A high security coding and anti-counterfeiting method based on the nonlinear magnetization response of superparamagnetic nanomaterials.

Traditional coding methods based on graphics and digital or magnetic labels have gradually decreased their anti-counterfeiting because of market popularity. This paper presents a new magnetic anti-counterfeiting coding method. This method uses a high-performance coding material, which, along with small changes to the material itself and the particle size of the superparamagnetic nanomaterials, results in a large difference in the nonlinear magnetization response. This method, which adopts 12-site coding and establishes a screening model by measuring the voltage amplitude of 12-site variables, can code different kinds of products, establishing long-term stable coding and decoding means. Through the anti-counterfeiting experiment of wine, the experiment results show that the authenticity of the coded products can be verified using the self-developed magnetic encoding and decoding system. The new coding technology can verify the anti-counterfeiting of 9000 products, with a single detection accuracy of 97% and a detection time of less than one minute. Moreover, this coding method completely depends on the production batch of the superparamagnetic nanomaterials, which is difficult to imitate, and it provides a new coding anti-counterfeiting technology for related industries with a wide range of potential applications.

Oral dehydroepiandrosterone supplementation enhances osteoporotic fracture healing in the OVX rats.

Osteoporosis easily causes delayed fracture union, even non-union. It has been demonstrated that dehydroepiandrosterone (DHEA) supplementation can increase estrogen levels and improve bone mineral density (BMD) in the elderly, while the role of DHEA on fracture healing remains unknown. This study aimed to elucidate the impact of DHEA supplementation on osteoporotic fracture healing. Seventy-two female Sprague-Dawley rats were used. Forty-eight rats received ovariectomy (OVX), and the remaining rats received a sham OVX operation (sham group). A right transverse femoral osteotomy was performed in all rats at 12 weeks post-OVX. OVX rats were randomly allocated into 2 groups (n = 24 in each group): (i) ovariectomized rats (control group) and (ii) ovariectomized rats treated with DHEA (DHEA group, 5 mg/kg/day). The DHEA supplementation was initiated on the first day post-fracture for 3, 6, and 12 weeks. Fracture healing was evaluated by radiography, histology, biomechanical analysis, and dual-energy X-ray absorptiometry (DEXA). Serum biomarkers were analyzed using enzyme-linked immunosorbent assay (ELISA). At 3 and 6 weeks, radiographs revealed reduced calluses formation and lower radiographic scores in the control group than in other groups. The sham and DHEA groups showed higher BMD and bone mineral content (BMC) at the fracture site than the control group after fracture. Histological analysis revealed the fracture callus was remodeled better in the sham and DHEA groups than in the control group. At the early phase of healing, DHEA supplementation increased osteoblast number, callus area, and cartilage area than the control group. An increased bone area was observed in the DHEA group than in the control group at the late phase of healing. Additionally, improved biomechanical characteristics were observed in both the sham and DHEA groups than those in the control group post-fracture. ELISA showed higher levels of insulin-like growth factor-1 (IGF-1) and 17ß-estradiol (E2) in the DHEA group than in the control group post-fracture. Furthermore, the DHEA group exhibited significantly elevated alkaline phosphatase (ALP) and osteocalcin (OC) levels compared to the control group at 6 and 12 weeks. The DHEA group and the control group did not exhibit a notable difference in TRAP-5b levels. The present study demonstrated that the DHEA treatment has a favorable impact on osteoporotic fracture healing by enhancing callus formation, consolidation, and strength in the OVX rats.

Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Effectiveness of instant versus text messaging intervention on antiretroviral therapy adherence among men who have sex with men living with HIV.

Objective: This study aimed to compare the effectiveness of instant versus text messaging intervention (TMI) on antiretroviral therapy (ART) adherence among men who have sex with men (MSM) living with HIV. Methods: This study was conducted in an infectious disease hospital of Jinan, China from October 2020 to June 2021, using non-randomized concurrent controlled design to compare the effectiveness of instant messaging intervention (IMI) versus TMI. The intervention strategies (health messaging, medication reminder, and peer education) and contents were consistent between the two groups, and the difference was service delivery method and type of information. The primary outcome was the proportion of achieving optimal ART adherence, defined as never missing any doses and delayed any doses more than 1 hour. Results: A total of 217 participants (including 72 in TMI group and 145 in IMI group) were included in the study. The proportion of achieving optimal adherence was higher in IMI group than TMI group at the first follow-up (90.2% versus 77.6%, p = 0.021) and second follow-up (86.5% versus 76.6%, p = 0.083). The effect of IMI versus TMI on improving ART adherence was found not to be statistically significant (risk ratio (RR) = 1.93, 95% confidence interval (CI): 0.95-3.94) in complete-case analysis. However, when excluding participants who did not adhere to the interventions, a significant improvement was observed (RR = 2.77, 95%CI: 1.21-6.38). More participants in IMI group expressed highly rated satisfaction to the intervention services than those in TMI group (67.3% versus 50.0%). Conclusions: The IMI demonstrated superior efficacy over TMI in improving ART adherence and satisfaction with intervention services. It is suggested that future digital health interventions targeting ART adherence should prioritize instant messaging with multimedia information in areas with Internet access. Trial registration: The study was registered at the Chinese Clinical Trial Register (ChiCTR), with number [ChiCTR2000041282].

Design of Selective PARP-1 Inhibitors and Antitumor Studies.

Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

Associations between perceived and actual risk of HIV infection and HIV prevention services uptake among men who have sex with men in Shandong province, China: a cross-sectional study.

BACKGROUND: Associations between perceived and actual risk of HIV infection and HIV prevention services uptake are inconclusive. This study aimed to evaluate the discrepancy between the perceived and actual HIV risk, and quantify the associations between perceived and actual risk of HIV infection and three HIV prevention services utilization among men who have sex with men (MSM) in Shandong province, China. METHODS: A cross-sectional study was conducted in Shandong province in June 2021. Participants were eligible if they were born biologically male, aged 18 years or older, had negative or unknown HIV status, and had sex with men in the past year. Participants were recruited online. The discrepancy between their perceived and actual risk of HIV infection was evaluated by calculating the Kappa value. Bayesian model averaging was used to assess the associations between perceived and actual risk of HIV infection and HIV prevention services uptake. RESULTS: A total of 1136 MSM were recruited, most of them were 30 years old or younger (59.9%), single (79.5%), with at least college education level (74.7%). Most participants (97.4%) perceived that they had low risk of HIV infection, and 14.1% were assessed with high actual risk. The discrepancy between their perceived and actual risk of HIV infection was evaluated with a Kappa value of 0.076 (P < 0.001). HIV testing uptake had a weak association with perceived high HIV prevalence among social networks (aOR = 1.156, post probability = 0.547). The perceived high HIV prevalence among national MSM was positive related to willingness to use PrEP (aOR = 1.903, post probability = 0.943) and PEP (aOR = 1.737, post probability = 0.829). Perceived personal risk (aOR = 4.486, post probability = 0.994) and perceived HIV prevalence among social networks (aOR = 1.280, post probability = 0.572) were related to history of using PrEP. Perceived personal risk (aOR = 3.144, post probability = 0.952), actual risk (aOR = 1.890, post probability = 0.950), and perceived risk among social networks (aOR = 1.502, post probability = 0.786) were related to history of using PEP. CONCLUSIONS: There is discordance between perceived and actual personal risk of HIV infection among MSM in China. HIV risk assessment and education on HIV prevalence among MSM should be strengthened to assist high-risk populations aware their risk accurately and hence access HIV prevention services proactively.

Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia.

Tauopathies exhibit a characteristic accumulation of misfolded tau aggregates in the brain. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying molecular mechanisms that prevent tau propagation is critical for developing therapeutic strategies for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In the present study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. We found that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to either of them. Inhibiting CR4, but not CR3, significantly reduces the uptake of tau fibrils by BV2 cells and primary microglia. By contrast, inhibiting CR4 has no effect on the uptake of tau monomers by BV2 cells. Furthermore, inhibiting CR4 suppresses the clearance of extracellular tau fibrils, leading to more seed-competent tau fibrils remaining in the extracellular space relative to control samples. We also provide evidence that the expression of CR4 is upregulated in the brains of human Alzheimer's disease patients and the PS19 mouse model of tauopathy. Taken together, our data strongly support that CR4 is a previously undescribed receptor for the clearance of tau fibrils in microglia and may represent a novel therapeutic target for tauopathy.

Development of high-efficiency superparamagnetic drug delivery system with MPI imaging capability.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

DWSSA: Alleviating over-smoothness for deep Graph Neural Networks.

Graph Neural Networks (GNNs) have demonstrated great potential in achieving outstanding performance in various graph-related tasks, e.g., graph classification and link prediction. However, most of them suffer from the following issue: shallow networks capture very limited knowledge. Prior works design deep GNNs with more layers to solve the issue, which however introduces a new challenge, i.e., the infamous over-smoothness. Graph representation over emphasizes node features but only considers the static graph structure with a uniform weight are the key reasons for the over-smoothness issue. To alleviate the issue, this paper proposes a Dynamic Weighting Strategy (DWS) for addressing over-smoothness. We first employ Fuzzy C-Means (FCM) to cluster all nodes into several groups and get each node's fuzzy assignment, based on which a novel metric function is devised for dynamically adjusting the aggregation weights. This dynamic weighting strategy not only enables the intra-cluster interactions, but also inter-cluster aggregations, which well addresses undifferentiated aggregation caused by uniform weights. Based on DWS, we further design a Structure Augmentation (SA) step for addressing the issue of underutilizing the graph structure, where some potentially meaningful connections (i.e., edges) are added to the original graph structure via a parallelable KNN algorithm. In general, the optimized Dynamic Weighting Strategy with Structure Augmentation (DWSSA) alleviates over-smoothness by reducing noisy aggregations and utilizing topological knowledge. Extensive experiments on eleven homophilous or heterophilous graph benchmarks demonstrate the effectiveness of our proposed method DWSSA in alleviating over-smoothness and enhancing deep GNNs performance.

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-ß40 Aggregation and Toxicity in Alzheimer's Disease.

Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP-C31 that is suspected to be involved in the pathology of AD. But details about the role of APP-C31 in the development of the disease are not known. Here, this work reports that APP-C31 directly interacts with the N-terminal and self-recognition regions of amyloid-ß40 (Aß40 ) to form transient adducts, which facilitates the aggregation of both metal-free and metal-bound Aß40 peptides and aggravates their toxicity. Specifically, APP-C31 increases the perinuclear and intranuclear generation of large Aß40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aß40 -induced degeneration of neurites and inflammation are also intensified by APP-C31 in human neurons and murine brains. This study demonstrates a new function of APP-C31 as an intracellular promoter of Aß40 amyloidogenesis in both metal-free and metal-present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity.

Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S's) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 µg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.

Digital, Crowdsourced, Multilevel Intervention to Promote HIV Testing Among Men Who Have Sex With Men: Cluster Randomized Controlled Trial.

BACKGROUND: Despite great efforts in HIV prevention worldwide, HIV testing uptake among men who have sex with men (MSM) remains suboptimal. The effectiveness of digital, crowdsourced, multilevel interventions in improving HIV testing is still unclear. OBJECTIVE: The aim of this study was to evaluate the effect of a digital, crowdsourced, multilevel intervention in improving HIV testing uptake among MSM in China. METHODS: We conducted a 2-arm cluster randomized controlled trial among MSM in 11 cities in Shandong province, China, from August 2019 to April 2020. Participants were men who were HIV seronegative or had unknown serum status, had anal sex with a man in the past 12 months, and had not been tested for HIV in the past 3 months. Participants were recruited through a gay dating app and community-based organizations from preselected cities; these cities were matched into 5 blocks (2 clusters per block) and further randomly assigned (1:1) to receive a digital, crowdsourced, multilevel intervention (intervention arm) or routine intervention (control arm). The digital multilevel intervention was developed through crowdsourced open calls tailored for MSM, consisting of digital intervention images and videos, the strategy of providing HIV self-testing services through digital tools, and peer-moderated discussion within WeChat groups. The primary outcome was self-reported HIV testing uptake in the previous 3 months. An intention-to-treat approach was used to examine the cluster-level effect of the intervention in the 12-month study period using generalized linear mixed models and the individual-level effect using linear mixed models. RESULTS: A total of 935 MSM were enrolled (404 intervention participants and 531 controls); 751 participants (80.3%) completed at least one follow-up survey. Most participants were younger than 30 years (n=601, 64.3%), single (n=681, 72.8%), had a college degree or higher (n=629, 67.3%), and had an HIV testing history (n=785, 84%). Overall, the proportion of testing for HIV in the past 3 months at the 3-, 6-, 9-, and 12-month follow-ups was higher in the intervention arm (139/279, 49.8%; 148/266, 55.6%; 189/263, 71.9%; and 171/266, 64.3%, respectively) than the control arm (183/418, 43.8%; 178/408, 43.6%; 206/403, 51.1%; and 182/397, 48.4%, respectively), with statistically significant differences at the 6-, 9-, and 12-month follow-ups. At the cluster level, the proportion of participants who had tested for HIV increased 11.62% (95% CI 0.74%-22.5%; P=.04) with the intervention. At the individual level, participants in the intervention arm had 69% higher odds for testing for HIV in the past 3 months compared with control participants, but the result was not statistically significant (risk ratio 1.69, 95% CI 0.87-3.27; P=.11). CONCLUSIONS: The intervention effectively improved HIV testing uptake among Chinese MSM. Our findings highlight that digital, crowdsourced, multilevel interventions should be made more widely available for HIV prevention and other public health issues. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900024350; http://www.chictr.org.cn/showproj.aspx?proj=36718. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-04860-8.

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease.

The underlying causes of Alzheimer's disease (AD) remain a mystery, with multiple pathological components, including oxidative stress, acetylcholinesterase, amyloid-ß, and metal ions, all playing a role. Here we report a strategic approach to designing flavonoids that can effectively tackle multiple pathological elements involved in AD. Our systematic investigations revealed key structural features for flavonoids to simultaneously target and regulate pathogenic targets. Our findings led to the development of a highly promising flavonoid that exhibits a range of functions, based on a complete structure-activity relationship analysis. Furthermore, our mechanistic studies confirmed that this flavonoid's versatile reactivities are driven by its redox potential and direct interactions with pathogenic factors. This work highlights the potential of multi-target-directed flavonoids as a novel solution in the fight against AD.

Coronaviral Main Protease Induces LPCAT3 Cleavage and Endoplasmic Reticulum (ER) Stress.

Zoonotic coronaviruses infect mammals and birds, causing pulmonary and gastrointestinal infections. Some animal coronaviruses, such as the porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV), lead to severe diarrhea and animal deaths. Gastrointestinal symptoms were also found in COVID-19 and SARS patients. However, the pathogenesis of gastrointestinal symptoms in coronavirus diseases remains elusive. In this study, the main protease-induced LPCAT3 cleavage was monitored by exogenous gene expression and protease inhibitors, and the related regulation of gene expression was confirmed by qRT-PCR and gene knockdown. Interestingly, LPCAT3 plays an important role in lipid absorption in the intestines. The Mpro of coronaviruses causing diarrhea, such as PEDV and MERS-CoV, but not the Mpro of HCoV-OC43 and HCoV-HKU1, which could induce LPCAT3 cleavage. Mutagenesis analysis and inhibitor experiments indicated that LPCAT3 cleavage was independent of the catalytic activity of Mpro. Moreover, LPCAT3 cleavage in cells boosted CHOP and GRP78 expression, which were biomarkers of ER stress. Since LPCAT3 is critical for lipid absorption in the intestines and malabsorption may lead to diarrhea in coronavirus diseases, Mpro-induced LPCAT3 cleavage might trigger gastrointestinal symptoms during coronavirus infection.

An archaeal transcription factor EnfR with a novel 'eighth note' fold controls hydrogen production of a hyperthermophilic archaeon Thermococcus onnurineus NA1.

Thermococcus onnurineus NA1, a hyperthermophilic carboxydotrophic archaeon, produces H2 through CO oxidation catalyzed by proteins encoded in a carbon monoxide dehydrogenase (CODH) gene cluster. TON_1525 with a DNA-binding helix-turn-helix (HTH) motif is a putative repressor regulating the transcriptional expression of the codh gene cluster. The T55I mutation in TON_1525 led to enhanced H2 production accompanied by the increased expression of genes in the codh cluster. Here, TON_1525 was demonstrated to be a dimer. Monomeric TON_1525 adopts a novel 'eighth note' symbol-like fold (referred to as 'eighth note' fold regulator, EnfR), and the dimerization mode of EnfR is unique in that it has no resemblance to structures in the Protein Data Bank. According to footprinting and gel shift assays, dimeric EnfR binds to a 36-bp pseudo-palindromic inverted repeat in the promoter region of the codh gene cluster, which is supported by an in silico EnfR/DNA complex model and mutational studies revealing the implication of N-terminal loops as well as HTH motifs in DNA recognition. The DNA-binding affinity of the T55I mutant was lowered by ∼15-fold, for which the conformational change of N-terminal loops is responsible. In addition, transcriptome analysis suggested that EnfR could regulate diverse metabolic processes besides H2 production.

Prediction of Return of Spontaneous Circulation in a Pediatric Swine Model of Cardiac Arrest Using Low-Resolution Multimodal Physiological Waveforms.

Monitoring physiological waveforms, specifically hemodynamic variables (e.g., blood pressure waveforms) and end-tidal CO2 (EtCO2), during pediatric cardiopulmonary resuscitation (CPR) has been demonstrated to improve survival rates and outcomes when compared to standard depth-guided CPR. However, waveform guidance has largely been based on thresholds for single parameters and therefore does not leverage all the information contained in multimodal data. We hypothesize that the combination of multimodal physiological features improves the prediction of the return of spontaneous circulation (ROSC), the clinical indicator of short-term CPR success. We used machine learning algorithms to evaluate features extracted from eight low-resolution (4 samples per minute) physiological waveforms to predict ROSC. The waveforms were acquired from the 2nd to 10th minute of CPR in pediatric swine models of cardiac arrest (N = 89, 8-12 kg). The waveforms were divided into segments with increasing length (both forward and backward) for feature extraction, and machine learning algorithms were trained for ROSC prediction. For the full CPR period (2nd to 10th minute), the area under the receiver operating characteristics curve (AUC) was 0.93 (95% CI: 0.87-0.99) for the multivariate model, 0.70 (0.55-0.85) for EtCO2 and 0.80 (0.67-0.93) for coronary perfusion pressure. The best prediction performances were achieved when the period from the 6th to the 10th minute was included. Poor predictions were observed for some individual waveforms, e.g., right atrial pressure. In conclusion, multimodal waveform features carry relevant information for ROSC prediction. Using multimodal waveform features in CPR guidance has the potential to improve resuscitation success and reduce mortality.

Non-invasive diffuse optical monitoring of cerebral physiology in an adult swine-model of impact traumatic brain injury.

In this study, we used diffuse optics to address the need for non-invasive, continuous monitoring of cerebral physiology following traumatic brain injury (TBI). We combined frequency-domain and broadband diffuse optical spectroscopy with diffuse correlation spectroscopy to monitor cerebral oxygen metabolism, cerebral blood volume, and cerebral water content in an established adult swine-model of impact TBI. Cerebral physiology was monitored before and after TBI (up to 14 days post injury). Overall, our results suggest that non-invasive optical monitoring can assess cerebral physiologic impairments post-TBI, including an initial reduction in oxygen metabolism, development of cerebral hemorrhage/hematoma, and brain swelling.

Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-ß aggregation and toxicity.

Cytochrome c (Cyt c), a multifunctional protein with a crucial role in controlling cell fate, has been implicated in the amyloid pathology associated with Alzheimer's disease (AD); however, the interaction between Cyt c and amyloid-ß (Aß) with the consequent impact on the aggregation and toxicity of Aß is not known. Here we report that Cyt c can directly bind to Aß and alter the aggregation and toxicity profiles of Aß in a manner that is dependent on the presence of a peroxide. When combined with hydrogen peroxide (H2O2), Cyt c redirects Aß peptides into less toxic, off-pathway amorphous aggregates, whereas without H2O2, it promotes Aß fibrillization. The mechanisms behind these effects may involve a combination of the complexation between Cyt c and Aß, the oxidation of Aß by Cyt c and H2O2, and the modification of Cyt c by H2O2. Our findings demonstrate a new function of Cyt c as a modulator against Aß amyloidogenesis.

Projecting future risk of dengue related to hydrometeorological conditions in mainland China under climate change scenarios: a modelling study.

BACKGROUND: We have limited knowledge on the impact of hydrometeorological conditions on dengue incidence in China and its associated disease burden in a future with a changed climate. This study projects the excess risk of dengue caused by climate change-induced hydrometeorological conditions across mainland China. METHODS: In this modelling study, the historical association between the Palmer drought severity index (PDSI) and dengue was estimated with a spatiotemporal Bayesian hierarchical model from 70 cities. The association combined with the dengue-transmission biological model was used to project the annual excess risk of dengue related to PDSI by 2100 across mainland China, under three representative concentration pathways ([RCP] 2·6, RCP 4·5, and RCP 8·5). FINDINGS: 93 101 dengue cases were reported between 2013 and 2019 in mainland China. Dry and wet conditions within 3 months lag were associated with increased risk of dengue. Locations with potential dengue risk in China will expand in the future. The hydrometeorological changes are projected to substantially affect the risk of dengue in regions with mid-to-low latitudes, especially the coastal areas under high emission scenarios. By 2100, the annual average increased excess risk is expected to range from 12·56% (95% empirical CI 9·54-22·24) in northwest China to 173·62% (153·15-254·82) in south China under the highest emission scenario. INTERPRETATION: Hydrometeorological conditions are predicted to increase the risk of dengue in the future in the south, east, and central areas of mainland China in disproportionate patterns. Our findings have implications for the preparation of public health interventions to minimise the health hazards of non-optimal hydrometeorological conditions in a context of climate change. FUNDING: National Natural Science Foundation of China.

An amphiphilic material arginine-arginine-bile acid promotes α-synuclein amyloid formation.

Amyloid generation plays essential roles in various human diseases, biological functions, and nanotechnology. However, developing efficient chemical and biological candidates for regulating amyloid fibrillation remains difficult because information on the molecular actions of modulators is insufficient. Thus, studies are needed to understand how the intermolecular physicochemical properties of the synthesised molecules and amyloid precursors influence amyloidogenesis. In this study, we synthesised a novel amphiphilic sub-nanosized material, arginine-arginine (RR)-bile acid (BA), by conjugating positively charged RR to hydrophobic BA. The effects of RR-BA on amyloid formation were investigated on α-synuclein (αSN) in Parkinson's disease and on K18 and amyloid-ß (1-42) (Aß42) in Alzheimer's disease. RR-BA showed no appreciable effect on the kinetics of K18 and Aß42 amyloid fibrillation because of their weak and non-specific interactions. However, RR-BA specifically bound to αSN with moderate binding affinity through electrostatic interactions between the positively charged RR and the negatively charged cluster in the C-terminus of αSN. In addition, hydrophobic BA in the αSN-RR-BA complex transiently condensed αSN for primary nucleation, thereby accelerating αSN amyloid fibrillation. We propose an electrostatic binding and hydrophobic condensation model of RR-BA-driven amyloid formation of αSN, which will contribute to the rational design and development of molecules for controlling amyloid aggregation in diverse fields.