Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.

After the discovery of insulin, a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of a human ß cell line, healthy and type 2 diabetic (T2D) human islets and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human ß cells results in increased insulin secretion. Consistently, high-fat-diet-fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human ß cells in both healthy and T2D conditions.

Stretchable multifunctional hydrogels for sensing electronics with effective EMI shielding properties.

Hydrogel-based soft and stretchable materials with skin/tissue-like mechanical properties provide new avenues for the design and fabrication of wearable sensors. However, synthesizing multifunctional hydrogels that simultaneously possess excellent mechanical, electrical and electromagnetic interference (EMI) shielding effectiveness is still a great challenge. In this work, the freeze-casting method is employed to fabricate a multifunctional hydrogel by filling Fe3O4 clusters into poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT:PSS) and polyvinyl alcohol (PVA) composite aqueous solution. The hydrogel possesses superior electrical and mechanical properties as well as great electromagnetic wave shielding properties. Benefiting from the high stretchability (∼904.5%) and fast sensing performance (response time ∼9 ms and self-recovery time ∼12 ms within the strain range ∼100%), the monitoring of human activities and manipulation of a remote-controlled toy car using the hydrogel-based stretchable strain sensors are successfully demonstrated. In addition, a great EMI shielding effectiveness with more than 46 dB in the frequencies of 8-12.5 GHz can be obtained, which provides an alternative strategy for designing next-generation EMI shielding materials. These results indicate that the multifunctional hydrogels can be used as flexible and stretchable sensing electronics requiring effective EMI shielding.

Coherent phonon dynamics in a c-plane sapphire crystal before and after intense femtosecond laser irradiation.

Femtosecond pump-probe experiments with a ∼6.4 fs time-resolution were performed to investigate the coherent phonon dynamics in a c-plane sapphire crystal before and after intense 800 nm femtosecond laser irradiation. The intense femtosecond laser induced defect/distortion and even re-crystallization of crystalline structures, which result in the appearance of new peaks and relative intensity change in coherent phonon and Raman spectra. The combination of these two spectra was found to be beneficial to evidence the variation of crystalline structure and further to differentiate the origins of new Raman peaks after irradiation. Further analysis of time-dependent differential absorbance with damped cosine function fitting and Fourier transfer calculation yields the vibrational parameters, including periods, damping times and initial phases, before and after irradiation. With these parameters, the defect-effects on damping time and the mechanism of coherent phonon generation were addressed.

Moisture-Driven Power Generation for Multifunctional Flexible Sensing Systems.

Flexible self-powered multifunctional sensing systems provide a promising direction for the development of wearable electronics. Although increased efforts have been devoted to developing self-powered integrated devices, the development of flexible and adaptable sensing systems with miniaturized stable power supplies is highly desirable yet greatly challenging. Herein, an ambient moisture-induced self-powered wearable sensing system was fabricated by integrating a porous polydopamine layer with a hydroxy group gradient (called g-PDA) based moisture-enabled power generator and a flexible pressure sensor. Due to the large amount of gradient-distributed free cations (H+) and locally confined anions produced in wide electrode spaces during hydration of the thin porous g-PDA film, the moisture-induced potential and effective output power density of the g-PDA-based power generator rapidly reaches up to 0.52 V and 0.246 mW cm-2, respectively. Importantly, the voltage output within 120 s only has 6% change, and a continuously open-circuit voltage can be maintained after 1900 s of attenuation, which is a breakthrough for the duration of humidity generation. Finally, a self-powered wearable multifunctional sensing system has been demonstrated to be able to provide real-time monitoring of human physiological signals, without an external power supply, which opens new opportunities for future self-powered multifunctional sensing systems.

Anisotropic Boron-Carbon Hetero-Nanosheets for Ultrahigh Energy Density Supercapacitors.

A 2D boron nanosheet that exhibits high theoretical capacitance, around four times that of graphene, is a significant supercapacitor electrode. However, its bulk structure with low interlaminar conduction and porosity restricts the charge transfer, ion diffusion, and energy density. Herein, we develop a new 2D hetero-nanosheet made of anisotropic boron-carbon nanosheets (ABCNs) by B-C chemical bonds via gas-phase exfoliation and condensation bottom-up strategy. The ABCNs are constructed into high flexible supercapacitor electrode by microfluidic electrospinning. The ABCN electrode greatly promotes smooth migration and excessive storage of electrolyte ions due to large interlayer conductivity, ionic pathways, and accessible surfaces. The flexible supercapacitor delivers ultrahigh volumetric energy density of 167.05 mWh cm-3 and capacitance of 534.5 F cm-3 . A wearable energy-sensor system is designed to stably monitor physiological signals.

