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Data availability: The datasets analyzed for the current study reflect collaborative efforts of two research consortia: ALLFTD and GENFI. Each consortium provides clinical data access based on established policies for data use: processes for request are available for review at allftd.org/data for ALLFTD data and by emailing genfi@ucl.ac.uk. Certain data elements from both consortia (for example raw MRI images) may be restricted due to the potential for identifiability in the context of the sensitive nature of the genetic data. The deidentified combined dataset will be available for request through the FTD Prevention Initiative in 2023 (https://www.thefpi.org/). Code availability: Custom R code is available at https://doi.org/10.5281/zenodo.6687486. Copyright © The Author(s). Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects. Data collection and dissemination of the data presented in this paper were supported by the ALLFTD Consortium (U19: AG063911, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL and LEFFTDS Consortia (ARTFL: U54 NS092089, funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke). The manuscript was reviewed by the ALLFTD Executive Committee for scientific content. The authors acknowledge the invaluable contributions of the study participants and families as well as the assistance of the support staffs at each of the participating sites. This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, Larry L. Hillblom Foundation (2018-A-025-FEL (A.M.S.)), the National Institutes of Health (AG038791 (A.L.B.), AG032306 (H.J.R.), AG016976 (W.K.), AG062677 (Ron C. Peterson), AG019724 (B.L.M.), AG058233 (Suzee E. Lee), AG072122 (Walter Kukull), P30 AG062422 (B.L.M.), K12 HD001459 (N.G.), K23AG061253 (A.M.S.), AG062422 (RCP), K24AG045333 (H.J.R.)) and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886 (T.F.)) awarded by the National Institute on Aging (NIA), were used in this study. This work was also supported by Medical Research Council UK GENFI grant MR/M023664/1 (J.D.R.), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres and a JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project 739510. J.D.R. and L.L.R. are also supported by the National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is also supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). RC and C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care), the Wellcome Trust (220258), the Cambridge Centre for Parkinson-plus and the Medical Research Council (SUAG/092 G116768); I.L.B. is supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN, and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project 739510). J.L. is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). R.S.-V. was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to R.S.-V.). M.M. was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, by Canadian Institutes of Health Research operating grants (MOP- 371851 and PJT-175242) and by funding from the Weston Brain Institute. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 Synergy 390857198). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

Alcohol use presents a serious risk to women's health. Of particular interest is the association of harmful alcohol consumption and risky behaviors, such as drinking before sexual intercourse, an understudied phenomenon in the Mexican population. AIM The aim of this study was to identify whether the harmful use of alcohol is associated with an increased probability of presex drinking in Mexican young women. METHOD This was a study with a predictive design. Multiple logistic regressions were performed in a random sample of 304 young college women (between the ages of 18 and 24 years) from Guanajuato and Tamaulipas, Mexico. Participants completed a sociodemographic data survey and the Alcohol Use Disorders Identification Test questionnaire. RESULTS Women with a pattern of harmful use of alcohol were more likely to report drinking before sex (adjusted odds ratio = 4.679, 95% confidence interval [1.619, 13.520], McFadden's pseudo R2 = 25.5%). Further analyses revealed that presex drinking by partners was an even stronger predictor of alcohol use before sexual intercourse in women (adjusted odds ratio = 12.749, 95% confidence interval [4.714, 34.483], McFadden's pseudo R2 = 34.7%). CONCLUSIONS The findings demand additional nursing studies to corroborate-and to better understand-the relationship between harmful use of alcohol in Mexican women, their partners' drinking behavior, and unhealthy behaviors like drinking before sexual intercourse.

This paper proposes a novel ultra-Fast self-powered bidirectional solid-state circuit breaker (SSCB) with voltage overshoot suppression that uses gallium nitride (GaN) switches with very low conduction losses. This SSCB can be used in low and medium AC/DC networks for both short-circuit protection and overcurrent protection. An exhaustive methodology for RCD snubber design applied to SSCBs is provided. A comprehensive review of the technical literature is presented exhibiting that the proposed SSCB reduces conduction losses and detection time in comparison with other similar SSCBs. The performance features of the proposed SSCB are verified through the functional tests that are carried out employing a hardware-implemented prototype. Experimental results confirm that our proposal is able to detect and process the short-circuit failure in 282ns; the authors have not found any faster results in the literature.

Introduction A better understanding of how menthol cigarette flavoring and ENDS impact smoking initiation, cessation, and transitions between tobacco products could help elucidate the potential impact of a U.S. menthol ban on combustible tobacco products. Methods A multistate transition model was applied to data on 23,232 adults from Waves 1–4 (2013–2017) of the Population Assessment of Tobacco and Health Study (analysis was conducted in 2020–2021). Transition rates among never, noncurrent, nonmenthol versus menthol cigarette, ENDS, and dual everyday/someday use were estimated, as were transition-specific hazard ratios for age, sex, race/ethnicity, education, and income. Results Non-Hispanic Blacks who smoked menthol discontinued smoking at a much lower rate than those who smoked nonmenthol (hazard ratio=0.43, 95% CI=0.29, 0.64), but there was no statistically significant difference in the discontinuation rates among non-Hispanic Whites (hazard ratio=0.97, 95% CI=0.80, 1.16) or Hispanics (hazard ratio=0.81, 95% CI=0.56, 1.16). Non-Hispanic Whites who smoked menthol were more likely to become dual users than those who smoked nonmenthol (hazard ratio=1.43, 95% CI=1.14, 1.80). Young adults initiated menthol smoking at a higher rate than older adults (age 18–24 years versus ≥55 years: hazard ratio=2.45, 95% CI=1.44, 4.15) but not nonmenthol smoking (hazard ratio=1.02, 95% CI=0.62, 1.69). There were differences by sex in the impact of menthol flavor on smoking initiation and discontinuation but little difference by education or income. Conclusions Sociodemographic differences in product transitions should be accounted for when estimating the potential impact of a menthol ban.

