biological ion channels is regulated not only by their structural characteristics but also by the composition of the phospholipid membrane, which serves as a carrier for nanochannels. Inspired by the modulation of ion currents by lipid membrane composition, exemplified by the activation of the K+ channel of Streptomyces A by anionic lipids, we present a biomimetic nanochannel system based on combining DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By designing multibranched DNA nanowires, we assemble programmable DNA scaffold networks (DSNs) on the GO surface to precisely control membrane composition. Modulating the DSN layers from one to five enhances DNA composition, yielding a maximum 12-fold enhancement in ion current, primarily due to charge effects. Incorporating DNAzymes facilitates reversible modulation of membrane composition, enabling cyclic conversion of ion current. This approach offers a pathway for creating devices with highly efficient, tunable ion transport, applicable in diverse fields like mass transport, environmental protection, biomimetic channels, and biosensors.

Precisely Manipulating Steric Hindrance Effect on DNA Walker for Tunable Detection of MicroRNA Using Enzymatic Strand Displacement Amplification.

The spatial constraints imposed by the DNA structure have significant implications for the walking efficiency of three-dimensional DNA walkers. However, accurately quantifying and manipulating steric hindrance remains a challenging task. This study presents a steric hindrance-controlled DNA walker utilizing an enzymatic strand displacement amplification (ESDA) strategy for detecting microRNA-21 (miR-21) with tunable dynamic range and sensitivity. The steric hindrance of the DNA walker was precisely manipulated by varying the length of empty bases from 6.5 Što 27.4 Šat the end of the track strand and adjusting the volumetric dimensions of the hairpin structure from 9.13 nm3 to 26.2 nm3 at the terminus of the single-foot DNA walking strand. This method demonstrated a tunable limit of detection for miR-21 ranging from 3.6 aM to 35.6 nM, along with a dynamic range from ∼100-fold to ∼166 000-fold. Impressively, it exhibited successful identification of cancer cells and clinical serum samples with high miR-21 expression. The proposed novel strategy not only enables tunable detection of miRNA through the regulation of steric hindrance but also achieves accurate and quantitative analysis of the steric hindrance effect, promising broader applications in personalized medicine, early disease detection, and drug development.

CffDNA screening for Niemann-pick disease, type C1: a case series.

Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions.

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance.

Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell-like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell-intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell-dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.

Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.

Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.

Ferricyanide-Mediated, Electrocatalytic Mechanism of Electrochemical Aptamer-Based Sensor Supports Ultrasensitive Analysis of Cardiac Troponin I in Clinical Samples.

Rapid, reagent-free, and ultrasensitive analysis of cardiac troponin I (cTnI) is of significance for early diagnosis of acute myocardial infarction (AMI). The electrochemical aptamer-based (EAB) sensors are promising candidates to fill this role as they are reagentless and can be directly interrogated in complex matrices (e.g., blood). To achieve high sensitivity, EAB sensors typically require nanomaterials or other amplification strategies, which often involves a cumbersome fabrication process. To circumvent this, here we develop a simple yet effective electrocatalytic electrochemical aptamer-based (Ec-EAB) sensor that utilizes target-induced regulation of the catalytic mechanism to achieve ultrasensitive measurement of cTnI. In this assay, we employed a probe-attached redox reporter (i.e., methylene blue, MB) and a solution-diffusive redox reporter (i.e., Fe(CN)63-) to generate two signals, of which the latter is used to catalyze MB to amplify aptamer-mediated charge transfer. The recognition of target altered the diffusion of catalysts (2.2 × 10-9 mol/cm2 in the target-free state versus 1.2 × 10-9 mol/cm2 in the target-bound state) and thus electrocatalytical efficiency, enabling ultrasensitive measurement of cTnI with a 1000-fold improvement in their sensitivity (a limit of detection value: 10 pg/mL).

Precise Preparation of Supramolecular Spherical Nucleic Acids for Nucleolin-Targeted Gene Delivery.

