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Cardiac arrest often results in severe neurologic injury. Improving care for these patients is difficult as few noninvasive biomarkers exist that allow physicians to monitor neurologic health. The amount of low-frequency power (LFP, 0.01-0.1 Hz) in cerebral haemodynamics has been used in functional magnetic resonance imaging as a marker of neuronal activity. Our hypothesis was that increased LFP in cerebral blood flow (CBF) would be correlated with improvements in invasive measures of neurologic health.We adapted the use of LFP for to monitoring of CBF with diffuse correlation spectroscopy. We asked whether LFP (or other optical biomarkers) correlated with invasive microdialysis biomarkers (lactate-pyruvate ratio - LPR - and glycerol concentration) of neuronal injury in the 4 h after return of spontaneous circulation in a swine model of paediatric cardiac arrest (Sus scrofa domestica, 8-11 kg, 51% female). Associations were tested using a mixed linear effects model.We found that higher LFP was associated with higher LPR and higher glycerol concentration. No other biomarkers were associated with LPR; cerebral haemoglobin concentration, oxygen extraction fraction, and one EEG metric were associated with glycerol concentration.Contrary to expectations, higher LFP in CBF was correlated with worse invasive biomarkers. Higher LFP may represent higher neurologic activity, or disruptions in neurovascular coupling. Either effect may be harmful in the acute period after cardiac arrest. Thus, these results suggest our methodology holds promise for development of new, clinically relevant biomarkers than can guide resuscitation and post-resuscitation care. Institutional protocol number: 19-001327.

Aim Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA. Methods After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology. Results During CPR, the iNO group had higher mean aortic pressure (41.6 ± 2.0 vs. 36.0 ± 1.4 mmHg; p = 0.005); diastolic BP (32.4 ± 2.4 vs. 27.1 ± 1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ± 2.6 vs. 19.1 ± 1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ± 54.1 vs. 115.5 ± 37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O2/s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O2/s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups. Conclusions Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model.

Summary Recent findings have garnered a substantial amount of attention toward tau based on its pathological contribution to neurodegenerative diseases, such as Alzheimer’s disease (AD). Studies investigating the structure and aggregation of tau under various in vitro and in vivo conditions have revealed its intrinsically disordered structures and amyloidogenesis process. The aggregation behavior of tau is strongly dependent on the experimental conditions due to the high sensitivity of both the soluble tau conformations and the amyloid nucleation process toward its surrounding environments. Herein, we review and discuss (1) the effects of different physicochemical and biological factors as well as intermolecular interactions with various molecular chaperones on tau aggregation, (2) context-dependent liquid-liquid phase separation of tau and its amyloidogenic transformation, and (3) the utility of the phase diagram in comprehending the phase transition and separation of proteins.

Background: Antigen based rapid diagnostic test (Ag-RDT) is faster and applicable for self-testing of SARS-CoV-2. Nasopharyngeal swab (NPS) is not technically feasible for self-testing due to requirement of heath professional and risk of contaminated aerosol during sample collection. Thus, saliva specimen can be appropriate for self-sampling technique required for Ag-RDT. However, the detection of virus by Ag-RDT in saliva could be less sensitive. Therefore, we aimed to evaluate novel Beanguard gargleTM (BG)-based virus collection method that can be applied to antigen-rapid detection test (Ag-RDT) as an alternative to the current RT-PCR with a nasopharyngeal swab (NPS) for early diagnosis of COVID-19. Methods: Paired BG-based saliva and NPS specimens were collected from 102 patients with COVID-19 and 100 healthy subjects. The diagnostic performance of Ag-RDT (BG-Ag-RDT) and RT-PCR (BG-RT-PCR) of BG-based saliva specimens for SARS-CoV-2 detection was compared to NPS-RT-PCR. Physical interactions between the bean extract (BE) in BG and SARS-CoV-2 were evaluated using cryo-electron microscopy (cryo-EM), isothermal titration calorimetry, and ELISA. Findings: BG-Ag-RDTs showed high sensitivity (97·8%) and specificity (100%) in all patients within 6 days of illness associated with the infection of SARS-CoV-2 along with Alpha and Delta variants. Notably, in 11 asymptomatic early-stage cases, both BG-Ag-RDTs and BG-RT-PCR showed excellent performance with sensitivity and specificity of 100%. The interaction between SARS-CoV-2 spike proteins and truncated canavalin, an active ingredient from BE, was shown by calorimetry. The ultrastructural features of SARS-CoV-2 particles coated by BE were well observed in cryo-EM, and the detachment of the receptor binding domain of SARS-CoV-2 from hACE2 was increased with increasing concentration of BE in ELISA, allowing us to apply for releasing the virus from hACE2 in the oral cavity to early diagnosis. Interpretation: BG-based saliva specimens applied to Ag-RDT can be an alternative to NPS-RT-PCR for early diagnosis of COVID-19. The method can facilitate self-testing without trained healthcare workers for mass screening, surveillance, and efficient quarantine. Funding: BIO3S, Inc., Korea Basic Science Institute, and Jeonbuk National University Hospital. Declaration of Interest: DSK received grant support for clinical study from BIO3S, Inc. DK, JK and BV were involved in developing Beanguard gargleTM. All disclosures are unrelated to present clinical study. All other authors declare no competing interests. Ethical Approval: Ethical approval for the study was granted by the Institutional Review Board of Jeonbuk National University Hospital (CUH 2021-04-036-002) and written informed consent statements were obtained from all participants.

Amyloid fibrillation causes serious neurodegenerative diseases and amyloidosis; however, the detailed mechanisms by which the structural states of precursor proteins in a lipid membrane-associated environment contribute to amyloidogenesis still remains to be elucidated. We examined the relationship between structural states of intrinsically-disordered wild-type and mutant α-synuclein (αSN) and amyloidogenesis on two-types of model membranes. Highly-unstructured wild-type αSN (αSNWT) and a C-terminally-truncated mutant lacking negative charges (αSN103) formed amyloid fibrils on both types of membranes, the model membrane mimicking presynaptic vesicles (Mimic membrane) and the model membrane of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC membrane). Unstructured αSNWT and αSN103 both bound to Mimic membranes in a helical conformation with similar binding affinity. Promotion and then inhibition of amyloidogenesis of αSNWT were observed as the concentration of Mimic lipids increased. We explain this by the two-state binding model: at lower lipid concentrations, binding of αSNWT to membranes enhances amyloidogenicity by increasing the local concentration of membrane-bound αSN and so promoting amyloid nucleation; at higher lipid concentrations, membrane-bound αSNWT is actually in a sense diluted by increasing the number of model membranes, which blocks amyloid fibrillation due to an insufficient bound population for productive nucleation. Meanwhile, αSN103 formed amyloid fibrils over the whole concentration of Mimic lipids used here without inhibition, revealing the importance of helical structures for binding affinity and negatively charged unstructured C-terminal region for modulating amyloidogenesis. We propose that membrane binding-induced initial conformations of αSN, its overall charge states, and the population of membrane-bound αSN are key determinants of amyloidogenesis on membranes.

Amyloidogenic proteins often form many types of aggregates, which are a critical determinant of cytotoxicity and tissue specificity. However, the molecular mechanisms underlying the generation of distinct amyloids and their influence on cells remain largely unknown. We herein investigated the polymorphic amyloid formation of the yeast prion protein, Sup35NM, an intrinsically disordered N-terminal fragment of Sup35, under various conditions and its potential relationship to cytotoxicity. Sup35NM aggregated to amyloid fibrils with distinct kinetics, structures, morphologies, tinctorial properties, and conformational stabilities depending on the concentration of NaCl, pH, and temperature, indicating the polymorphic amyloidogenesis of Sup35NM. Detailed kinetic analyses of Sup35NM amyloid formation revealed a strong inverse correlation between the lag time and elongation rate without a correlation between kinetic and structural parameters. These results suggest that kinetic polymorphisms due to distinct nucleation and elongation rates result in structural polymorphs of amyloid fibrils, and also that conditions that enhance or inhibit the nucleation of Sup35NM promote or delay fibril growth. The deleterious effects of polymorphic Sup35NM amyloid fibrils on membrane integrity and cell vitality were minimal. We hypothesize that the innocuous polymorphic nature of Sup35NM amyloid fibrils may be beneficial for gaining time for prion infection prior to cell death.

Aims To explore the effects of glucose, insulin, and glycosylated hemoglobin (HbA1c) levels on the outcome of sarcopenia in patients with type 2 diabetes mellitus (T2DM). Methods A total of 482 T2DM patients were enrolled in the follow-up study. The median follow-up time was 36 months. Muscle mass and HbA1c were measured in all participants. And glucose, C-peptide and insulin levels were measured at 0 min, 30 min, and 120 min after glucose load. We subsequently analyzed daily glucose fluctuations and islet function before and after readmission as well as the influence of their changes on sarcopenia outcome. Results After glucose load, incident sarcopenia patients showed greater glucose fluctuations and worse islet function than did non-sarcopenia patients. As HbA1c and standard deviation of blood glucose (SDBG) increased, readmitted non-sarcopenia patients showed a significantly increased odds ratio of incident sarcopenia; however, only patients with higher quartiles were statistically significant. Increased ΔAUC-C-peptide reduced the risk of incident sarcopenia (P Conclusions Patients with incident sarcopenia have poor glucose regulation and insufficient insulin secretion. Furthermore, as HbA1c and SDBG increased, AUC-C-peptide and AUC-insulin decreased in readmitted non-sarcopenia patients, the risk of incident sarcopenia increased.

The aggregation of amyloid-β (Aβ) on lipid bilayers has been implicated as a mechanism by which Aβ exerts its toxicity in Alzheimer's disease (AD). Lipid bilayer thinning has been observed during both oxidative stress and protein aggregation in AD, but whether these pathological modifications of the bilayer correlate with Aβ misfolding is unclear. Here, we studied peptide-lipid interactions in synthetic bilayers of the short-chain lipid dilauroyl phosphatidylcholine (DLPC) as a simplified model for diseased bilayers to determine their impact on Aβ aggregate, protofibril, and fibril formation. Aβ aggregation and fibril formation in membranes composed of dioleoyl phosphatidylcholine (DOPC) or 1- palmitoyl-2-oleoyl phosphatidylcholine mimicking normal bilayers served as controls. Differences in aggregate formation and stability were monitored by a combination of thioflavin-T fluorescence, circular dichroism, atomic force microscopy, transmission electron microscopy, and NMR. Despite the ability of all three lipid bilayers to catalyze aggregation, DLPC accelerates aggregation at much lower concentrations and prevents the fibrillation of Aβ at low micromolar concentrations. DLPC stabilized globular, membrane-associated oligomers, which could disrupt the bilayer integrity. DLPC bilayers also remodeled preformed amyloid fibrils into a pseudo-unfolded, molten globule state, which resembled on-pathway, protofibrillar aggregates. Whereas the stabilized, membrane-associated oligomers were found to be nontoxic, the remodeled species displayed toxicity similar to that of conventionally prepared aggregates. These results provide mechanistic insights into the roles that pathologically thin bilayers may play in Aβ aggregation on neuronal bilayers, and pathological lipid oxidation may contribute to Aβ misfolding.

Aim Most pediatric in-hospital cardiac arrests (IHCAs) occur in ICUs where invasive hemodynamic monitoring is frequently available. Titrating cardiopulmonary resuscitation (CPR) to the hemodynamic response of the individual improves survival in preclinical models of adult cardiac arrest. The objective of this study was to determine if titrating CPR to systolic blood pressure (SBP) and coronary perfusion pressure (CoPP) in a pediatric porcine model of asphyxia-associated ventricular fibrillation (VF) IHCA would improve survival as compared to traditional CPR. Methods After 7min of asphyxia followed by VF, 4-week-old piglets received either hemodynamic-directed CPR (HD-CPR; compression depth titrated to SBP of 90mmHg and vasopressor administration to maintain CoPP ≥20mmHg); or Standard Care (compression depth 1/3 of the anterior–posterior chest diameter and epinephrine every 4min). All animals received CPR for 10min prior to the first defibrillation attempt. CPR was continued for a maximum of 20min. Protocolized intensive care was provided to all surviving animals for 4h. The primary outcome was 4-h survival. Results Survival rate was greater with HD-CPR (12/12) than Standard Care (6/10; p=0.03). CoPP during HD-CPR was higher compared to Standard Care (point estimate +8.1mmHg, CI 95 : 0.5–15.8mmHg; p=0.04). Chest compression depth was lower with HD-CPR than Standard Care (point estimate −14.0mm, CI95: −9.6 to −18.4mm; p Conclusions Hemodynamic-directed CPR improves short-term survival compared to standard depth-targeted CPR in a porcine model of pediatric asphyxia-associated VF IHCA.

Fabrication of ultra-thin 2D film of carbon nanotubes (CNTs) is achieved by employing a self-assembly protein of α-synuclein (αS). Electron energy loss spectroscopy-transmission electron microscopy and circular dichroism spectroscopy analyses indicate that αS binds to the hydrophobic surface of CNT through its N-terminal region by forming α-helix. 1H-15N heteronuclear single-quantum coherence correlation-nuclear magnetic resonance spectra show that the acidic C-terminus of αS is exposed outward from the CNT surface. Following a slow vacuum filtration of the CNTs complexed with αS through a polycarbonate membrane filter, chloroform is used to unleash the free-floating ultra-thin CNT film from the substrate by causing unique αS-αS interactions of the enhanced anti-parallel β-sheet and α-helix formation. To make a graphically patterned CNT film stable in the free-floating state, gold nanoparticles (AuNPs) encapsulated with αS are employed to generate the αS-mediated CNT/AuNP hybrid film. The CNT-AuNP hybrid pattern is also directly transferred onto a thermo-responsive hydrogel sheet and sandwiched with a passive polymer layer. The resulting triply structure exhibits a shape deformation upon the light exposure. The light-responsive controllable soft material, therefore, has been suggested to be utilized in various areas including not only soft robotics but also human-machine interface by providing stimuli-responsive electroconductive and biocompatible matrix.

In this paper several new structures of all-optical logic gate in a two-dimensional photonic crystal (PC) based on multi-mode interference (MMI) are proposed and designed. 3 π /2 phase shift is introduced between two input ports in the photonic crystal devices through different lengths of the waveguide of two input ports, which makes the logic gates to be directly used for logic operations of binary-phase-shift-keyed (BPSK) signals. XOR, XNOR, OR and NAND logic gates are realized. In order to simulate the performance of the proposed logic gates, the plane wave expansion method (PWEM) and finite difference time domain (FDTD) method are employed. Numerical results reveal that the contrast ratio between Logic 1 and Logic 0 logic-levels is more than 21 dB for XOR, 17 dB for XNOR, and 13 dB for OR and NAND logic operations in the whole C-Band (1530–1565 nm). This kind of structure does not adopt nonlinear optical properties, and hence, the power consumption of the device is very low and the size of the device is very small. Therefore, the proposed logic gate has the potential to constitute photonic integrated components that will be used in all-optical signal processing, photonic computing and all-optical networks.

Summary In vitro studies have demonstrated a critical role for high-mobility group box 1 (HMGB1) in autophagy and the autophagic clearance of dysfunctional mitochondria, resulting in severe mitochondrial fragmentation and profound disturbances of mitochondrial respiration in HMGB1-deficient cells. Here, we investigated the effects of HMGB1 deficiency on autophagy and mitochondrial function in vivo, using conditional Hmgb1 ablation in the liver and heart. Unexpectedly, deletion of Hmgb1 in hepatocytes or cardiomyocytes, two cell types with abundant mitochondria, did not alter mitochondrial structure or function, organ function, or long-term survival. Moreover, hepatic autophagy and mitophagy occurred normally in the absence of Hmgb1 , and absence of Hmgb1 did not significantly affect baseline and glucocorticoid-induced hepatic gene expression. Collectively, our findings suggest that HMGB1 is dispensable for autophagy, mitochondrial quality control, the regulation of gene expression, and organ function in the adult organism.

Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Proper autophagic flux is vital for both functional skeletal muscle, which controls the support and movement of the skeleton, and muscle metabolism. The role of autophagy as a metabolic regulator in muscle has been previously studied; however, the underlying molecular mechanisms that control autophagy in skeletal muscle have only recently begun to emerge. We review recent literature on the molecular pathways controlling skeletal muscle autophagy and discuss how they connect autophagy to metabolic regulation. We also focus on the implications these studies hold for understanding metabolic and muscle-wasting diseases.

Purpose: Feedback devices to improve quality of cardiac pulmonary resuscitation (CPR) and software for reviewof resuscitation attempts are now available. This enables evaluating chest compression quality in clinical events. However, calculations involve periods where CPR is not performed, thereby affecting the compression quality results. In this report, accuracy of automatically performed calculations, by the review software, andmanual calculations were compared. Materials and methods: Fifty-two in-hospital cardiac arrest events were analyzed. Zoll AED Pro and RescueNet Code Review software (Zoll Medical, Chelmsford) was used in all events. The software automatically calculated compression quality fromwhen the AED was started until it was switched off. To investigate how periods without CPR affected the results of the automatic review, qualitywasmanually estimatedwhenCPRwas actually performed. Compressions given with a rate between 100 and 120 per minute and a depth of ≥5 to ≤10 cm were considered to be correctly performed. Each event from the manual review was sorted into one of three groups