Objective In the hospital of La Princesa, the "Sepsis Code" (CSP) began in 2015, as a multidisciplinary group that provides health personnel with clinical, analytical and organizational tools, with the aim of the detection and early treatment of patients with sepsis. The objective of this study is to evaluate the impact of CSP implantation on mortality and to determine the variables associated with an increase in it. Methods A retrospective analytical study of patients with CSP alert activation from 2015 to 2018 was conducted. Clinical-epidemiological variables, analytical parameters, and severity factors such as admission to critical care units (UCC) and the need for amines were collected. Statistical significance was established at p Results We included 1,121 patients. The length of stay was 16 days and 32% required admission to UCC. Mortality showed a statistically significant linear downward trend from 24% in 2015 to 15% in 2018. The predictive mortality variables with statistically significant association were lactate > 2 mmol/L, creatinine > 1.6 mg/dL and the need for amines.>5.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. Conclusions The implementation of Sepsis Code decreases the mortality of patients with sepsis and septic shock. The presence of a lactate > 2 mmol/L, creatinine > 1.6 mg/dL and/or the need to administer amines in the first 24 hours, are associated with an increase in mortality in the patient with sepsis.

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance., Krebs and colleagues identify multiple mAbs that recognize either the RBD or the NTD of SARS-CoV-2 spike protein that have potent cross-neutralizing activities against variants of concern. Combinatorial mAb cocktails have complementary effects on viral neutralization and Fc effector functions and can protect against SARS-CoV-2 escape mutants.

BACKGROUND Platelets are now recognized as immunological sentries in the first line of defense that participate in the detection and response to pathogens. This frequently results in a decrease in the number of circulating platelets. Different mechanisms have been hypothesized to explain the thrombocytopenia in patients with severe dengue, one of them is the participation of the non-structural protein 1 (NS1) of dengue virus (DENV), which can be secreted into circulation during DENV infection and promotes a more efficient infection. OBJECTIVE The present study aimed to investigate the ability of platelet response to stimulation with full-length DENV NS1 protein and its domains. METHODS DENV NS1 plasmid was transfected into HEK-293T. Proteins were purified by Niquel Sepharose affinity chromatography. Secreted proteins were assessed by sodium dodecylsulfate polyacrylamide gel electrophoresis, Coomassie staining and western blot. Platelet-rich plasma was directly incubated with DENV NS1 proteins. Platelet activation was confirmed by expression of αIIbβIII and P-selectin by flow cytometry. Platelet aggregation was also assessed using DENV NS1 protein and its individual domains as agonists. RESULTS DENV NS1 protein and its domains induce P-selectin and αIIbβ3 complex expression on platelet surfaces. DENV NS1 induce a stable platelet aggregation after the addition of a minimal dose of adenosine diphosphate (ADP), epinephrine (EPI), or collagen. Interestingly, only EPI could induce the formation of platelet aggregates after incubation with the protein domains of NS1. CONCLUSION Our results suggest that the full DENV NS1 protein and also its domains promote platelet recognition, activation, and aggregation.

Background The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population. Methods Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons. Results After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P Conclusions Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.

Fluorescence-guided surgery (FGS) is an emerging technique for tissue visualization during surgical procedures. Structures of interest are labeled with exogenous probes whose fluorescent emissions are acquired and viewed in real-time with optical imaging systems. This study investigated rare-earth-doped albumin-encapsulated nanocomposites (REANCs) as short-wave infrared emitting contrast agents for FGS. Experiments were conducted using an animal model of 4T1 breast cancer. The signal-to-background ratio (SBR) obtained with REANCs was compared to values obtained using indocyanine green (ICG), a near-infrared dye used in clinical practice. Prior to resection, the SBR for tumors following intratumoral administration of REANCs was significantly higher than for tumors injected with ICG. Following FGS, evaluation of fluorescence intensity levels in excised tumors and at the surgical bed demonstrated higher contrast between tissues at these sites with REANC contrast than ICG. REANCs also demonstrated excellent photostability over 2 hours of continuous illumination, as well as the ability to perform FGS under ambient lighting, establishing these nanocomposites as a promising contrast agent for FGS applications.

The axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These functions are supported by a distinctive actin and microtubule cytoskeleton that controls axonal trafficking and maintains a high density of voltage-gated ion channels linked by scaffold proteins to the AIS cytoskeleton. However, our knowledge of the mechanisms and proteins involved in AIS cytoskeleton regulation to maintain or modulate AIS structure is limited. In this context, formins play a significant role in the modulation of actin and microtubules. We show that pharmacological inhibition of formins modifies AIS actin and microtubule characteristics in cultured hippocampal neurons, reducing F-actin density and decreasing microtubule acetylation. Moreover, formin inhibition diminishes sodium channels, ankyrinG and ßIV-spectrin AIS density, and AIS length, in cultured neurons and brain slices, accompanied by decreased neuronal excitability. We show that genetic downregulation of the mDia1 formin by interference RNAs also decreases AIS protein density and shortens AIS length. The ankyrinG decrease and AIS shortening observed in pharmacologically inhibited neurons and neuron-expressing mDia1 shRNAs were impaired by HDAC6 downregulation or EB1-GFP expression, known to increase microtubule acetylation or stability. However, actin stabilization only partially prevented AIS shortening without affecting AIS protein density loss. These results suggest that mDia1 maintain AIS composition and length contributing to the stability of AIS microtubules., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The work was supported by agrant from Ministerio de Ciencia y Universidades (RTI2018-095156-B-100) to JJG and INSERM funding to DD. Wei Zhang was supported by a fellowship from China Scholarship Council (No.201506300085) and Beatriz Achon by a Master fellowship from Universidad Autónoma de Madrid.

Objectives. Among strategies used to improve the photocatalytic properties of titanium dioxide (TiO2), coupled semiconductor has been widely studied. Bismuth oxychloride (BiOCl) semiconductor has been highlighted, specially, with hierarchical structures (3D), because it has been shown to have higher performance in the photodegradation of organic dyes in wastewater. Therefore, in this work the degradation efficiency of acid orange 7 (AO7) was studied using TiO2 (P25 Degussa), synthesized BiOCl with hierarchical structure, and mixtures of them as photocatalysts. Methodology. BiOCl was synthesized by the solvothermal method. The BiOCl was characterized by different techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). In addition, the pore distribution and the surface area were determined. Photocatalytic experiments were carried out with a photocatalyst dose of 1 g‧L-1, initial dye concentration of 50 mg‧L-1, and UV light illumination. Contribution. The interaction of P25 Degussa with BiOCl microspheres (75/25, respectively) improved the photocatalytic degradation achieving a 50% degradation efficiency.

Acute iodide sialadenitis is a rare adverse reaction to iodinated contrast that causes self-limited salivary gland swell-ing. Its pathogenesis is still unclear, although kidney failure may be a risk factor. The diagnosis is initially clinical but angioedema, infections and lithiasis should be included in the differential diagnosis. No treatment or prophylaxis was proven to be beneficial. Although its prognosis is benign, associated complications have been reported. We report a case of 68-year-old man with swelling of the submandibular salivary glands after the administration of iodine-based contrast media during an abdominal computed tomography examination. Because of the widespread use of iodinated contrast enhanced imaging and interventional techniques, clinicians should be aware of this issue.

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis., This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

The peptide, denominated Ct1a, is a β-toxin of 66 amino acids, isolated from venom of the scorpion, Centruroides tecomanus, collected in Colima, Mexico. This toxin was purified using size exclusion, cationic exchange, and reverse phase chromatography. It is the most abundant toxin, representing 1.7% of the soluble venom. Its molecular mass of 7588.9 Da was determined by mass spectrometry. The amino acid sequence was determined by Edman degradation and confirmed by transcriptomic analysis. Since neurons of the suprachiasmatic nucleus (SCN) maintain a spontaneous firing rate (SFR), we evaluated the physiological effects of toxin Ct1a on these neurons. The SFR exhibited a bimodal concentration-dependent response: 100 nM of Ct1a increased the SFR by 223%, whereas 500 nM and 1000 nM reduced it to 42% and 7%, respectively. Control experiments, consisting of recordings of the SFR during a time similar to that used in Ct1a testing, showed stability throughout the trials. Experiments carried out with denatured Ct1a toxin (500 nM) caused no variation in SFR recordings. Action potentials of SCN neurons, before and after Ct1a (100 nM) showed changes in the time constants of depolarization and repolarization phases, amplitude, and half-time. Finally, recordings of hNav1.6 sodium currents indicated that Ct1a shifts the channel activation to a more negative potential and reduces the amplitude of the peak current. These results all demonstrate that toxin Ct1a affects the SFR of SCN neurons by acting upon sodium channels of sub-type 1.6, implicating them in regulation of the SFR of SCN neurons.

Gangliosides are glycosphingolipids abundantly expressed in the vertebrate nervous system, and are classified in a-, b-, or c- series according to the number of sialic-acid residues. The enzyme GD3 synthase converts GM3 (an a- series ganglioside) to GD3, a b- series ganglioside highly expressed in the developing and adult retina. The present study evaluated the visual system of GD3 synthase knockout mice (GD3s-/- ), morphologically and functionally. The absence of b- series gangliosides in the retinas of knockout animals was confirmed by mass spectrometry imaging, which also indicated an accumulation of a-series gangliosides, such as GM3. Retinal ganglion cell (RGC) density was significantly reduced in GD3s-/- mice, with a similar reduction in the number of axons in the optic nerve. Knockout animals also showed a 15% reduction in the number of photoreceptor nuclei, but no difference in the bipolar cells. The area occupied by GFAP-positive glial cells was smaller in GD3s-/- retinas, but the number of microglial cells/macrophages did not change. In addition to the morphological alterations, a 30% reduction in light responsiveness was detected through quantification of pS6-expressing RGC, an indicator of neural activity. Furthermore, electroretinography (ERG) indicated a significant reduction in RGC and photoreceptor electrical activity in GD3s-/- mice, as indicated by scotopic ERG and pattern ERG (PERG) amplitudes. Finally, evaluation of the optomotor response demonstrated that GD3s-/- mice have reduced visual acuity and contrast sensitivity. These results suggest that b- series gangliosides play a critical role in regulating the structure and function of the mouse visual system.

