Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice.

NR2D subunit-containing NMDA receptors (NMDARs) gradually disappear during brain maturation but can be recruited by pathophysiological stimuli in the adult brain. Here, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication recruited NR2D subunit-containing NMDARs that generated an Mg2+-resistant tonic NMDA current (INMDA) in dopaminergic (DA) neurons in the midbrain of mature male mice. MPTP selectively generated an Mg2+-resistant tonic INMDA in DA neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Consistently, MPTP increased NR2D but not NR2B expression in the midbrain regions. Pharmacological or genetic NR2D interventions abolished the generation of Mg2+-resistant tonic INMDA in SNpc DA neurons, and thus attenuated subsequent DA neuronal loss and gait deficits in MPTP-treated mice. These results show that extrasynaptic NR2D recruitment generates Mg2+-resistant tonic INMDA and exacerbates DA neuronal loss, thus contributing to MPTP-induced Parkinsonism. The state-dependent NR2D recruitment could be a novel therapeutic target for mitigating cell type-specific neuronal death in neurodegenerative diseases.SIGNIFICANCE STATEMENT NR2D subunit-containing NMDA receptors (NMDARs) are widely expressed in the brain during late embryonic and early postnatal development, and then downregulated during brain maturation and preserved at low levels in a few regions of the adult brain. Certain stimuli can recruit NR2D subunits to generate tonic persistent NMDAR currents in nondepolarized neurons in the mature brain. Our results show that MPTP intoxication recruits NR2D subunits in midbrain dopaminergic (DA) neurons, which leads to tonic NMDAR current-promoting dopaminergic neuronal death and consequent abnormal gait behavior in the MPTP mouse model of Parkinson's disease (PD). This is the first study to indicate that extrasynaptic NR2D recruitment could be a target for preventing neuronal death in neurodegenerative diseases.

High-efficiency Lithium Metal Stabilization and Polysulfide Suppression in Li-S Battery Enabled by Weakly Solvating Solvent.

Lithium-sulfur batteries (LSBs) are considered a highly promising next-generation energy storage technology due to their exceptional energy density and cost-effectiveness. However, the practical use of current LSBs is hindered primarily by issues related to the "shuttle effect" of lithium polysulfide (LiPS) intermediates and the growth of lithium dendrites. In strongly solvating electrolytes, the solvent-derived solid electrolyte interphase (SEI) lacks mechanical strength due to organic components, leading to ineffective lithium dendrite suppression and severe LiPS dissolution and shuttling. In contrast, the weakly solvating electrolyte (WSE) can create an anion-derived SEI layer which can enhance compatibility with lithium metal anode, and restricting LiPS solubility. Herein, a WSE consisting of 0.4 Ð¼ LiTFSI in the mixture of 1,4-dioxane (DX):dimethoxymethane (DMM) is designed to overcome the issues associated with LSB. Surface analyses confirmed the formation of a beneficial SEI layer rich in LiF, enabling homogeneous lithium deposition with an average Coulombic efficiency CE exceeding 99% over 100 cycles. Implementing the low-concentration WSE in Li||SPAN cells yielded an impressive initial specific capacity of 671 mAh g-1. This research highlights the advantages of WSE and offers the pathway for cost-effective electrolyte development, enabling the realization of high-performance LSBs.

SARS-CoV-2 exploits cellular RAD51 to promote viral propagation: implication of RAD51 inhibitor as a potential drug candidate against COVID-19.

IMPORTANCE: Viruses are constantly evolving to promote propagation in the host. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes host RAD51 for replication. Silencing of RAD51 impaired SARS-CoV-2 propagation. Viral RNA colocalized with RAD51 in the cytoplasm of SARS-CoV-2-infected cells, suggesting that both viral RNA and RAD51 may form a replication complex. We, therefore, evaluated RAD51 inhibitors as possible therapeutic agents against SARS-CoV-2. Indeed, RAD51 inhibitors exerted antiviral activities against not only Wuhan but also variants of SARS-CoV-2. Molecular docking model shows that RAD51 inhibitors impede SARS-CoV-2 propagation by interfering with dimerization of RAD51. These data suggest that RAD51 may represent a novel host-based drug target for coronavirus disease 2019 treatment.