Apoptotic ß-cells induce macrophage reprogramming under diabetic conditions.

Type 2 diabetes mellitus (T2DM) occurs when insulin-producing pancreatic ß-cells fail to secrete sufficient insulin to compensate for insulin resistance. As T2DM progresses, apoptotic ß-cells need to be removed by macrophages through efferocytosis that is anti-inflammatory by nature. Paradoxically, infiltrating macrophages are a main source of inflammatory cytokines that leads to T2DM. It is unclear how apoptotic ß-cells impact macrophage function. We show under diabetic conditions, phagocytosis of apoptotic ß-cells causes lysosomal permeabilization and generates reactive oxygen species that lead to inflammasome activation and cytokine secretion in macrophages. Efferocytosis-induced lipid accumulation transforms islet macrophages into foam cell-like outside the context of atherosclerosis. Our study suggests that whereas macrophages normally play a protective anti-inflammatory role, the increasing demand of clearing apoptotic cells may trigger them to undergo proinflammatory reprogramming as T2DM progresses. This shift in the balance between opposing macrophage inflammatory responses could contribute to chronic inflammation involved in metabolic diseases. Our study highlights the importance of preserving macrophage lysosomal function as a therapeutic intervention for diabetes progression.

Bioinspired Flexible Volatile Organic Compounds Sensor Based on Dynamic Surface Wrinkling with Dual-Signal Response.

Living systems can respond to external stimuli by dynamic interface changes. Moreover, natural wrinkle structures allow the surface to switch dynamically and reversibly from flat to rough in response to specific stimuli. Artificial wrinkle structures have been developed for applications such as optical devices, mechanical sensors, and microfluidic devices. However, chemical molecule-triggered flexible sensors based on dynamic surface wrinkling have not been demonstrated. Inspired by human skin wrinkling, herein, a volatile organic compound (VOC)-responsive flexible sensor with a switchable dual-signal response (transparency and resistance) is achieved based on a multilayered Ag nanowire (AgNW)/SiOx /polydimethylsiloxane (PDMS) film. Wrinkle structures can form dynamically in response to VOC vapors (such as ethanol, toluene, acetone, formaldehyde, and methanol) due to the instability of the multilayer induced by their different swelling capabilities. By controlling the modulus of PDMS and the thickness of the SiOx layer, tunable sensitivities in resistance and transparency of the device are achieved. Additionally, the proximity mechanism of the solubility parameter is proposed, which explains the high selectivity of the device toward ethanol vapor compared with that of other VOCs well. This stimuli-responsive sensor exhibits the dynamic visual feedback and the quantitative electrical signal, which provide a novel approach for developing smart flexible electronics.

Self-assembled three-dimensional periodic micro-nano structures in bulk quartz crystal induced by femtosecond laser pulses.

In-volume, self-assembled, three-dimensional, periodic micro-nano structures are induced in quartz crystal by tightly focused, 500-kHz femtosecond laser pulses. With suitable pulse energy, three different types of periodic structures can be observed in modified regions using scanning electron microscopy. The first one with period (ΛE) of ~400 nm in the direction of the laser polarization, i.e. nanograting, shows indicative features similar to that in fused silica. The second one with period (ΛS) in the scan direction and the third one with period (Λk) in the laser propagation direction are both equally spaced by ~1 µm, which is close to the laser wavelength. Moreover, the structure with period (Λk) covers almost the whole cross-section of modified regions, which is distinctive to that observed in fused silica. Through the comparison of the structures induced by 1-kHz pluses and those by 500-kHz pluses, we deduce that the heat accumulation effect may have a positive influence on the formation of nanogratings in quartz crystal.

MOF-253-Supported Ru Complex for Photocatalytic CO2 Reduction by Coupling with Semidehydrogenation of 1,2,3,4-Tetrahydroisoquinoline (THIQ).