This work presents a methodology based on the WO3/Ag/WO3 (WAW) tri-layer configuration for obtaining indium-free TCOs by RF sputtering at room temperature. The tri-layer performance is shown to be very sensitive to the thickness variations. Through the optimization of the WO3 top layer, it was possible to obtain a combination of thicknesses that allow to maximize the optical transmittance and at the same time lower the sheet resistance, this translates into an excellent compromise between these two properties that are usually antagonists. Using a metallic layer with a thickness that is just at its percolation limit, high electrical conductivity values can be obtained without compromising the optical transmittance. Thickness variation of the dielectric layers in turn, allowed to optimize the transport of the electrons to the metallic film. The overall tri-layer performance was evaluated using multifigure of merit analysis. Our best results were obtained for WO3(40 nm)/Ag(7 nm)/WO3(20 nm) with 1.2 Ω/sq sheet resistance and transmittance above 85%. Therefore, it is possible to obtain a TCO in an indium-free tri-layer WAW configuration at room temperature with good performance that represents a viable alternative that is not restricted by the scarcity of indium.

Hydrogels are crosslinked polymer networks that can absorb and retain a large fraction of liquid. Near a critical sliding velocity, hydrogels pressed against smooth surfaces exhibit time-dependent frictional behavior occurring over multiple timescales. The origin of these dynamics is unresolved Here, we characterize this time-dependent regime and show that it is consistent with two distinct molecular processes: sliding-induced relaxation and quiescent recovery. Our experiments use a custom pin-on-disk tribometer to examine poly(acrylic acid) hydrogels on smooth poly(methyl methacrylate) surfaces over a variety of sliding conditions, from minutes to hours. We show that at a fixed sliding velocity, the friction coefficient decays exponentially and reaches a steady-state value. The time constant associated with this decay varies exponentially with the sliding velocity, and is sensitive to any precedent frictional shearing of the interface. This process is reversible; upon cessation of sliding, the friction coefficient recovers to its original state. We also show that the initial direction of shear can be imprinted as an observable “memory”, and is visible after 24 hrs of repeated frictional shearing. We attribute this behavior to nanoscale extension and relaxation dynamics of the near-surface polymer network, leading to a model of frictional relaxation and recovery with two parallel timescales.

Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P‐glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2‐specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5‐dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate‐sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5‐dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors., Tetrahydroquinoline/4,5‐dihydroisoxazole hybrids can inhibit the ABCG2 transporter activity and increase the ATP hydrolysis in cells overexpressing ABCG2. Molecular docking and molecular dynamics simulation results suggest that molecular hybrids inhibit ABCG2 activity by binding at the inhibitor binding region, as well as the substrate binding regions.

Pathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02316-0.

Pacific dulse (Devaleraea mollis), a type of red macroalgae, is of particular interest in the context of plant-based protein given its high protein content. One challenge in utilizing seaweed-derived protein is the poor protein recovery/yield and high cost that limits wider adaptation. In this study we aimed to evaluate methods for protein extraction from Pacific dulse to achieve a higher protein recovery rate. We evaluated the effect of cellulase treatment, under two extraction approaches, on the protein recovery and phenolic interference in Pacific dulse extracts. Commercial cellulases Viscozyme and Celluclast (2%, v/v) improved crude protein recoveries in both aqueous-alkaline and sequential protein fractionation approaches. The use of Osborne method to sequentially recover water-, saline-, alkaline-, and ethanol-soluble protein fractions resulted in more than a threefold increase in yield even at low-temperature conditions, mainly with the recovery of more protein in both albumin and globulin fractions. Without cellulase treatment, extending extraction time provides no improvement in protein yield but rather favors an increase in phenolic interference. Collectively, these results show that cellulase-aided sequential protein extraction can be used for improved protein recovery from Pacific dulse.

In most eukaryotic organisms, mitochondrial uncoupling mechanisms control ATP synthesis and reactive oxygen species production. One such mechanism is the permeability transition of the mitochondrial inner membrane. In mammals, ischemia-reperfusion events or viral diseases may induce ionic disturbances, such as calcium overload; this cation enters the mitochondria, thereby triggering the permeability transition. This phenomenon increases inner membrane permeability, affects transmembrane potential, promotes mitochondrial swelling, and induces apoptosis. Previous studies have found that the mitochondria of some crustaceans do not exhibit a calcium-regulated permeability transition. However, in the whiteleg shrimp Litopenaeus vannamei, contradictory evidence has prevented this phenomenon from being confirmed or rejected. Both the ability of L. vannamei mitochondria to take up large quantities of calcium through a putative mitochondrial calcium uniporter with conserved characteristics and permeability transition were investigated in this study by determining mitochondrial responses to cations overload. By measuring mitochondrial swelling and transmembrane potential, we investigated whether shrimp exposure to hypoxia-reoxygenation events or viral diseases may induce mitochondrial permeability transition. The results of this study demonstrate that shrimp mitochondria take up large quantities of calcium through a canonical mitochondrial calcium uniporter. Neither calcium nor other ions were observed to promote permeability transition. This phenomenon does not depend on the life cycle stage of shrimp, and it is not induced during hypoxia/reoxygenation events or in the presence of viral diseases. The absence of the permeability transition phenomenon and its adaptive meaning are discussed as a loss with biological advantages, possibly enabling organisms to survive under harsh environmental conditions.

Titanium Diboride (TiB2) has excellent performances in terms of hardness, mechanical strength, wear resistance, and corrosion resistance, but its application is still limited due to its poor manufacturability. Selective Laser Additive Manufacturing using elemental powders of Titanium and Boron provides a transforming technology for the application of TiB2 by enabling its 3D free forming capability. In this paper, to investigate the joint effects of selective laser melting and chemical reactions in the Selective Laser Alloying (SLA) process, a numerical based simulation was conducted using COMSOL Multiphysics 5.4. This is the first successful numerical study of melting and reaction in the selective laser alloying process providing details about the molten pool. The influences of the evolution of free solid-liquid interface, species transport, the chemical reaction rate, and the evaporation latent heat were discussed by considering the production of TiB2 and its concentration distribution in the computational domain. The simulation results show that the melting front of the free surface has a relatively high velocity, at the instant when the powder particles melt, the first speed jump will occur, and when the reaction is triggered, the second speed jump will occur; the heat released from the exothermic reaction between Titanium and Boron is an important energy source which can reduce the energy input and help improve the manufacturing efficiency of the SLA process; the evaporation latent heat also has a significant influence to the temperature field in the computational domain; the concentration distribution of TiB2 strongly relies on the chemical reaction rate and the diffusion coefficient. This study may blueprint a design strategy for the Additive Manufacturing research community by considering to adopt the proposed numerical model, predict the reactions and species concentration, and explore the structures of microscale molten pool and the macroscale defects or so.

Background Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown. Methods Cpa3Cre /+ mice, which lack mast cells, were used to assess the role of mast cells in house dust mite (HDM)-induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function and in lung mast cells in vitro. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation, and HDM-induced bronchoconstriction were evaluated. Results Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc-receptors, or antagonizing serotonin (5-HT)2A receptors abolished HDM-induced trachea contractions. HDM-sensitized mice lacking mast cells had diminished lung-associated 5-HT levels, reduced AHR and methacholine-induced airway contraction, while blocking 5-HT2A receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5-HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5-HT intracellularly, and methacholine induces release of 5-HT from lung-derived mouse mast cells and Ca2+ flux in human LAD-2 mast cells. Conclusions Methacholine activates mast cells to release 5-HT, which by acting on 5-HT2A receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.

Arabinoxylans (AX) are gelling polysaccharides with potential applications as colon-targeted biomaterials. Nevertheless, the fermentation of highly cross-linked AX particles (AXP) by colonic bacteria and the effect of its fermentation supernatants on the proliferation of human colon cancer cells have not been investigated so far. In this study, electrosprayed AXP were fermented by Bifidobacterium longum , Bifidobacterium adolescentis , and Bacteroides ovatus . The effect of AXP fermentation supernatant (AXP-fs) on the inhibition of the human colon cancer cell line Caco-2 proliferation was investigated. AXP presented a mean diameter of 533 µm, a spherical shape, and a cross-linking content (dimers and trimers of ferulic acid) of 1.65 µg/mg polysaccharide. After 48 h of bacteria exposure, AXP were only partly fermented, probably due to polymeric network steric hindrance that limits the access of bacterial enzymes to the polysaccharide target sites. AXP partial fermentation was evidenced by a moderate short-chain fatty acid production (SCFA) (23 mM) and a collapsed and disintegrated microstructure revealed by scanning electron microscopy. AXP-fs exerted slight inhibition of Caco-2 cell proliferation (11%), which could be attributed to the SCFA generated during partly polysaccharide fermentation. These findings indicate that electrosprayed AXP are a slow-fermentable biomaterial presenting slight anti-cancer properties and potential application in colon cancer prevention.