Molecular spherical nucleic acids (m-SNAs) are a second generation of spherical nucleic acids (SNAs), which are of significance in potential application of targeted delivery of nucleic acids or gene regulation due to their defined molecular structures. Nevertheless, m-SNAs typically involve a single DNA sequence which greatly limits its functions as either targeting purpose or gene regulation. In response, we proposed here a third generation, supramolecular spherical nucleic acids (Supra-SNAs) with two different sequences to achieve both above-mentioned functions. Specifically, we constructed a series of supramolecular self-assembly structures by coupling a cell membrane receptor (i.e., nucleolin)-recognizing aptamer (AS1411)-modified adamantine as targeting probe and human epithelial growth factor receptor 2 (HER2) antisense-functionalized ß-cyclodextrin to specifically inhibit the overexpression of HER2 proteins for gene regulations. In comparison to the m-SNA precursors, such Supra-SNA structures exhibited enhanced levels of resistance to nuclease degradation, cellular uptake, gene regulation capabilities and tumor retention capacity. We demonstrated that Supra-SNAs exhibited optimal cell suppression rates and cell apoptosis via a phosphatidylinositol 3-kinase/protein kinase B signaling pathway. The well-defined molecular structures provide an attractive platform for investigating interrelationship between structure and property at the molecular level.

Global, regional, and national time trends in incidence for depressive disorders, from 1990 to 2019: an age-period-cohort analysis for the GBD 2019.

BACKGROUND: Even with advances in primary health care, depressive disorders remain a major global public health problem. We conducted an in-depth analysis of global, regional and national trends in depressive disorders incidence over the past 30 years. METHODS: Data on the incidence of depressive disorders were obtained by sex (female, male, and both), location (204 countries), age (5-84 years), year (1990-2019) from the Global Burden of Disease Study (GBD) 2019. Further, age-period-cohort modeling was used to estimate the net drift, local drift, age, period and cohort effects between 1990 and 2019. RESULTS: In 2019, although the incidence of depressive disorders has increased by 59.3% to 290 million (95% UI: 256, 328), the age-standardized incidence rate has decreased by 2.35% to 3588.25 per 100,000 people (3152.71, 4060.42) compared to 1990. There was an emerging transition of incidences from the young and middle-aged population to the old population. From 1990 to 2019, the net drift of incidence rate ranged from -0.54% (-0.61%, -0.47%) in low-middle Socio-demographic Index (SDI) regions to 0.52% (0.25%, 0.79%) in high SDI regions. Globally, the incidence rate of depressive disorders increases with age, period effects showing a decreasing risk and cohort effects beginning to decline after the 1960s. CONCLUSIONS: Our current findings reflect substantial health disparities and potential priority-setting of depressive disorders incidence in the three dimensions of age, period and cohort across SDI regions, countries. The scope of healthcare to improve the progression of depressive disorders events can be expanded to include males, females of all ages.

Magneto-Controlled Tubular Liquid Actuators with Pore Engineering for Liquid Transport and Regulation.

Liquid manipulation using tubular actuators finds diverse applications ranging from microfluidics, printing, liquid transfer to micro-reactors. Achieving flexible and simple regulation of manipulated liquid droplets during transport is crucial for the tubular liquid actuators to perform complex and multiple functions, yet it remains challenging. Here, a facile tubular actuator for directional transport of various liquid droplets under the control of an externally applied magnetic field is presented. The surfaces of the actuator can be engineered with submillimeter-sized through-hole pores, which enables the liquid droplet to be easily modulated in the transport process. Furthermore, the liquid actuator with featured through-hole pores is expanded to function as a switch in an integrated external electric circuit by magnetically controlling the motion of a conductive liquid droplet. This work develops a strategy for regulating liquid droplets in the tubular actuation systems, which may inspire ideas for designing functional liquid actuators with potential applications in microfluidics, microchemical reaction, liquid switch, and liquid robotics.

PP2C phosphatase Pic14 negatively regulates tomato Pto/Prf-triggered immunity by inhibiting MAPK activation.