Barriers and enablers to people-centred viral hepatitis care in Vietnam and the Philippines: Results of a patient journey mapping study.

In Vietnam and the Philippines, viral hepatitis is the leading cause of cirrhosis and liver cancer. This study aims to understand the barriers and enablers of people receiving care for hepatitis B and C to support both countries' efforts to eliminate viral hepatitis as a public health threat by 2030. Retrospective, semi-structured interviews were conducted with a purposive, quota-based sample of 63 people living with hepatitis B or C in one province of Vietnam and one region of the Philippines. A rapid deductive approach to thematic analysis produced key findings among the three phases of care: (1) pre-awareness and testing, (2) linkage and treatment initiation and (3) ongoing treatment and recovery. The research found that participants followed five typical journeys, from a variety of entry points. Barriers during the pre-awareness and testing phase included limited awareness about hepatitis and its management, stigma and psychological impacts. Enablers included being familiar with the health system and/or patients benefiting from social connections within the health systems. During the linkage and treatment initiation phase, barriers included difficult physical access, complex navigation and inadequate counselling. In this phase, family support emerged as a critical enabler. During the ongoing treatment and recovery phase, the cost of care and socially and culturally informed perceptions of the disease and medication use were both barriers and enablers. Exploring peoples' journeys with hepatitis B and C in Vietnam and the Philippines revealed many similarities despite the different cultural and health system contexts. Insights from this study may help generate a contextualized, people-centred evidence base to inform the design and improvement of primary care services for hepatitis in both research sites.

Association of green tea consumption with prediabetes, diabetes and markers of glucose metabolism in rural Vietnam: a cross-sectional study.

The literature on green tea consumption and glucose metabolism has reported conflicting findings. This cross-sectional study examined the association of green tea consumption with abnormal glucose metabolism among 3000 rural residents aged 40-60 years in Khánh Hòa province in Vietnam. Multinomial logistic regression analysis was conducted to examine the association of green tea consumption (0, < 200, 200-< 400, 400-< 600 or ≥ 600 ml/d) with prediabetes and diabetes (based on the American Diabetes Association criteria). Linear regression analysis was performed to examine the association between green tea consumption and the log-transformed homeostatic model assessment of insulin resistance (HOMA-IR) (a marker of insulin resistance) and the log-transformed homeostatic model assessment of ß-cell function (HOMA-ß) (a marker of insulin secretion). The OR for prediabetes and diabetes among participants who consumed ≥ 600 ml/d v. those who did not consume green tea were 1·61 (95 % CI = 1·07, 2·42) and 2·04 (95 % CI = 1·07, 3·89), respectively. Higher green tea consumption was associated with a higher level of log-transformed HOMA-IR (Pfor trend = 0·04) but not with a lower level of log-transformed HOMA-ß (Pfor trend = 0·75). Higher green tea consumption was positively associated with the prevalence of prediabetes, diabetes and insulin resistance in rural Vietnam. The findings of this study indicated prompting the need for further research considering context in understanding the link between green tea consumption and glucose metabolism, especially in rural settings in low- and middle-income countries.

Sex differences in the association between socioeconomic status and untreated hypertension among residents with hypertension in rural Khánh Hòa, Vietnam: a post-hoc analysis.

BACKGROUND: Several studies have examined the association between socioeconomic status (SES) and the proportion of untreated hypertension, but have produced conflicting findings. In addition, no study has been conducted to determine sex differences in the association between SES and untreated hypertension. Thus, the aim of this study was to examine whether the associations between SES and the proportion of untreated hypertension differed by sex in Vietnam. METHODS: This study was conducted using the data of 1189 individuals (558 males and 631 females) who were judged to have hypertension during the baseline survey of a prospective cohort study of 3000 residents aged 40-60 years in the Khánh Hòa Province. A multilevel Poisson regression model with a robust variance estimator was used to examine whether sex and SES indicators (household income and educational attainment) interacted in relation to untreated hypertension. RESULTS: The proportion of untreated hypertension among individuals identified as hypertensive was 69.1%. We found significant interaction between sex and SES indicators in relation to untreated hypertension (education: p < 0.001; household income: p < 0.001). Specifically, the association between SES and untreated hypertension was inverse among males while it was rather positive among females. CONCLUSIONS: Our finding suggests that the role of SES in the proportion of untreated hypertension might differ by sex.