MOF-253 (Al(OH)(dcbpy), dcbpy = 2,2'-bipyridine-5,5'-dicarboxylic acid) obtained via a microwave-assisted synthesis was used for the construction of a supported Ru complex containing dcbpy (MOF-253-Ru(dcbpy)2) by coordinating its open N,N'-chelating sites with Ru(II) in Ru(dcbpy)2Cl2. The as-obtained MOF-253-Ru(dcbpy)2 acts as a bifunctional photocatalyst for simultaneous CO2 reduction to produce formic acid and CO, as well as semidehydrogenation of 1,2,3,4-tetrahydroisoquinoline (THIQ) to obtain 3,4-dihydroisoquinoline (DHIQ). The performance over the surface-supported MOF-253-Ru(dcbpy)2 is superior to that over Ru-doped MOF-253 (Ru-MOF-253) obtained via a mix-and-match strategy, indicating that the use of open coordination sites in the MOFs for direct construction of a surface-supported complex is a superior strategy to obtain an MOF-supported homogeneous complex. This study shows the possibility of using an MOF as a platform for the construction of multifunctional heterogeneous photocatalytic systems. The coupling of photocatalytic CO2 reduction with the highly selective dehydrogenation of organics provides an economical and green strategy in photocatalytic CO2 reduction and production of valuable organics simultaneously.

Highly Sensitive Microstructure-Based Flexible Pressure Sensor for Quantitative Evaluation of Motor Function Recovery after Spinal Cord Injury.

Behavioral assessment, such as systematic scoring or biomechanical measurement, is often used to evaluate the extent of the damage and the degree of recovery after spinal cord injury. However, the use of these methods in standardized evaluation is limited because they are subjective and require complex test systems to implement. Here, we report a novel, flexible, microstructure-based pressure sensor and demonstrate its superior sensitivity (235.12 kPa-1 for 5.5~135 Pa and 2.24 kPa-1 for 0.6~25 kPa), good waterproofness, fast response and recovery times (response time: 8 ms, recovery time: 12 ms), stable response over 8000 loading/unloading cycles, and wide sensing range. These features readily allow the sensor to be comfortably attached to the hindlimbs of mice for full-range, real-time detection of their behavior, such as crawling and swimming, helping to realize quantitative evaluation of animal motor function recovery after spinal cord injury.

Multifunctional in vivo imaging of pancreatic islets during diabetes development.

Pancreatic islet dysfunction leading to insufficient glucose-stimulated insulin secretion triggers the clinical onset of diabetes. How islet dysfunction develops is not well understood at the cellular level, partly owing to the lack of approaches to study single islets longitudinally in vivo Here, we present a noninvasive, high-resolution system to quantitatively image real-time glucose metabolism from single islets in vivo, currently not available with any other method. In addition, this multifunctional system simultaneously reports islet function, proliferation, vasculature and macrophage infiltration in vivo from the same set of images. Applying our method to a longitudinal high-fat diet study revealed changes in islet function as well as alternations in islet microenvironment. More importantly, this label-free system enabled us to image real-time glucose metabolism directly from single human islets in vivo for the first time, opening the door to noninvasive longitudinal in vivo studies of healthy and diabetic human islets.

Excess cholesterol inhibits glucose-stimulated fusion pore dynamics in insulin exocytosis.

Type 2 diabetes is caused by defects in both insulin sensitivity and insulin secretion. Glucose triggers insulin secretion by causing exocytosis of insulin granules from pancreatic ß-cells. High circulating cholesterol levels and a diminished capacity of serum to remove cholesterol from ß-cells are observed in diabetic individuals. Both of these effects can lead to cholesterol accumulation in ß-cells and contribute to ß-cell dysfunction. However, the molecular mechanisms by which cholesterol accumulation impairs ß-cell function remain largely unknown. Here, we used total internal reflection fluorescence microscopy to address, at the single-granule level, the role of cholesterol in regulating fusion pore dynamics during insulin exocytosis. We focused particularly on the effects of cholesterol overload, which is relevant to type 2 diabetes. We show that excess cholesterol reduced the number of glucose-stimulated fusion events, and modulated the proportion of full fusion and kiss-and-run fusion events. Analysis of single exocytic events revealed distinct fusion kinetics, with more clustered and compound exocytosis observed in cholesterol-overloaded ß-cells. We provide evidence for the involvement of the GTPase dynamin, which is regulated in part by cholesterol-induced phosphatidylinositol 4,5-bisphosphate enrichment in the plasma membrane, in the switch between full fusion and kiss-and-run fusion. Characterization of insulin exocytosis offers insights into the role that elevated cholesterol may play in the development of type 2 diabetes.

Cholesterol accumulation increases insulin granule size and impairs membrane trafficking.

The formation of mature secretory granules is essential for proper storage and regulated release of hormones and neuropeptides. In pancreatic ß cells, cholesterol accumulation causes defects in insulin secretion and may participate in the pathogenesis of type 2 diabetes. Using a novel cholesterol analog, we show for the first time that insulin granules are the major sites of intracellular cholesterol accumulation in live ß cells. This is distinct from other, non-secretory cell types, in which cholesterol is concentrated in the recycling endosomes and the trans-Golgi network. Excess cholesterol was delivered specifically to insulin granules, which caused granule enlargement and retention of syntaxin 6 and VAMP4 in granule membranes, with concurrent depletion of these proteins from the trans-Golgi network. Clathrin also accumulated in the granules of cholesterol-overloaded cells, consistent with a possible defect in the last stage of granule maturation, during which clathrin-coated vesicles bud from the immature granules. Excess cholesterol also reduced the docking and fusion of insulin granules at the plasma membrane. Together, the data support a model in which cholesterol accumulation in insulin secretory granules impairs the ability of these vesicles to respond to stimuli, and thus reduces insulin secretion.

Refrigeration provides a simple means to synchronize in vitro cultures of Plasmodium falciparum.

Plasmodium falciparum is usually asynchronous during in vitro culture. Highly synchronized cultures of P. falciparum are routinely used in malaria research. Here, we describe a simple synchronization procedure for P. falciparum asexual erythrocytic culture, which involves storage at 4°C for 8-24 h followed by routine culture. When cultures with 27-60% of ring stage were synchronized using this procedure, 70-93% ring stages were obtained after 48 h of culture and relative growth synchrony remained for at least two erythrocytic cycles. To test the suitability of this procedure for subsequent work, drug sensitivity assays were performed using four laboratory strains and four freshly adapted clinical P. falciparum isolates. Parasites synchronized by sorbitol treatment or refrigeration showed similar dose-response curves and comparable IC50 values to four antimalarial drugs. The refrigeration synchronization method is simple, inexpensive, time-saving, and should be especially useful when large numbers of P. falciparum culture are handled.

Comparison of perfluoroalkyl substance adsorption performance by inorganic and organic silicon modified activated carbon.

Owing to the persistence and increasingly stringent regulations of perfluoroalkyl substances (PFAS), it is necessary to improve their adsorption capacities using activated carbon (AC). However, their adsorption capacities are suppressed by dissolved organic matter (DOM). In this study, two ACs modified with organic silicon (C-OS) and inorganic silicon (C-IS) were synthesized and used for the adsorption of PFAS in raw water (RW). The results showed that the PFAS adsorption capacity of C-IS was much less influenced by DOM than that of the original AC (C-virgin). In RW, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) adsorption capacities on C-IS were 15.08 and 3.65 times higher than those on C-virgin, respectively. DOM had less influence on the PFOA and PFOS adsorption kinetics of C-IS than C-OS and C-virgin. Under multi-PFAS condition, C-IS also exhibited slower desorption of short-chain PFAS and breakthrough in batch and column tests, respectively. Characterization of the ACs before and after adsorption and independent gradient modelling indicated that hydrogen bond interactions between the O-Si of C-IS and the -COOH or -CSO3H groups of PFAS contributed to PFAS adsorption. Density functional theory calculations demonstrated that the adsorption energy of C-IS was much lower than that of C-OS and C-virgin. The arrangement of PFAS molecules on C-OS was chaotic owing to the hydrophobic siloxane chain, whereas the arrangement of PFAS on C-IS was orderly in multi-layer or semi-micelle status and more favorable to PFAS adsorption. This study provides a new strategy for avoiding adverse effects of DOM on PFAS adsorption.

Re-tear after arthroscopic rotator cuff repair can be predicted using deep learning algorithm.

The application of artificial intelligence technology in the medical field has become increasingly prevalent, yet there remains significant room for exploration in its deep implementation. Within the field of orthopedics, which integrates closely with AI due to its extensive data requirements, rotator cuff injuries are a commonly encountered condition in joint motion. One of the most severe complications following rotator cuff repair surgery is the recurrence of tears, which has a significant impact on both patients and healthcare professionals. To address this issue, we utilized the innovative EV-GCN algorithm to train a predictive model. We collected medical records of 1,631 patients who underwent rotator cuff repair surgery at a single center over a span of 5 years. In the end, our model successfully predicted postoperative re-tear before the surgery using 62 preoperative variables with an accuracy of 96.93%, and achieved an accuracy of 79.55% on an independent external dataset of 518 cases from other centers. This model outperforms human doctors in predicting outcomes with high accuracy. Through this methodology and research, our aim is to utilize preoperative prediction models to assist in making informed medical decisions during and after surgery, leading to improved treatment effectiveness. This research method and strategy can be applied to other medical fields, and the research findings can assist in making healthcare decisions.

Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury.

The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10-20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.

Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation.

To promote glucose uptake into fat and muscle cells, insulin causes the translocation of GLUT4 glucose transporters from intracellular vesicles to the cell surface. Previous data support a model in which TUG traps GLUT4-containing vesicles and tethers them intracellularly in unstimulated cells and in which insulin mobilizes this pool of vesicles by releasing this tether. Here we show that TUG undergoes site-specific endoproteolytic cleavage, which separates a GLUT4-binding, N-terminal region of TUG from a C-terminal region previously suggested to bind an intracellular anchor. Cleavage is accelerated by insulin stimulation in 3T3-L1 adipocytes and is highly dependent upon adipocyte differentiation. The N-terminal TUG cleavage product has properties of a novel 18-kDa ubiquitin-like modifier, which we call TUGUL. The C-terminal product is observed at the expected size of 42 kDa and also as a 54-kDa form that is released from membranes into the cytosol. In transfected cells, intact TUG links GLUT4 to PIST and also binds Golgin-160 through its C-terminal region. PIST is an effector of TC10α, a GTPase previously shown to transmit an insulin signal required for GLUT4 translocation, and we show using RNAi that TC10α is required for TUG proteolytic processing. Finally, we demonstrate that a cleavage-resistant form of TUG does not support highly insulin-responsive GLUT4 translocation or glucose uptake in 3T3-L1 adipocytes. Together with previous results, these data support a model whereby insulin stimulates TUG cleavage to liberate GLUT4 storage vesicles from the Golgi matrix, which promotes GLUT4 translocation to the cell surface and enhances glucose uptake.

In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes.

The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.

Occurrence of metals, phthalate esters, and perfluoroalkyl substances in cellar water and their relationship with bacterial community in rural areas of China.

Water cellars are traditional rainwater harvesting facilities that have been widely used in rural areas of northwest China. However, there are few reports about the water quality and health risk caused by the cellar water, especially phthalate esters (PAEs) and perfluoroalkyl substances (PFASs). This study investigated and assessed the health risks caused by the metals, PAEs, PFASs and bacterial communities in cellar water. The results showed that the turbidity and total number of bacterial colonies ranged from 4.7 to 58.5 NTU and 5-557 CFU/mL, respectively. The turbidity and total number of bacterial colonies were the main water quality problems. Due to high concentration of Tl (0.005-0.171 µg/L), the samples reached a high level of metal pollution. PAEs showed no non-carcinogenic and carcinogenic risk. The perfluorobutanoic acid (PFBA), perfluorobutanesulfonic acid (PFBS), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) were the main components of PFASs. PFOA and PFOS reached a moderate risk level in many cellar water samples. Moreover, Tl, Pb, As, PFBA and PFBS could change the bacterial community composition and induce the enrichment of bacterial functions related to human diseases. Besides these parameters, dissolved oxygen (DO) also affected the bacterial functions related to human diseases. Therefore, more attention should be paid to turbidity, DO, Tl, Pb, As, PFOA, PFOS, PFBA and PFBS in the cellar water. These results are meaningful for the water quality guarantee and health protection in rural areas of China.