Type 2C protein phosphatases (PP2Cs) are emerging as important regulators of plant immune responses, although little is known about how they might impact nucleotide-binding, leucine-rich repeat (NLR)-triggered immunity (NTI). We discovered that expression of the PP2C immunity-associated candidate 14 gene (Pic14) is induced upon activation of the Pto/Prf-mediated NTI response in tomato. Pto/Prf recognizes the effector AvrPto translocated into plant cells by the pathogen Pseudomonas syringae pv. tomato (Pst) and activate a MAPK cascade and other responses which together confer resistance to bacterial speck disease. Pic14 encodes a PP2C with an N-terminal kinase-interacting motif (KIM) and a C-terminal phosphatase domain. Upon inoculation with Pst-AvrPto, Pto/Prf-expressing tomato plants with loss-of-function mutations in Pic14 developed less speck disease, specifically in older leaves, compared to wild-type plants. Transient expression of Pic14 in leaves of Nicotiana benthamiana and tomato inhibited cell death typically induced by Pto/Prf and the MAPK cascade members M3Kα and Mkk2. The cell death-suppressing activity of Pic14 was dependent on the KIM and the catalytic phosphatase domain. Pic14 inhibited M3Kα- and Mkk2-mediated activation of immunity-associated MAPKs and Pic14 was shown to be an active phosphatase that physically interacts with and dephosphorylates Mkk2 in a KIM-dependent manner. Together, our results reveal Pic14 as an important negative regulator of Pto/Prf-triggered immunity by interacting with and dephosphorylating Mkk2.

Spatiotemporally Controllable Covalent Bonding of RNA for Multi-Protein Interference.

Many diseases are associated with genetic mutation and expression of mutated proteins, such as cancers. Therapeutic approaches that selectively target the synthesis process of multiple proteins show greater potential compared to single-protein approaches in oncological diseases. However, conventional agents to regulate the synthesis of multiple protein still suffer from poor spatiotemporal selectivity and stability. Here, a new method using a dye-peptide conjugate, PRFK, for multi-protein interference with spatiotemporal selectivity and reliable stability, is reported. By using the peptide sequence that targets tumor cells, PRFK can be efficiently taken up, followed by specific binding to the KDELR (KDEL receptor) protein located in the endoplasmic reticulum (ER). The dye generates 1O2 under light irradiation, enabling photodynamic therapy. This process converts the furan group into a cytidine-reactive intermediate, which covalently binds to mRNA, thereby blocking protein synthesis. Upon treating 4T1 cells, the proteomics data show alterations in apoptosis, ferroptosis, proliferation, migration, invasion, and immune infiltration, suggesting that multi-protein interference leads to the disruption of cellular physiological activities, ultimately achieving tumor treatment. This study presents a multi-protein interference probe with the potential for protein interference within various subcellular organelles in the future.

AI-MARRVEL - A Knowledge-Driven AI System for Diagnosing Mendelian Disorders.

BACKGROUND: Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis. METHODS: AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. The online version of AIM is available at https://ai.marrvel.org. To evaluate AIM, we benchmarked it with diagnosed patients from three independent cohorts. RESULTS: AIM improved the rate of accurate genetic diagnosis, doubling the number of solved cases as compared with benchmarked methods, across three distinct real-world cohorts. To better identify diagnosable cases from the unsolved pools accumulated over time, we designed a confidence metric on which AIM achieved a precision rate of 98% and identified 57% of diagnosable cases out of a collection of 871 cases. Furthermore, AIM's performance improved after being fine-tuned for targeted settings including recessive disorders and trio analysis. Finally, AIM demonstrated potential for novel disease gene discovery by correctly predicting two newly reported disease genes from the Undiagnosed Diseases Network. CONCLUSIONS: AIM achieved superior accuracy compared with existing methods for genetic diagnosis. We anticipate that this tool may aid in primary diagnosis, reanalysis of unsolved cases, and the discovery of novel disease genes. (Funded by the NIH Common Fund and others.).

Related type 2C protein phosphatases Pic3 and Pic12 negatively regulate immunity in tomato to Pseudomonas syringae.