Comparison of waist circumference and waist-to-height ratio as predictors of clustering of cardiovascular risk factors among middle-aged people in rural Khanh Hoa, Vietnam.

OBJECTIVE: Given the population-level variation in stature, a universal cut-off for waist circumference (WC) may not be appropriate for some populations. We compared the performance of WC and waist-to-height ratio (WHtR) to detect the clustering of cardiovascular disease (CVD) risk factors in rural Vietnam. METHODS: We obtained data from a baseline survey of the Khanh Hoa Cardiovascular Study comprising 2942 middle-aged residents (40-60 years). We used areas under the receiver operating characteristics curve (AUROC), net reclassification index (NRI), and integrated discrimination improvement (IDI) to compare the performance of WC and WHtR in predicting CVD risk clustering (≥2 of the following risk factors: hypertension, diabetes, dyslipidemia, and elevated C-reactive protein). RESULTS: The optimal cut-off values for WC were 81.8 and 80.7 cm for men and women, respectively. Regarding the clustering of CVD risk factors, the AUROC (95% CI) of WC and WHtR were 0.707 (0.676 to 0.739) and 0.719 (0.689 to 0.749) in men, and 0.682 (0.654 to 0.709) and 0.690 (0.663 to 0.717) in women, respectively. Compared with WC, WHtR had a better NRI (0.229; 0.102-0.344) and IDI (0.012; 0.004-0.020) in men and a better NRI (0.154; 0.050-0.257) in women. CONCLUSIONS: The optimal WC cut-off for Vietnamese men was approximately 10 cm below the recommended Asian cut-off. WHtR might perform slightly better in predicting the clustering of CVD risk factors among the rural population in Vietnam.

OsLRR-RLP2 Gene Regulates Immunity to Magnaporthe oryzae in Japonica Rice.

Rice is an important cereal crop worldwide, the growth of which is affected by rice blast disease, caused by the fungal pathogen Magnaporthe oryzae. As climate change increases the diversity of pathogens, the disease resistance genes (R genes) in plants must be identified. The major blast-resistance genes have been identified in indica rice varieties; therefore, japonica rice varieties with R genes now need to be identified. Because leucine-rich repeat (LRR) domain proteins possess R-gene properties, we used bioinformatics analysis to identify the rice candidate LRR domain receptor-like proteins (OsLRR-RLPs). OsLRR-RLP2, which contains six LRR domains, showed differences in the DNA sequence, containing 43 single-nucleotide polymorphisms (SNPs) in indica and japonica subpopulations. The results of the M. oryzae inoculation analysis indicated that indica varieties with partial deletion of OsLRR-RLP2 showed susceptibility, whereas japonica varieties with intact OsLRR-RLP2 showed resistance. The oslrr-rlp2 mutant, generated using clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), showed increased pathogen susceptibility, whereas plants overexpressing this gene showed pathogen resistance. These results indicate that OsLRR-RLP2 confers resistance to rice, and OsLRR-RLP2 may be useful for breeding resistant cultivars.

Subgingival 0.75% boric acid vs 1% povidone-iodine adjunctive to subgingival instrumentation in stage II and III periodontitis-A double-blind randomized clinical trial.

PURPOSE: To compare the effects of subgingival irrigation with 0.75% boric acid (BA) and 1% povidone-iodine (PVP-I) as an adjunct to scaling and root planing (SRP) on clinical and microbiologic parameters in the management of patients with periodontitis after a 12-month follow-up. METHODS: Sixty systemically healthy individuals diagnosed with periodontitis were included in this double-blind randomised clinical trial. The patients were randomly allocated to treatment groups: (1) SRP plus 0.75% BA and (2) SRP plus 1% PVP-I. Whole-mouth periodontals were clinically examined, and the counts of bacteria including Aggregatibacter actinomycetemcomitans (Aa), Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg), Treponema denticola (Td), Tannerella forsythia (Tf), Solobacterium moorei (Sm) and Streptococcus salivarius (Ss) were tested by real-time polymerase chain reaction (PCR). RESULTS: All periodontal parameters and the counts of Aa, Fn, Pg, Td, Tf, Sm and Ss in both groups showed statistically significant reductions at T3, T6 and T12 compared to T0. Whole-mouth or moderate or severe PD and CAL improvements were significantly found in the 0.75% BA group compared to the 1% PVP-I group at T3, T6 and T12. The reduction in Aa or Fn and the reduction in Ss were significantly higher in the 0.75% BA group at T6 and T12 than in the 1% PVP-I group. CONCLUSION: This study shows that subgingival irrigation with 0.75% BA may be an alternative to 1% PVP-I because it promotes greater PD reductions and CAL gain, particularly up to 12 months after treatment.