The in vitro bioactivity of slightly hypereutectic glass-ceramics of the pseudo-binary system diopside (CMS2, CaMgSi2O6)–tricalcium phosphate [Ca3P, Ca3(PO4)2], was tested in a Simulated Body Fluid (SBF) from 7 to 21 days at pH = 7.3 and 36.5 °C. The materials were synthesized by the petrurgic method, using cooling rates of 0.5, 1 and 2 °C/h through the mushy zone. Their microstructure consisted of β-C3Pss (solid solution of CMS2 in Ca3P) primary dendrites in a matrix of CMS2–β-C3Pss lamellar eutectic phase. The dissolution of the interdendritic matrix into the SBF lead to the formation of an interconnected porous structure at the surface of the samples. Subsequently, the β-C3Pss primary dendrites were pseudomorphically converted into (Ca10−yMgy)(PO4)6−z(SiO4)z(OH)2−z (Mg and Si co-substituted hydroxyapatite, HAp). The cavities left by the dissolved matrix were then filled with HAp, and a layer of this phase was formed on the surface of the material. The rate of dissolution of the material's matrix into the SBF, the rate of precipitation of HAp from the solution, the composition of the precipitated HAp, and pH and ionic composition of the SBF during the tests, were all affected by the cooling rate used to synthesize the materials. Resumen: La bioactividad in vitro de vitrocerámicas ligeramente hipereutécticas del sistema seudobinario diópsido (CMS2, CaMgSi2O6)–fosfato tricálcico [Ca3P, Ca3(PO4)2], se probó en un fluido fisiológico simulado (FFS) por 7 a 21 días a pH = 7.3 y 36.5 °C. Los materiales sintetizados por el método petrúrgico, usando velocidades de enfriamiento de 0.5, 1 y 2 °C/h a través de la zona de transición sólido/líquido, presentaron una microestructura de dendritas primarias de β-C3Pss (solución sólida de CMS2 en Ca3P) en una matriz de fase eutéctica laminar de CMS2–β-C3Pss. La disolución de la matriz en el FFS creó una estructura porosa interconectada en la superficie de las muestras. Posteriormente, las dendritas primarias de β-C3Pss se convirtieron seudomórficamente en (Ca10−yMgy)(PO4)6−z(SiO4)z(OH)2−z (hidroxiapatita, HAp, co-sustituida con Mg y Si). Las cavidades creadas al disolverse la matriz se llenaron con HAp, y se formó una capa de esta misma fase sobre la superficie del material. Las velocidades de disolución de la matriz en el FFS y de precipitación de la HAp de la solución, la composición de la HAp precipitada, y el pH y la composición iónica del FFS durante las pruebas, fueron afectados por la velocidad de enfriamiento utilizada para sintetizar los materiales.

Marcio Carneiro Vieira,1,2 Fernanda Bezerra de Mello Monte,3 Bruno Eduardo Dematte,3 Tadeu Lima Montagnoli,3 Guilherme Carneiro Montes,3 Jaqueline Soares da Silva,3 Rosalia Mendez-Otero,4 Margarete Manhães Trachez,3 Roberto Takashi Sudo,1,3 Gisele Zapata-Sudo1,3 1Programa de Pós-graduação em Ciências Cirúrgicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 2Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 3Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil; 4Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio De Janeiro, 21941-902, BrazilCorrespondence: Gisele Zapata-SudoInstituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, BrazilTel +55 21 3938 6505Email gsudo@icb.ufrj.brIntroduction: New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3ʹ,5ʹ-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models.Methods and Results: Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.6 ± 39.1 to 81.9 ± 18.8 s at 10 μmol/kg, p= 0.0172) and this effect was totally blocked by NO synthase inhibitor, L-Nω-nitroarginine methyl ester (L-NAME). Lodenafil carbonate (10 μmol/kg p.o.) significantly reduced nociceptive response as demonstrated by increased paw withdrawal latency to thermal stimulus (from 6.8 ± 0.7 to 10.6 ± 1.3 s, p= 0.0006) and paw withdrawal threshold to compressive force (from 188.0 ± 14.0 to 252.5 ± 5.3 g, p< 0.0001) in carrageenan-induced paw inflammation model. In a spinal nerve ligation-induced neuropathic pain, oral lodenafil carbonate (10 μmol/kg) also reversed thermal hyperalgesia and mechanical allodynia by increasing paw withdrawal latency from 17.9 ± 1.5 to 22.8 ± 1.9 s (p= 0.0062) and paw withdrawal threshold from 26.0 ± 2.8 to 41.4 ± 2.9 g (p= 0.0196). These effects were reinforced by the reduced GFAP (3.4 ± 0.5 to 1.4 ± 0.3%, p= 0.0253) and TNF-alpha (1.1 ± 0.1 to 0.4 ± 0.1%, p= 0.0111) stained area densities as detected by immunofluorescence in ipsilateral dorsal horns.Conclusion: Lodenafil carbonate demonstrates important analgesic activity by promoting presynaptic hyperpolarization and preventing neuroplastic changes, which may perpetuate chronic pain, thus representing a potential treatment for neuropathic pain.Keywords: neuropathic pain, inflammatory pain, phosphodiesterase 5 inhibitor, lodenafil carbonate, spinal cord, GFAP

BackgroundFor many years, national surveys have shown a consistently disproportionately high prevalence of menthol smokers among African Americans compared with the general population. However, to our knowledge, no prior study has quantified the harm that menthol smoking has caused on that population. In this work, we estimate the public health harm that menthol cigarettes have caused to the African American community over the last four decades.MethodsUsing National Health Interview Survey data, we employed a well-established simulation model to reproduce the observed smoking trajectory over 1980–2018 in the African American population. Then, we repeat the experiment, removing the effects of menthol on the smoking initiation and cessation rates over that period, obtaining a new hypothetical smoking trajectory. Finally, we compared both scenarios to calculate the public health harm attributable to menthol cigarettes over 1980–2018.ResultsOur results show that menthol cigarettes were responsible for 1.5 million new smokers, 157 000 smoking-related premature deaths and 1.5 million life-years lost among African Americans over 1980–2018. While African Americans constitute 12% of the total US population, these figures represent, respectively, a staggering 15%, 41% and 50% of the total menthol-related harm.DiscussionOur results show that menthol cigarettes disproportionally harmed African Americans significantly over the last 38 years and are responsible for exacerbating health disparities among that population. Removing menthol cigarettes from the market would benefit the overall US population but, particularly, the African American community.

Small molecules that target the spliceosome SF3B complex are potent inhibitors of cancer cell growth. The compounds affect an early stage of spliceosome assembly when U2 snRNP first engages the branch point sequence of an intron. Employing an inactive herboxidiene analog (iHB) as a competitor, we investigated factors that influence inhibitor interactions with SF3B to inhibit pre-mRNA splicing in vitro. Order-of addition experiments show that inhibitor interactions are long lasting and affected by both temperature and the presence of ATP. Our data are also consistent with the idea that not all SF3B conformations observed in structural studies are conducive to productive inhibitor interactions. Notably, SF3B inhibitors do not impact an ATP-dependent rearrangement in U2 snRNP that exposes the branch binding sequence for base pairing. We also report extended structure activity relationship analysis of the splicing inhibitor herboxidiene. We identified features of the tetrahydropyran ring that mediate its interactions with SF3B and its ability to interfere with splicing. Analyzing our data in the context of recent structural models of SF3B interactions with inhibitors, our results lead us to extend the model for early spliceosome assembly and inhibitor mechanism. We postulate that interactions between a carboxylic acid substituent of herboxidiene and positively charged SF3B1 sidechains in the inhibitor binding channel are required to maintain inhibitor occupancy while counteracting the SF3B transition to a closed state that is required for stable U2 snRNP interactions with the intron.

We recently reported the synthesis of 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides, which are based on a bicyclo[3.1.0]hexane scaffold. Here, we analyzed RNAi-mediated gene silencing activity in cell culture and demonstrated that a single incorporation of 2′-F-NMC within the guide or passenger strand of the tri-N-acetylgalactosamine-conjugated siRNA targeting mouse Ttr was generally well tolerated. Exceptions were incorporation of 2′-F-NMC into the guide strand at positions 1 and 2, which resulted in a loss of the in vitro activity. Activity at position 1 was recovered when the guide strand was modified with a 5′ phosphate, suggesting that the 2′-F-NMC is a poor substrate for 5′ kinases. In mice, the 2′-F-NMC-modified siRNAs had comparable RNAi potencies to the parent siRNA. 2′-F-NMC residues in the guide seed region position 7 and at positions 10, 11 and 12 were well tolerated. Surprisingly, when the 5′-phosphate mimic 5′-(E)-vinylphosphonate was attached to the 2′-F-NMC at the position 1 of the guide strand, activity was considerably reduced. The steric constraints of the bicyclic 2′-F-NMC may impair formation of hydrogen-bonding interactions between the vinylphosphonate and the MID domain of Ago2. Molecular modeling studies explain the position- and conformation-dependent RNAi-mediated gene silencing activity of 2′-F-NMC. Finally, the 5′-triphosphate of 2′-F-NMC is not a substrate for mitochondrial RNA and DNA polymerases, indicating that metabolites should not be toxic.

Reinforced glass ionomer cements have been widely used in pediatric dentistry to prevent dental caries. However, the influence of biomaterial light-curing and its anti-cariogenic effects remain unclear. This study evaluates the influence of the light-curing time on fluoride release, surface topography, and bacterial adhesion in two types of resin-modified glass ionomer cements (RMGICs). One hundred disks were made, and samples were divided into two groups (n = 50 per group), according to each dental material (Vitremer™ and Ketac™ N100), and also divided into different light-cured times (10, 20, 30, 40, and 60 s). They were placed in phosphate-buffered saline solution (PBS) to measure the fluoride release. Subsequently, an independent sample of RMGICs per group was examined using atomic force microscopy (AFM). Four disks per group were incubated in a brain heart infusion (BHI) medium that was inoculated with Streptococcus mutans GS5 to evaluate the bacterial adhesion by 3-4, [5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide cell viability assay (MTT assay). The fluoride release was related to the light-curing time and gradually decreased as the light-curing time increased in both materials. Surface topography in Vitremer™ presents more irregular surfaces than Ketac™ N100. For S. mutans adhesion, the smallest number of cells per milliliter (cell/ml) was found at 40 s for Vitremer™ and at 30 s for Ketac™ N100. Thus, the shorter light-curing times allowed for major fluoride release in both materials. However, the RMGICs showed different patterns of bacterial adhesion according to the brand and light-curing time.

This article reports a simple one-step method for anisotropic gold nanoparticle synthesis for plasmonic photothermal therapy medical purposes, using 1,4-bis[(2-ethylhexyl) oxy]-1,4-dioxo-2-butanesulfonic acid-sodium (AOT) reverse micelles as nanoreactor, where under specific condition, AOT acts as both a reducing and stabilizing agent. Obtained AuNPs were functionalized by attaching compounds derived from 2-aminopteridin-4(3H)-ona (pterin family) such as (2S)-2-[(4-{[(2-amino-4-hydroxypteridin-6-yl) methyl] amino} phenyl) formamido] pentanedioic acid (folic acid/FA) and 2-amino-4-hydroxypteridine-6-carboxylic acid (PCA) in order to evaluate its effect as targets for folate receptor-mediated cellular uptake in HeLa and normal human endocervical cells. The nanoconjugates were characterized through transmission electron microscopy (TEM), ultraviolet-visible, fluorescence, and Fourier transform infrared spectroscopies. Results showed an effective photothermal response of AuNPs in solution under NIR exposure with concentration dependence and none effect of the conjugation. In vitro studies in HeLa cells showed a concentration-dependent cytotoxicity of AuNPs; thus, conjugation to biomolecules such as FA or PCA has provided a biocompatible coating onto AuNPs and made them highly cytocompatible. Results demonstrated despite AF and PCA are analogue molecules, the folate receptors in HeLa cells are specific, and the different chemical groups available on the AuNPs surface have drastically different cell membrane penetration properties. The specific cell uptake through folate receptor (FR) was observed for short treatment time, while for a long treatment time, other mechanisms as penetration or adhesion were shown involved. In the particular case, of AF@AuNPs, the cell uptake through FR-mediated endocytosis was evidenced to have been decreasing cell viability in 24% after 2 h of treatment and 5 min under NIR exposure. This was confirmed by morphological changes in cells, as well the selective uptake of the FA@AuNPs by HeLa cells compared to normal cells, due folate receptor overexpression in HeLa cells. The findings from this study will have implications in the chemical design of nanostructures for plasmonic photothermal therapy. The obtained results provide evidences at in vitro level to support the fact that AF@AuNP nanoconjugate will accumulate in the affected tissue preferentially through the EPR (enhanced permeability and retention) effect by folate-targeting mechanism which will significantly enhance the efficacy of NIR-induced local photothermal effects.

In the present article, the synthesis of copper and cobalt co-doped ferrites (Cu0.3Co0.7Fe2O4) and application as an electrode modifier were demonstrated. The synthesis of Cu0.3Co0.7Fe2O4 was conducted using the citrate sol-gel method by mixing the stoichiometric ratio of cobalt chloride, copper chloride, and ferrous chloride in aqueous solutions with citric acid and adjusting the pH of the solution to 7 using liquid ammonia. The spinel phase structure was confirmed by means of X-ray powder diffraction. Scanning electron microscopy were used to investigate the morphology of the sample and the vibrations of the functional groups were determined by Raman and IR-ATR spectroscopy. A promising modified electrode based on copper and cobalt co-doped ferrites (Cu0.3Co0.7Fe2O4)-modified glassy carbon electrode (Cu0.3Co0.7Fe2O4 / GCE) was presented for the sensitive detection of N-acetyl-p-aminophenol (NAP). The electrochemical behavior of NAP on Cu0.3Co0.7Fe2O4 / GCE was investigated by cyclic voltammetry. The modified electrode displayed excellent redox activity towards NAP, with a significant reduction of overpotential compared to bare GCE. A good linear relationship was obtained between the concentration and current response of NAP with a detection limit of 28.9 nM The excellent electrocatalytic activity of Cu0.3Co0.7Fe2O4 suggesting potential application of the modified electrode as an electrochemical sensor for N-acetyl-p-aminophenol.

Objective: The objective of the study was to establish potential uses of the fruit peel and seeds from Passiflora vitifolia collected in the Colombian Central Andes. Methods: The physical characteristics and chemical profile of the byproducts were determined. The ethanolic extracts of these materials were used to assess the content and phytophenols composition, to establish the antioxidant potential and the antidiabetic activity, in vitro inhibition of α-amylase enzyme and glucose diffusion. The performance and physicochemical composition of the seed oil was also evaluated. Results: The seeds contain almost 4 times more phenolic compounds (10 671 mg GAE/100 g sample) than the peel (2817 mg GAE/100 g sample). Likewise, crude protein and fat contents from the seeds are higher (15.5% and 25.6%) than the peel (6.60% and 5.70%, respectively). Nine phytoconstituents were positive for both extracts. Significant variation (p

For many thermal reactions, the effects of catalysis or the influence of solvents on reaction rates can be rationalized by simple transition state models. This is not the case for reactions controlled by quantum tunneling, which do not proceed via transition states, and therefore lack the simple concept of transition state stabilization. 1H-Bicyclo[3.1.0]-hexa-3,5-dien-2-one is a highly strained cyclopropene that rearranges to 4-oxocyclohexa-2,5-dienylidene via heavy-atom tunneling. H2O, CF3I, or BF3 form Lewis acid–base complexes with both reactant and product, and the influence of these intermolecular complexes on the tunneling rates for this rearrangement was studied. The tunneling rate increases by a factor of 11 for the H2O complex, by 23 for the CF3I complex, and is too fast to be measured for the BF3 complex. These observations agree with quantum chemical calculations predicting a decrease in both barrier height and barrier width upon complexation with Lewis acids, resulting in the observed Lewis acid catalysis of the tunneling rearrangement.