Type 2C protein phosphatases (PP2Cs) constitute a large family in most plant species but relatively few of them have been implicated in immunity. To identify and characterize PP2C phosphatases that affect tomato (Solanum lycopersicum) immunity, we used CRISPR/Cas9 to generate loss-of-function mutations in 11 PP2C-encoding genes whose expression is altered in response to immune elicitors or pathogens. We report that two closely related PP2C phosphatases, Pic3 (PP2C immunity-associated candidate 3) and Pic12, are involved in regulating resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst). Loss-of-function mutations in Pic3 led to enhanced resistance to Pst in older but not younger leaves, whereas such mutations in Pic12 resulted in enhanced resistance in both older and younger leaves. Overexpression of Pic3 and Pic12 proteins in leaves of Nicotiana benthamiana inhibited resistance to Pst, and this effect was dependent on Pic3/12 phosphatase activity and an N-terminal palmitoylation motif associated with localization to the cell periphery. Pic3, but not Pic12, had a slight negative effect on flagellin-associated reactive oxygen species generation, although their involvement in the response to Pst appeared independent of flagellin. RNA-sequencing analysis of Rio Grande (RG)-PtoR wild-type plants and two independent RG-pic3 mutants revealed that the enhanced disease resistance in RG-pic3 older leaves is associated with increased transcript abundance of multiple defense related genes. RG-pic3/RG-pic12 double mutant plants exhibited stronger disease resistance than RG-pic3 or RG-pic12 single mutants. Together, our results reveal that Pic3 and Pic12 negatively regulate tomato immunity in an additive manner through flagellin-independent pathways.

Mitochondria of Porcine Oocytes Synthesize Melatonin, Which Improves Their In Vitro Maturation and Embryonic Development.

The in vitro maturation efficiency of porcine oocytes is relatively low, and this limits the production of in vitro porcine embryos. Since melatonin is involved in mammalian reproductive physiology, in this study, we have explored whether endogenously produced melatonin can help in porcine oocyte in vitro maturation. We have found, for the first time in the literature, that mitochondria are the major sites for melatonin biosynthesis in porcine oocytes. This mitochondrially originated melatonin reduces ROS production and increases the activity of the mitochondrial respiratory electron transport chain, mitochondrial biogenesis, mitochondrial membrane potential, and ATP production. Therefore, melatonin improves the quality of oocytes and their in vitro maturation. In contrast, the reduced melatonin level caused by siRNA to knockdown AANAT (siAANAT) is associated with the abnormal distribution of mitochondria, decreasing the ATP level of porcine oocytes and inhibiting their in vitro maturation. These abnormalities can be rescued by melatonin supplementation. In addition, we found that siAANAT switches the mitochondrial oxidative phosphorylation to glycolysis, a Warburg effect. This metabolic alteration can also be corrected by melatonin supplementation. All these activities of melatonin appear to be mediated by its membrane receptors since the non-selective melatonin receptor antagonist Luzindole can blunt the effects of melatonin. Taken together, the mitochondria of porcine oocytes can synthesize melatonin and improve the quality of oocyte maturation. These results provide an insight from a novel aspect to study oocyte maturation under in vitro conditions.

Advancing Lithium-Ion Batteries' Electrochemical Performance: Ultrathin Alumina Coating on Li(Ni0.8Co0.1Mn0.1)O2 Cathode Materials.

Ni-rich Li(NixCoyMnz)O2 (x ≥ 0.8)-layered oxide materials are highly promising as cathode materials for high-energy-density lithium-ion batteries in electric and hybrid vehicles. However, their tendency to undergo side reactions with electrolytes and their structural instability during cyclic lithiation/delithiation impairs their electrochemical cycling performance, posing challenges for large-scale applications. This paper explores the application of an Al2O3 coating using an atomic layer deposition (ALD) system on Ni-enriched Li(Ni0.8Co0.1Mn0.1)O2 (NCM811) cathode material. Characterization techniques, including X-ray diffraction, scanning electron microscopy, and transmission electron microscopy, were used to assess the impact of alumina coating on the morphology and crystal structure of NCM811. The results confirmed that an ultrathin Al2O3 coating was achieved without altering the microstructure and lattice structure of NCM811. The alumina-coated NCM811 exhibited improved cycling stability and capacity retention in the voltage range of 2.8-4.5 V at a 1 C rate. Specifically, the capacity retention of the modified NCM811 was 5%, 9.11%, and 11.28% higher than the pristine material at operating voltages of 4.3, 4.4, and 4.5 V, respectively. This enhanced performance is attributed to reduced electrode-electrolyte interaction, leading to fewer side reactions and improved structural stability. Thus, NCM811@Al2O3 with this coating process emerges as a highly attractive candidate for high-capacity lithium-ion battery cathode materials.