Surveillance and treatment of primary hepatocellular carcinoma (aka. STOP HCC): protocol for a prospective cohort study of high-risk patients for HCC using GALAD-score.

BACKGROUND: Vietnam and Saudi Arabia have high disease burden of primary hepatocellular carcinoma (HCC). Early detection in asymptomatic patients at risk for HCC is a strategy to improve survival outcomes in HCC management. GALAD score, a serum-based panel, has demonstrated promising clinical utility in HCC management. However, in order to ascertain its potential role in the surveillance of the early detection of HCC, GALAD needs to be validated prospectively for clinical surveillance of HCC (i.e., phase IV biomarker validation study). Thus, we propose to conduct a phase IV biomarker validation study to prospectively survey a cohort of patients with advanced fibrosis or compensated cirrhosis, irrespective of etiologies, using semi-annual abdominal ultrasound and GALAD score for five years. METHODS: We plan to recruit a cohort of 1,600 patients, male or female, with advanced fibrosis or cirrhosis (i.e., F3 or F4) and MELD ≤ 15, in Vietnam and Saudi Arabia (n = 800 each). Individuals with a liver mass ≥ 1 cm in diameter, elevated alpha-fetoprotein (AFP) (≥ 9 ng/mL), and/or elevated GALAD score (≥ -0.63) will be scanned with dynamic contrast-enhanced magnetic resonance imaging (MRI), and a diagnosis of HCC will be made by Liver Imaging Reporting and Data System (LiRADS) assessment (LiRADS-5). Additionally, those who do not exhibit abnormal imaging findings, elevated AFP titer, and/or elevated GALAD score will obtain a dynamic contrast-enhanced MRI annually for five years to assess for HCC. Only MRI nearest to the time of GALAD score measurement, ultrasound and/or AFP evaluation will be included in the diagnostic validation analysis. MRI will be replaced with an abdominal computed tomography scan when MRI results are poor due to patient conditions such as movement etc. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI will not be carried out in study sites in both countries. Bootstrap resampling technique will be used to account for repeated measures to estimate standard errors and confidence intervals. Additionally, we will use the Cox proportional hazards regression model with covariates tailored to the hypothesis under investigation for time-to-HCC data as predicted by time-varying biomarker data. DISCUSSION: The present work will evaluate the performance of GALAD score in early detection of liver cancer. Furthermore, by leveraging the prospective cohort, we will establish a biorepository of longitudinally collected biospecimens from patients with advanced fibrosis or cirrhosis to be used as a reference set for future research in early detection of HCC in the two countries. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov Registration date: 22 April 2022 Trial registration number: NCT05342350 URL of trial registry record.

Fluid-solid transitions in photonic crystals of soft, thermoresponsive microgels.

Microgels are often discussed as well-suited model system for soft colloids. In contrast to rigid spheres, the microgel volume and, coupled to this, the volume fraction in dispersion can be manipulated by external stimuli. This behavior is particularly interesting at high packings where phase transitions can be induced by external triggers such as temperature in the case of thermoresponsive microgels. A challenge, however, is the determination of the real volume occupied by these deformable, soft objects and consequently, to determine the boundaries of the phase transitions. Here we propose core-shell microgels with a rigid silica core and a crosslinked, thermoresponsive poly-N-isopropylacrylamide (PNIPAM) shell with a carefully chosen shell-to-core size ratio as ideal model colloids to study fluid-solid transitions that are inducible by millikelvin changes in temperature. Specifically, we identify the temperature ranges where crystallization and melting occur using absorbance spectroscopy in a range of concentrations. Slow annealing from the fluid to the crystalline state leads to photonic crystals with Bragg peaks in the visible wavelength range and very narrow linewidths. Small-angle X-ray scattering is then used to confirm the structure of the fluid phase as well as the long-range order, crystal structure and microgel volume fraction in the solid phase. Thanks to the scattering contrasts and volume ratio of the cores with respect to the shells, the scattering data do allow for form factor analysis revealing osmotic deswelling at volume fractions approaching and also exceeding the hard sphere packing limit.

