Acinar to ß-like cell conversion through inhibition of focal adhesion kinase.

Insufficient functional ß-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of a subset of peri-islet acinar cells into insulin producing ß-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore ß-cell mass, and significantly improve glucose homeostasis in diabetic mice. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.

Extracellular vesicles-based point-of-care testing for the diagnosis and monitoring of Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating condition that affects millions of people worldwide. One promising strategy for detecting and monitoring AD early on is using extracellular vesicles (EVs)-based point-of-care testing; however, diagnosing AD using EVs poses a challenge due to the low abundance of EV-biomarkers. Here, we present a fully integrated organic electrochemical transistor (OECT) that enables high accuracy, speed, and convenience in the detection of EVs from AD patients. We incorporated self-aligned acoustoelectric enhancement of EVs on a chip that rapidly propels, enriches, and specifically binds EVs to the OECT detection area. With our enhancement of pre-concentration, we increased the sensitivity to a limit of detection of 500 EV particles/µL and reduced the required detection time to just two minutes. We also tested the sensor on an AD mouse model to monitor AD progression, examined mouse Aß EVs at different time courses, and compared them with intraneuronal Aß cumulation using MRI. This innovative technology has the potential to diagnose Alzheimer's and other neurodegenerative diseases accurately and quickly, enabling monitoring of disease progression and treatment response.

Benchmarking the CoW with the TopCoW Challenge: Topology-Aware Anatomical Segmentation of the Circle of Willis for CTA and MRA.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neuro-vascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited public datasets with annotations on CoW anatomy, especially for CTA. Therefore we organized the TopCoW Challenge in 2023 with the release of an annotated CoW dataset. The TopCoW dataset was the first public dataset with voxel-level annotations for thirteen possible CoW vessel components, enabled by virtual-reality (VR) technology. It was also the first large dataset with paired MRA and CTA from the same patients. TopCoW challenge formalized the CoW characterization problem as a multiclass anatomical segmentation task with an emphasis on topological metrics. We invited submissions worldwide for the CoW segmentation task, which attracted over 140 registered participants from four continents. The top performing teams managed to segment many CoW components to Dice scores around 90%, but with lower scores for communicating arteries and rare variants. There were also topological mistakes for predictions with high Dice scores. Additional topological analysis revealed further areas for improvement in detecting certain CoW components and matching CoW variant topology accurately. TopCoW represented a first attempt at benchmarking the CoW anatomical segmentation task for MRA and CTA, both morphologically and topologically.

Miniature battery-free bioelectronics.

Miniature wireless bioelectronic implants that can operate for extended periods of time can transform how we treat disorders by acting rapidly on precise nerves and organs in a way that drugs cannot. To reach this goal, materials and methods are needed to wirelessly transfer energy through the body or harvest energy from the body itself. We review some of the capabilities of emerging energy transfer methods to identify the performance envelope for existing technology and discover where opportunities lie to improve how much-and how efficiently-we can deliver energy to the tiny bioelectronic implants that can support emerging medical technologies.

Inhibition of LncRNA SNHG14 protects chondrocyte from injury in osteoarthritis via sponging miR-137.

Long-chain noncoding small nucleolar RNA host gene 14 (LncRNA SNHG14) is highly expressed in various diseases and promotes diseases progression, but the role and mechanism of LncRNA SNHG14 on targeting miR-137 in promoting osteoarthritis (OA) chondrocyte injury remains unclear. To measure the expression of the LncRNAs SNHG14 and miR-137, cell survival, inflammatory response, chondrocyte apoptosis, and extracellular matrix (ECM) levels, we subjected human chondrocytes to a variety of lipopolysaccharide (LPS) concentrations. To measure the luciferase activity of SNHG14-WT and SNHG14-MUT transfected with miR-137 mimic or miR-NC mimic, luciferase reporter genes were utilized. The results showed that chondrocyte viability was significantly inhibited with LPS treatment and chondrocyte inflammatory response, apoptosis and extracellular matrix degradation were significantly increased. However, the above results were significantly reversed after LncRNA SNHG14 inhibition. The luciferase activity bound to miR-137 was decreased in SNHG14-WT group, but there was no change in SNHG14-mut group, which indicated that LncRNA SNHG14 inhibited miR-137 expression as a miRNA sponge. In conclusion, inhibition of LncRNA SNHG14 attenuates chondrocyte inflammatory response, apoptosis and extracellular matrix degradation by targeting miR-137 in LPS induced chondrocytes.