Polygalic acid inhibits african swine fever virus polymerase activity: findings from machine learning and in vitro testing.

African swine fever virus (ASFV), an extremely contagious virus with high mortality rates, causes severe hemorrhagic viral disease in both domestic and wild pigs. Fortunately, ASFV cannot be transmitted from pigs to humans. However, ongoing ASFV outbreaks could have severe economic consequences for global food security. Although ASFV was discovered several years ago, no vaccines or treatments are commercially available yet; therefore, the identification of new anti-ASFV drugs is urgently warranted. Using molecular docking and machine learning, we have previously identified pentagastrin, cangrelor, and fostamatinib as potential antiviral drugs against ASFV. Here, using machine learning combined with docking simulations, we identified natural products with a high affinity for AsfvPolX proteins. We selected five natural products (NPs) that are located close in chemical space to the six known natural flavonoids that possess anti-ASFV activity. Polygalic acid markedly reduced AsfvPolX polymerase activity in a dose-dependent manner. We propose an efficient protocol for identifying NPs as potential antiviral drugs by identifying chemical spaces containing high-affinity binders against ASFV in NP databases.

Parental absence during childhood and weight status in adulthood among middle-aged community dwellers in rural Vietnam.

OBJECTIVES: While adverse childhood experiences (ACEs) have been shown to be associated with adulthood obesity, less is known about their association with underweight. We examined the associations between parental absence (i.e., a major component of ACEs) and both underweight and excess weight among middle-aged rural community dwellers in Vietnam, where experiences of parental absence was not uncommon during and after the Vietnam War (1955-1975). METHODS: Data came from 3000 middle-aged adults who participated in the baseline survey of Khánh Hòa Cardiovascular Study. Parental absence was defined as parental absence due to death, divorce, or out-migration. Using information on the timing of such events, we categorized participants into those who experienced parental absence before the age of 3, between the ages of 3 and 15, and those without such experiences. BMI was calculated based on measured height and weight (kg/m2 ) and categorized into three groups: underweight <18.5; normal 18.5-24.9; excess weight ≥ 25. Multinomial logistic regression was then used to investigate the association between parental absence and adult weight status. RESULTS: Parental absence that occurred before the age of 3 was marginally significantly associated with underweight (relative risk ratio [RRR] = 1.44, 95% confidence interval [CI] 0.95, 2.20) but not with overweight/obesity. Parental divorce was associated with overweight/obesity (RRR = 2.48, 95% CI 1.28, 4.81), but not parental absence due to migratory work. CONCLUSIONS: While previous studies in Western settings focused almost exclusively on the risk of obesity in relation to exposure to ACEs, our findings point to the potential importance of considering the risk of underweight in low- and middle-income countries.

Red meat consumption is associated with prediabetes and diabetes in rural Vietnam: a cross-sectional study.

OBJECTIVE: To examine the association between red/processed meat consumption and glycaemic conditions (i.e. prediabetes (preDM) and diabetes mellitus (DM)) among middle-aged residents in rural Khánh Hòa, Vietnam. DESIGN: In this cross-sectional study, a multinomial logistic regression model was used to examine the association between daily consumption of red/processed meat (0-99 g, 100-199 g or ≥ 200 g) and preDM/DM with adjustments for socio-demographic, lifestyle-related and health-related variables. SETTING: Khánh Hòa Province, Vietnam. PARTICIPANTS: The study used data collected through a baseline survey conducted during a prospective cohort study on CVD among 3000 residents, aged 40-60 years, living in rural communes in Khánh Hòa Province. RESULTS: The multinomial regression model revealed that the relative-risk ratios for DM were 1·00 (reference), 1·11 (95 % CI = 0·75, 1·62) and 1·80 (95 % CI = 1·40, 2·32) from the lowest to the highest red/processed meat consumption categories (Ptrend = 0·006). The corresponding values for preDM were 1·00 (reference), 1·25 (95 % CI = 1·01, 1·54) and 1·67 (95 % CI = 1·20, 2·33) (Ptrend = 0·004). We did not find any evidence of statistical significance in relation to poultry consumption. CONCLUSION: Increased red/processed meat consumption, but not poultry consumption, was positively associated with the prevalence of preDM/DM in rural communes in Khánh Hòa Province, Vietnam. Dietary recommendations involving a reduction in red/processed meat consumption should be considered in low- and middle-income countries.

Eating speed and abdominal adiposity in middle-aged adults: a cross-sectional study in Vietnam.

BACKGROUND: Several studies have associated fast eating speed with the risk of general obesity, but there are inadequate data on the association between eating speed and abdominal adiposity which may pose a higher threat to health than general obesity. The present study aimed to investigate the association between eating speed and abdominal obesity in a Vietnamese population. METHODS: Between June 2019 and June 2020, the baseline survey of an ongoing prospective cohort study on the determinants of cardiovascular disease in Vietnamese adults was conducted. A total of 3,000 people aged 40-60 years old (1,160 men and 1,840 women) were recruited from eight communes in the rural district of Cam Lam, Khanh Hoa province, in Central Vietnam. Self-reported eating speed was assessed on a 5-point Likert scale, and responses were collapsed into the following three categories: slow, normal, and fast. Abdominal obesity was defined as a waist-to-height ratio of ≥ 0.5. Poisson regression with a robust variance estimator was used to assess the association between eating speed and abdominal obesity. RESULTS: Compared with slow eating speed, the adjusted prevalence ratio (95% confidence interval) for abdominal obesity was 1.14 (1.05, 1.25)1.14 (1.05, 1.25) for normal eating speed and 1.30 (1.19, 1.41) for fast eating speed (P for trend < 0.001). CONCLUSION: A faster eating speed was associated with a higher prevalence of abdominal obesity in a middle-aged population in rural Vietnam.

Different associations of occupational and leisure-time physical activity with the prevalence of hypertension among middle-aged community dwellers in rural Khánh Hòa, Vietnam.

BACKGROUND: In contrast to high-income countries where physical activity (PA), particularly leisure-time PA, has been shown to be protective against hypertension, few studies have been conducted in low- and middle-income countries. We examined the cross-sectional association between PA and hypertension prevalence among rural residents in Vietnam. METHODS: We used data collected in the baseline survey of a prospective cohort study, among 3000 people aged 40-60 years old residing in rural Khánh Hòa, Vietnam. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medication. We assessed occupational PA and leisure-time PA using the Global Physical Activity Questionnaire. A robust Poisson regression model was used to investigate the associations, with adjustment for covariates. RESULTS: The prevalence of hypertension was 39.6%. After adjusting for socio-demographic and lifestyle-related variables, leisure-time PA was positively associated with hypertension prevalence (prevalence ratio [PR]: 1.03 per 10 MET-hour/week, 95% confidence interval [CI] 1.01-1.06). Occupational PA was inversely associated with hypertension prevalence (PR: 0.98 per 50 MET-hour/week, 95% CI = 0.96-0.996). After adjusting for BMI and other health-related variables, the association related to occupational PA became statistically non-significant, while the association related to leisure-time PA remained statistically significant. CONCLUSION: In contrast to previous studies in high-income countries, we found that leisure-time PA was positively associated with hypertension prevalence and occupational PA was associated with a lower hypertension prevalence. This suggests that the association between PA and hypertension might differ depending on the context.

Practical High-Voltage Lithium Metal Batteries Enabled by Tuning the Solvation Structure in Weakly Solvating Electrolyte.