Vibration rejection of phased array telescope systems via disturbance-propagation-characteristics-based feedforward control.

Vibration rejection is one of the key techniques to stabilize the line of sight (LOS) for phased array telescope systems. Conventionally, feedback control based on image sensors is mainly used to correct the tip/tilt errors caused by disturbances and to keep the LOS stable. However, it is restricted by the sampling rate and time delay of image sensors, leading to a limited closed-loop bandwidth. Disturbances in the middle and high frequencies are hard to suppress. In this paper, disturbance-propagation-characteristics-based feedforward control is proposed to overcome these problems. A theoretical imaging model of the phased array telescope is developed to analyze the LOS disruption caused by disturbance. In addition, to improve the disturbance suppression bandwidth and correction accuracy of the system, the disturbance propagation characteristics of the phased array telescope system are analyzed. Combined with the disturbance feedforward, targeted compensation is achieved for the sub-apertures. Finally, a comparative experiment is carried out based on the self-developed Fizeau phased array telescope system to verify the superiority of the proposed method.

Precise management system for chronic intractable pain patients implanted with spinal cord stimulation based on a remote programming platform: study protocol for a randomized controlled trial (PreMaSy study).

BACKGROUND: Spinal cord stimulation (SCS) is a surgical technique used in patients with chronic intractable pain, and its effectiveness and safety have been validated by multiple studies. However, to maintain an optimal and steady long-term effect is still challenging. Here, we report a new management paradigm integrating smartphone application and remote programming. Chronic pain patients with SCS implants can monitor their pain status on the phone and change stimulation parameters accordingly. The PreMaSy study is a randomized controlled trial to evaluate the clinical effectiveness and safety of this precise management system. METHODS: Patients with chronic intractable pain will be screened for eligibility, and 82 participants are anticipated to be enrolled in this trial. After the electrode implantation, the stimulation effectiveness will be tested. Participants with a reduction of more than 50% in the visual analog scale (VAS) will receive implantation of an implantable pulse generator and randomized (1:1) into the experimental group or control group. All participants will be asked to take online follow-ups and complete assessments using a smartphone application. Daily pain characteristic assessments and monthly quality of life questionnaires are integrated into the App, and participants will be required to complete these assessments. The daily VAS for pain intensity will be monitored and a threshold will be set based on baseline VAS score. The interventional appointment will be scheduled once the threshold is reached. The primary outcome is the health condition and quality of life assessed by the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L). Utility values of EQ-5D-5L will be assessed at baseline and 1, 3, and 6 months post-operative. DISCUSSION: The PreMaSy study aims to evaluate the effectiveness and safety of a novel App-based, patient-centered, self-assessment management system for chronic intractable pain. A randomized controlled trial is designed to test the non-inferiority of this precise management system compared to the monthly online follow-ups. It is also expected to yield valuable experiences regarding precision medicine. TRIAL REGISTRATION: ClinicalTrials.gov NCT05761392. Registered on March 07, 2023.

Microfluidic one-step synthesis of a metal-organic framework for osteoarthritis therapeutic microRNAs delivery.

As a class of short non-coding ribonucleic acids (RNAs), microRNAs (miRNA) regulate gene expression in human cells and are expected to be nucleic acid drugs to regulate and treat a variety of biological processes and diseases. However, the issues with potential materials toxicity, quantity production, poor cellular uptake, and endosomal entrapment limit their further applications in clinical practice. Herein, ZIF-8, a metal-organic framework with noncytotoxic zinc (II) as the metal coordination center, was selected as miRNA delivery vector was used to prepare miR-200c-3p@ZIF-8 in one step by Y-shape microfluidic chip to achieve intracellular release with low toxicity, batch size, and efficient cellular uptake. The obtained miR-200c-3p@ZIF-8 was identified by TEM, particle size analysis, XRD, XPS, and zeta potential. Compared with the traditional hydrothermal method, the encapsulation efficiency of miR-200c-3p@ZIF-8 prepared by the microfluidic method is higher, and the particle size is more uniform and controllable. The experimental results in cellular level verified that the ZIF-8 vectors with low cytotoxicity and high miRNAs loading efficiency could significantly improve cellular uptake and endosomal escape of miRNAs, providing a robust and general strategy for nucleic acid drug delivery. As a model, the prepared miR-200c-3p@ZIF-8 is confirmed to be effective in osteoarthritis treatment.

External magnetic field non-invasively stimulates spinal cord regeneration in rat via a magnetic-responsive aligned fibrin hydrogel.

Magnetic stimulation is becoming an attractive approach to promote neuroprotection, neurogenesis, axonal regeneration, and functional recovery in both the central nervous system and peripheral nervous system disorders owing to its painless, non-invasive, and deep penetration characteristics. Here, a magnetic-responsive aligned fibrin hydrogel (MAFG) was developed to import and amplify the extrinsic magnetic field (MF) locally to stimulate spinal cord regeneration in combination with the beneficial topographical and biochemical cues of aligned fibrin hydrogel (AFG). Magnetic nanoparticles (MNPs) were embedded uniformly in AFG during electrospinning to endow it magnetic-responsive feature, with saturation magnetization of 21.79 emu g-1. It is found that the MNPs under the MF could enhance cell proliferation and neurotrophin secretion of PC12 cellsin vitro. The MAFG that was implanted into a rat with 2 mm complete transected spinal cord injury (SCI) effectively enhanced neural regeneration and angiogenesis in the lesion area, thus leading to significant recovery of motor function under the MF (MAFG@MF). This study suggests a new multimodal tissue engineering strategy based on multifunctional biomaterials that deliver multimodal regulatory signals with the integration of aligned topography, biochemical cues, and extrinsic MF stimulation for spinal cord regeneration following severe SCI.

Multimodal-based machine learning strategy for accurate and non-invasive prediction of intramedullary glioma grade and mutation status of molecular markers: a retrospective study.

BACKGROUND: Determining the grade and molecular marker status of intramedullary gliomas is important for assessing treatment outcomes and prognosis. Invasive biopsy for pathology usually carries a high risk of tissue damage, especially to the spinal cord, and there are currently no non-invasive strategies to identify the pathological type of intramedullary gliomas. Therefore, this study aimed to develop a non-invasive machine learning model to assist doctors in identifying the intramedullary glioma grade and mutation status of molecular markers. METHODS: A total of 461 patients from two institutions were included, and their sagittal (SAG) and transverse (TRA) T2-weighted magnetic resonance imaging scans and clinical data were acquired preoperatively. We employed a transformer-based deep learning model to automatically segment lesions in the SAG and TRA phases and extract their radiomics features. Different feature representations were fed into the proposed neural networks and compared with those of other mainstream models. RESULTS: The dice similarity coefficients of the Swin transformer in the SAG and TRA phases were 0.8697 and 0.8738, respectively. The results demonstrated that the best performance was obtained in our proposed neural networks based on multimodal fusion (SAG-TRA-clinical) features. In the external validation cohort, the areas under the receiver operating characteristic curve for graded (WHO I-II or WHO III-IV), alpha thalassemia/mental retardation syndrome X-linked (ATRX) status, and tumor protein p53 (P53) status prediction tasks were 0.8431, 0.7622, and 0.7954, respectively. CONCLUSIONS: This study reports a novel machine learning strategy that, for the first time, is based on multimodal features to predict the ATRX and P53 mutation status and grades of intramedullary gliomas. The generalized application of these models could non-invasively provide more tumor-specific pathological information for determining the treatment and prognosis of intramedullary gliomas.

Redox-Neutral Synthesis of Sulfilimines through the S-Alkylation of Sulfenamides.

In this work, we developed a metal-free and redox-neutral strategy for the selective S-alkylation of sulfenamides under basic conditions to yield sulfilimines. The key step involves the resonance between bivalent nitrogen-centered anions, generated after deprotonation of sulfenamides under alkaline conditions, and sulfinimidoyl anions. Our sustainable and efficient approach employs sulfur-selective alkylation of readily accessible sulfenamides and commercially available halogenated hydrocarbons, resulting in the successful synthesis of 60 sulfilimines in high yields (36-99%) and short reaction times.

Hypervalent Iodine-Mediated Synthesis of Sulfinimidate Esters from Sulfenamides.

In this study, we present a novel and efficient approach for the oxidative esterification of sulfenamides using phenyliodonium diacetate, enabling the synthesis of sulfinimidate esters and sulfilimines under mild and metal-free conditions, with yields reaching up to 99%. The protocol is readily scalable and compatible with a diverse range of substrates and functional groups, and we demonstrate its potential for late-stage functionalization of pharmacologically relevant molecules. Furthermore, we propose a plausible reaction mechanism to account for the observed sequence of events.

3D bio-printed living nerve-like fibers refine the ecological niche for long-distance spinal cord injury regeneration.

3D bioprinting holds great promise toward fabricating biomimetic living constructs in a bottom-up assembly manner. To date, various emergences of living constructs have been bioprinted for in vitro applications, while the conspicuous potential serving for in vivo implantable therapies in spinal cord injury (SCI) has been relatively overlooked. Herein, living nerve-like fibers are prepared via extrusion-based 3D bioprinting for SCI therapy. The living nerve-like fibers are comprised of neural stem cells (NSCs) embedded within a designed hydrogel that mimics the extracellular matrix (ECM), assembled into a highly spatial ordered architecture, similar to densely arranged bundles of the nerve fibers. The pro-neurogenesis ability of these living nerve-like fibers is tested in a 4 mm-long complete transected SCI rat model. Evidence shows that living nerve-like fibers refine the ecological niche of the defect site by immune modulation, angiogenesis, neurogenesis, neural relay formations, and neural circuit remodeling, leading to outstanding functional reconstruction, revealing an evolution process of this living construct after implantation. This effective strategy, based on biomimetic living constructs, opens a new perspective on SCI therapies.

Rh(II)-catalyzed Doyle-Kirmse reaction: access to unprotected 3-allyl/3-allenyl-3-(thio)oxindoles.

The construction of the 3-allyl/3-allenyl-3-(thio)oxindole core remains a challenge in organic synthesis. Herein, we report a novel Rh2(esp)2 catalytic Doyle-Kirmse reaction to furnish the oxindole core, bearing unbiased NH as well as a quaternary stereogenic center at the 3-position, in good to excellent yields under mild conditions. These reactions are concise, practical, atom-economic, and highly efficient, and feature a TON of up to 3700. Moreover, a non-radical pathway was observed in this approach.

Magnetoelectric Bio-Implants Powered and Programmed by a Single Transmitter for Coordinated Multisite Stimulation.

This paper presents a hardware platform including stimulating implants wirelessly powered and controlled by a shared transmitter for coordinated leadless multisite stimulation. The adopted novel single-transmitter, multiple-implant structure can flexibly deploy stimuli, improve system efficiency, easily scale stimulating channel quantity and relieve efforts in device synchronization. In the proposed system, a wireless link leveraging magnetoelectric effects is co-designed with a robust and efficient system-on-chip to enable reliable operation and individual programming of every implant. Each implant integrates a 0.8-mm2 chip, a 6-mm2 magnetoelectric film, and an energy storage capacitor within a 6.2-mm3 size. Magnetoelectric power transfer is capable of safely transmitting milliwatt power to devices placed several centimeters away from the transmitter coil, maintaining good efficiency with size constraints and tolerating 60-degree, 1.5-cm misalignment in angular and lateral movement. The SoC robustly operates with 2-V source amplitude variations that spans a 40-mm transmitter-implant distance change, realizes individual addressability through physical unclonable function IDs, and achieves 90% efficiency for 1.5-to-3.5-V stimulation with fully programmable stimulation parameters.

Sub-scalp electroencephalography: A next-generation technique to study human neurophysiology.

Sub-scalp electroencephalography (ssEEG) is emerging as a promising technology in ultra-long-term electroencephalography (EEG) recordings. Given the diversity of devices available in this nascent field, uncertainty persists about its utility in epilepsy evaluation. This review critically dissects the many proposed utilities of ssEEG devices including (1) seizure quantification, (2) seizure characterization, (3) seizure lateralization, (4) seizure localization, (5) seizure alarms, (6) seizure forecasting, (7) biomarker discovery, (8) sleep medicine, and (9) responsive stimulation. The different ssEEG devices in development have individual design philosophies with unique strengths and limitations. There are devices offering primarily unilateral recordings (24/7 EEGTM SubQ, NeuroviewTM, Soenia® UltimateEEG™), bilateral recordings (Minder™, Epios™), and even those with responsive stimulation capability (EASEE®). We synthesize the current knowledge of these ssEEG systems. We review the (1) ssEEG devices, (2) use case scenarios, (3) challenges and (4) suggest a roadmap for ideal ssEEG designs.

Automatic and Efficient Prediction of Hematoma Expansion in Patients with Hypertensive Intracerebral Hemorrhage Using Deep Learning Based on CT Images.

Patients with hypertensive intracerebral hemorrhage (ICH) have a high hematoma expansion (HE) incidence. Noninvasive prediction HE helps doctors take effective measures to prevent accidents. This study retrospectively analyzed 253 cases of hypertensive intraparenchymal hematoma. Baseline non-contrast-enhanced CT scans (NECTs) were collected at admission and compared with subsequent CTs to determine the presence of HE. An end-to-end deep learning method based on CT was proposed to automatically segment the hematoma region, region of interest (ROI) feature extraction, and HE prediction. A variety of algorithms were employed for comparison. U-Net with attention performs best in the task of segmenting hematomas, with the mean Intersection overUnion (mIoU) of 0.9025. ResNet-34 achieves the most robust generalization capability in HE prediction, with an area under the receiver operating characteristic curve (AUC) of 0.9267, an accuracy of 0.8827, and an F1 score of 0.8644. The proposed method is superior to other mainstream models, which will facilitate accurate, efficient, and automated HE prediction.

Construction of tissue-engineered nucleus pulposus by stimulation with periodic mechanical stress and BMP-2.

Intervertebral disc (IVD) degeneration, which is common among elderly individuals, mainly manifests as low back pain and is caused by structural deterioration of the nucleus pulposus (NP) due to physiological mechanical stress. NP mesenchymal stem cells (NPMSCs) around the IVD endplate have multidirectional differentiation potential and can be used for tissue repair. To define favorable conditions for NPMSC proliferation and differentiation into chondroid cells for NP repair, the present study simulated periodic mechanical stress (PMS) of the NP under physiological conditions using MSC chondrogenic differentiation medium and recombinant human BMP-2 (rhBMP-2). rhBMP-2 effectively promoted NPMSC proliferation and differentiation. To clarify the mechanism of action of rhBMP-2, integrin alpha 1 (ITG A1) and BMP-2 were inhibited. PMS regulated the BMP-2/Smad1/RUNX2 pathway through ITG A1 and promoted NPMSC proliferation and differentiation. During tissue-engineered NP construction, PMS can effectively reduce osteogenic differentiation and promote extracellular matrix protein synthesis to enhance structural NP recovery.

A wireless millimetric magnetoelectric implant for the endovascular stimulation of peripheral nerves.

Implantable bioelectronic devices for the simulation of peripheral nerves could be used to treat disorders that are resistant to traditional pharmacological therapies. However, for many nerve targets, this requires invasive surgeries and the implantation of bulky devices (about a few centimetres in at least one dimension). Here we report the design and in vivo proof-of-concept testing of an endovascular wireless and battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via traditional surgeries. The device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable 1 mm × 0.8 mm system-on-a-chip. Implantation of the device directly on top of the sciatic nerve in rats and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter) allowed for wireless stimulation of the animals' sciatic and femoral nerves. Minimally invasive magnetoelectric implants may allow for the stimulation of nerves without the need for open surgery or the implantation of battery-powered pulse generators.

The Minimal Subcortical Electronic Threshold Predicts the Motor Deficit and Survivals in Non-Awake Surgery for Gliomas Involving the Motor Pathway.

Purpose: Direct subcortical motor mapping is the golden criterion to detect and monitor the motor pathway during glioma surgery. Minimal subcortical monopolar threshold (MSCMT) means the minimal distance away from the motor pathway and is critical to decide to continue or interrupt glioma resection. However, the optimal cutoff value of MSCMT for glioma resection in non-awake patients has not been reported discreetly. In this study, we try to establish the safe cutoff value of MSCMT for glioma resection and analyzed its relationship with postoperative motor deficit and long-term survivals. Methods: We designed this prospective study with high-frequency electronic stimulus method. The cutoff MSCMT of postoperative motor deficits was statistically calculated by receiver operating characteristic (ROC) curve, and its relationship with motor deficit and survivals was analyzed by logistic and Cox regression, respectively. Results: The cutoff MSCMT to predict motor deficit after surgery was 3.9 mA on day 1, 3.7 mA on day 7, 5.2 mA at 3 months, and 5.2 mA at 6 months. MSCMT ≤3.9 mA and MSCMT ≤5.2 mA independently predicted postoperative motor deficits at four times after surgery (P < 0.05) but had no effect on the removal degree of tumor (P > 0.05). In high-grade gliomas, MSCMT ≤3.9 mA independently predicted shorter progression-free survival [odds ratio (OR) = 3.381 (1.416-8.076), P = 0.006] and overall survival [OR = 3.651 (1.336-9.977), P = 0.012]. Power model has the best fitness for paired monopolar and bipolar high-frequency thresholds. Conclusions: This study showed strong cause-effect relation between MSCMT and postoperative motor deficit and prognoses. The cutoff MSCMT was dug out to avoid postoperative motor deficit. Further studies are needed to establish the results above.