Li metal batteries (LMBs) are ideal candidates for future high-energy-density battery systems. To date, high-voltage LMBs suffer severe limitations because of electrolytes unstable against Li anodes and high-voltage cathodes. Although ether-based electrolytes exhibit good stability with Li metal, compared to carbonate-based electrolytes, they have been used only in ≤4.0 V LMBs because of their limited oxidation stability. Here, a high concentration electrolyte (HCE) comprising lithium bis(fluorosulfonyl)imide (LiFSI) and a weakly solvating solvent (1,2-diethoxyethane, DEE) is designed, which can regulate unique solvation structures with only associated complexes at relatively lower concentration compared to the reported HCEs. This effectively suppresses dendrites on the anode side, and preserves the structural integrity of the cathode side under high voltages by the formation of stable interfacial layers on a Li metal anode and LiNi0.8 Mn0.1 Co0.1 O2 (NMC811) cathode. Consequently, a 3.5 m LiFSI-DEE plays an important role in enhancing the stability of the Li||NMC811 cell with a capacity retention of ≈94% after 200 cycles under a high current density of 2.5 mA cm-2 . In addition, the 3.5 m LiFSI-DEE electrolyte exhibits good performance with anode-free batteries. This study offers a promising approach to enable ether-based electrolytes for high-voltage LMBs applications.

Efficient neutralization of daratumumab in pretransfusion samples using a novel recombinant monoclonal anti-idiotype antibody.

BACKGROUND: Anti-CD38 antibodies such as daratumumab (DARA) are critical therapies for multiple myeloma and other diseases. Unfortunately, anti-CD38 antibodies cause panreactivity in indirect antiglobulin tests (IATs), complicating blood compatibility testing. The anti-CD38 interference is most often mitigated by treating reagent red blood cells (RBCs) with dithiothreitol (DTT). However, when using the DTT method, not all RBC antibody specificities can be detected (e.g., anti-K), and the DTT method is impractical for some transfusion services. We evaluated the ability of a new anti-idiotype antibody to neutralize DARA in vitro and eliminate the anti-CD38 interference. STUDY DESIGN AND METHODS: A recombinant monoclonal rabbit anti-DARA idiotype antibody ("anti-DARA") was generated. The ratio of anti-DARA required to neutralize DARA in spiked samples was evaluated in IATs performed in gel. IATs performed in tube were used to demonstrate that anti-DARA allows alloantibody detection in the presence of DARA. Plasma samples from 29 patients receiving DARA were treated with a fixed quantity of anti-DARA (120 µg) before performing antibody detection tests (screens) in tube. RESULTS: Anti-DARA used at or above a 1:1 ratio with DARA eliminated the DARA interference with IATs. Anti-DARA allowed detection of both alloanti-E and alloanti-K in the presence of DARA. In 27/29 (93.1%) clinical samples, 120 µg anti-DARA was sufficient to neutralize the DARA in 100 µl patient plasma. DISCUSSION: An anti-DARA:DARA ratio as low as 1:1 is sufficient to neutralize DARA in solution. A fixed amount of anti-DARA eliminates the anti-CD38 interference in most patient samples.

Collagen XI Alpha 1 (COL11A1) Expression in the Tumor Microenvironment Drives Neuroblastoma Dissemination.

BACKGROUND: Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination particularly cancer associated fibroblast (CAFs). CAFs synthesise the extracellular matrix to create a scaffold for tumor growth thus enabling the carcinogenesis of NB, Collagen, an abundant scaffold protein produced by CAFs, has been implicated in the creation of an optimal tumor microenvironment, however, the expression profile of collagen within NB is not yet known. METHODS: We characterised collagen expression within the tumor-stroma boundary by microarray and confirmed by qRT-PCR and immunohistochemistry. RESULTS: The collagen marker, COL11A1, was also upregulated in NB CD45+ cells and SMA+ CAFs. Furthermore, SMA+ CAFs led to neuroblastoma cell invasion in an in vitro co-culture system which was subsequently attenuated by gene silencing COL11A1. Immunohistochemical staining of clinical tumor samples revealed that high COL11A1 expression in the stroma adjacent to tumour site, significantly associated with advanced cancer stages, age ≥18 months, undifferentiated tumor status, relapse and poor overall survival. CONCLUSION: Collectively, these results suggest that a COL11A1 signature in the NB microenvironment could represent a novel target for therapeutic intervention.

Targeting spinal microglia with fexofenadine-loaded nanoparticles prolongs pain relief in a rat model of neuropathic pain.

Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain.