Search Results (601)

Background: Varicella zoster virus (VZV) is the causative agent for chickenpox and herpes zoster (HZ, shingles). HZ is a debilitating disease affecting elderly and immunocompromised populations. Glycoprotein E (gE) is indispensable for viral replication and cell-to-cell spread and is the primary target for anti-VZV antibodies. Importantly, gE is the sole antigen in Shingrix, a highly efficacious, AS01_B-adjuvanted vaccine approved in multiple countries for the prevention of HZ, yet the three-dimensional (3D) structure of gE remains elusive. Objectives: We sought to determine the structure of VZV gE and to understand in detail its interactions with neutralizing antibodies. Methods: We used X-ray crystallography and cryo-electron microscopy to elucidate structures of gE bound by recombinant Fabs of antibodies previously elicited through vaccination with Zostavax, a live, attenuated vaccine. Results: The 3D structures resolve distinct central and C-terminal antigenic domains, presenting an array of diverse conformational epitopes. The central domain has two beta-sheets and two alpha helices, including an IgG-like fold. The C-terminal domain exhibits 3 beta-sheets and an Ig-like fold and high structural similarity to HSV1 gE. Conclusions: gE from VZV-infected cells elicits a human antibody response with a preference for the gI binding domain of gE. These results yield insights to VZV gE structure and immunogenicity, provide a framework for future studies, and may guide the design of additional herpesvirus vaccine antigens. Teaser: Structures of varicella zoster virus glycoprotein E reveal distinct antigenic domains and define epitopes for vaccine-elicited human antibodies. Full article

Objective: This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. Methods: A non-cross-reactive antibody trastuzumab, and F(ab′)2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Results: Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab′)2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5–7-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10–100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100–1000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. Conclusions: The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration. Full article

Background: The Frontal Assessment Battery (FAB), which is used to assess executive function, has been translated into several languages and shown to be valid and reliable. However, the validity and reliability of the Japanese version in patients with stroke are unknown. This study aimed to investigate the validity and reliability of the Japanese version of the FAB in patients with stroke. Methods: The Japanese version of the FAB for dementia was modified and evaluated in 52 patients with stroke. FAB measurements were obtained twice over a 10-day period. Convergent validity was assessed using the Stroop Color Word Test (SCWT) and the Trail Making Test (TMT) part B. Internal consistency was measured using Cronbach’s alpha (Cα). Test-retest evaluations were performed using intraclass correlation coefficient [ICC (2.1)] measurements, and limits of agreement (LOA) were calculated using the total FAB score. Results: The mean total FAB score was 13.4 ± 2.8 points, the ICC (2.1) was 0.856, and Cα was 0.92. The total FAB score was correlated with SCWT scores for parts I through IV (r = 0.70 to 0.77) and the TMT score for part B (ρ = −0.53). The LOA were −1.7 to 2.9 points. Conclusions: The Japanese version of the FAB had higher validity and reliability in patients with stroke. Full article

Energy trade balance has been the main factor behind current account imbalances in many developed and developing countries. This study investigates whether or not renewable energy conveys information to the current account deficit of selected OECD countries. Utilizing a dataset spanning from 1990 to 2021, we apply a Panel Autoregressive Distributed Lag (ARDL) estimator to determine the interrelation of current account deficit (CAB) as a percentage of GDP with selected indicators, namely, net energy import in total final energy consumption (NEI), the share of renewable energy in total electricity production (REN_TEO), and fiscal deficit as a percentage of GDP (FAB). The results of long-term estimations reveal that as net energy import increases, the current account deficit deteriorates. On the other hand, in the case that countries utilize more of renewable energy in their total electricity generation, their current account deficits improve. Thus, we conclude that energy policy matters for the current account balances and subsequently for the well-being of OECD economies. Finally, we find strong evidence for the twin deficit hypothesis, as fiscal deficit is negatively interrelated with current account deficit both in the short-run and long run. In other words, an increase in the level of budget deficit is associated with an upsurge in the current account deficit problem. Furthermore, the Dumitrescu-Hurlin causality test reveals that there is bidirectional heterogeneous causality between current account deficit and budget deficit. Additionally, when the countries in the sample are grouped by their per capita GDP levels, estimations reveal that the direction of interaction between CAB and energy-related indicators (NEI and REN_TEO) does not differ between Group 2 (the ones whose per capita incomes are over USD 25,000 but below USD 50,000) and Group 3 (the ones having more than USD 50,000 per capita income) countries. However, the coefficients of energy-related indicators for Group 2 countries are higher than those of Group 3 ones, suggesting that energy policy matters more for Group 2 countries’ current account imbalances in the long-term. Full article

Background: Functionalized nanoparticles (NPs) represent a cutting edge in innovative clinical approaches, allowing for the delivery of selected compounds with higher specificity in a wider time frame. They also hold promise for novel theranostic applications that integrate both diagnostic and therapeutic functions. Pathogens are continuously evolving to try to escape the strategies designed to treat them. Objectives: In this work, we describe the development of a biotechnological device, Nano-Immuno-Probes (NIPs), for early detection and infections treatment. Human Herpes Simplex Virus 2 was chosen as model pathogen. Methods: NIPs consist of PLGA-PEG-Sulfone polymeric NPs conjugated to recombinant Fab antibody fragments targeting the viral glycoprotein G2. NIPs synthesis involved multiple steps and was validated through several techniques. Results: DLS analysis indicated an expected size increase with a good polydispersity index. Z-average and z-potential values were measured for PLGA-PEG-Bis-Sulfone NPs (86.6 ± 10.9 nm; –0.7 ± 0.3 mV) and NIPs (151 ± 10.4 nm; −5.1 ± 1.9 mV). SPR assays confirmed NIPs’ specificity for the glycoprotein G2, with an apparent K_D of 1.03 ± 0.61 µM. NIPs exhibited no cytotoxic effects on VERO cells at 24 and 48 h. Conclusions: This in vitro study showed that NIPs effectively target HSV-2, suggesting the potential use of these nanodevices to deliver both contrast agents as well as therapeutic compounds. Full article

The fading affect bias (FAB) occurs in autobiographical memory when unpleasant emotions fade faster than pleasant emotions and the phenomenon appears to be a form of emotion regulation. As emotion regulation is positively related to problem solving, the current study examined FAB in the context of problem solving. In-person and online studies asked participants to provide basic demographics, describe their problem-solving abilities, and rate various healthy and unhealthy variables, including emotional intelligence and positive problem-solving attitudes. Participants also completed an autobiographical event memory form for which they recalled and described two pleasant and two unpleasant problem-solving and non-problem-solving events and rated the initial and current affect and rehearsals for those events. We found a robust FAB effect that was larger for problem-solving events than for non-problem-solving events in Study 1 but not in Study 2. We also found that FAB was positively related to healthy variables, such as grit, and negatively related to unhealthy variables, such as depression. Moreover, many of these negative relations were inverted at high levels of positive problem-solving attitudes, and these complex interactions were partially mediated by talking rehearsals and thinking rehearsals. Full article

Secretogranin III (Scg3) is a diabetic retinopathy (DR)-restricted angiogenic factor identified in preclinical studies as a target for DR therapy. Previously, our group generated and characterized ML49.3, an anti-Scg3 monoclonal antibody (mAb) which we then converted into an EBP2 humanized antibody Fab fragment (hFab) with potential for clinical application. We also generated anti-Scg3 mT4 mAb and related EBP3 hFab. In this study, to identify the preferred hFab for DR therapy, we compared all four antibodies for binding, neutralizing and therapeutic activities in vitro and in vivo. Octet binding kinetics analyses revealed that ML49.3 mAb, EBP2 hFab, mT4 mAb and EBP3 hFab have Scg3-binding affinities of 35, 8.7, 0.859 and 0.116 nM, respectively. Both anti-Scg3 EBP2 and EBP3 hFabs significantly inhibited Scg3-induced proliferation and migration of human umbilical vein endothelial cells in vitro, and alleviated DR vascular leakage and choroidal neovascularization with high efficacy. Paired assays in DR mice revealed that intravitreally injected EBP3 hFab is 26.4% and 10.3% more effective than EBP2 hFab and aflibercept, respectively, for ameliorating DR leakage. In conclusion, this study confirms the markedly improved binding affinities of hFabs compared to mAbs and further identifies EBP3 hFab as the preferred antibody to develop for anti-Scg3 therapy. Full article

Introduction: Apraxia is a neurological disorder that is common after a stroke and impairs the planning and execution of movements. In the rehabilitation field, virtual reality (VR) presents new opportunities and offers advantages to both rehabilitation teams and individuals with neurological conditions. Indeed, VR can stimulate and improve cognitive reserve and abilities, including executive function, and enhance the patient’s emotional status. Aim: The objective of this research is to determine the effectiveness of VR in improving praxis skills and behavioural functioning in individuals with severe stroke. Methods: A total of 20 stroke patients were enrolled from February 2022 to March 2023 and divided by the order of their recruitment into two groups: the experimental group (EG: n = 10) received training to improve their praxis skills using VR whereas the control one (CG: n = 10) received the same amount of standard training. All patients underwent an evaluation using a psychometric battery that consisted of the Hamilton Rating Scale for Depression (HRS-D), Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Spinnler and Tognoni test, and De Renzi and Faglioni test. Valuations were performed before rehabilitation (T0) and after its completion (T1). Results: Both groups demonstrated significant improvements post-intervention. The EG showed a greater enhancement in their MMSE scores (p = 0.002), and reductions in both ideomotor and constructive apraxia (p = 0.002 for both), compared to the CG. The VR-based training also resulted in significant improvements in their depression symptoms (HRSD scores improved, p = 0.012 in EG vs. p = 0.021 in CG). Conclusions: This pilot study suggests that VR could help reduce cognitive, constructive apraxia and ideomotor apraxia symptoms caused by stroke injury. Full article

The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively resulted in animal survival with a rate comparable to a previous study that utilized anti-CD40 monotherapy. Importantly, no incidence of thromboembolic events associated with the administration of the anti-CD40L PAS-Fab was observed. Two experiments failed early because of technical reasons, two were terminated deliberately after 90 days with the baboons in excellent condition and two were extended to 120 and 170 days, respectively. Unexpectedly, and despite the absence of any clinical signs, histopathology revealed fungal infections in all four recipients. This study provides, for the first time, insights into a combination therapy with anti-CD40/anti-CD40L antibodies to block this immune checkpoint. Full article

Idiopathic normal-pressure hydrocephalus (iNPH) is a clinic-radiological neurological syndrome presenting with cognitive deficits, gait disturbances and urinary incontinence. It often coexists with Alzheimer’s disease (AD). Due to the reversible nature of iNPH when promptly treated, a lot of studies have focused on possible biomarkers, among which are cerebrospinal fluid (CSF) biomarkers. The aim of the present study was to determine the rate of beta-amyloid pathology and AD co-pathology by measuring AD CSF biomarkers, namely, amyloid beta with 42 and 40 amino acids (Aβ42), the Aβ42/Aβ40 ratio, total Tau protein (t-Tau) and phosphorylated Tau protein at threonine 181 (p-Tau), in a cohort of iNPH patients, as well as to investigate the possible associations among CSF biomarkers and iNPH neuropsychological profiles. Fifty-three patients with iNPH were included in the present study. CSF Aβ42, Aβ40, t-Tau and p-Tau were measured in duplicate with double-sandwich ELISA assays. The neuropsychological evaluation consisted of the Mini-Mental State Examination, Frontal Assessment Battery, Five-Word Test and CLOX drawing tests 1 and 2. After statistical analysis, we found that amyloid pathology and AD co-pathology are rather common in iNPH patients and that higher values of t-Tau and p-Tau CSF levels, as well as the existence of the AD CSF profile, are associated with more severe memory impairment in the study patients. In conclusion, our study has confirmed that amyloid pathology and AD-co-pathology are rather common in iNPH patients and that CSF markers of AD pathology and t-Tau are associated with a worse memory decline in these patients. Full article

(1) Background: Functional abdominal bloating and distension (FAB/FAD) are common disorders of the gut–brain interaction. Their physiopathology is complex and not completely clarified, although gut microbiota imbalances play a central role. The treatment of FAB/FAD still represents a clinical challenge for both patients and healthcare providers. Gut microbiota modulation strategies might play a crucial role in their management. The aim of this narrative review was to update the current evidence on FAB/FAD, with a focus on gut microbiota. (2) Methods: In October 2023, a review was conducted through the Medline, PubMed, and Embase databases. Selected literature included all available English-edited studies (randomized controlled trials and cross-sectional, cohort, and case-control studies). (3) Results: Twelve studies were selected, most of which investigated the relationship between IBS and microbiota, with bloating being one of its symptoms. The studies suggest that restoring a balanced microbiome appears to be the most promising solution for better management of FAB/FAD. Targeted approaches, such as the use of probiotics, prebiotics, antibiotics such as rifaximin or dietary modifications, may hold the key to alleviating symptoms. Other therapeutic options, such as diet, neuromodulators, and brain–gut behavioral therapies (i.e., cognitive-behavioral therapy) have shown promising outcomes, but strong data are still lacking. (4) Conclusions: Targeted approaches that focus on the gut microbiota, such as the use of probiotics, prebiotics, and antibiotics, are essential in managing FAB/FAD. Understanding the complex relationship between gut microbiota and FAB/FAD is crucial for developing effective treatments. Further studies are needed to explore the specific roles of different microbial populations in patients with FAB/FAD to enhance therapeutic strategies. Full article

Perovskite solar cells (PSCs) are the most rapidly advancing photovoltaic technology in terms of power conversion efficiency. An efficiency of 26.1% was achieved in a decade, which is on par with the efficiency of very mature silicon panels. However, PSC commercialisation is partly hindered by the difficulty of scaling these devices without efficiency loss, mostly due to the increasing sheet resistance of the transparent conductive layer substrates and the nonuniformity of the layers when deposited across large areas. Therefore, it is crucial for the commercialisation of PSCs to implement easily scalable deposition processes with low material waste and compatibility with roll-to-roll (R2R) processes to reduce manufacturing costs. Slot-die coating can meet all these requirements, allowing for great uniformity over large areas. The most recent developments in PSC upscaling using slot-die coating as the main deposition process, along with its extension to the R2R process, are reviewed, including a thorough discussion of the slot-die coating process and the theory behind its operating limits. In fact, R2R coating is a very promising strategy for PSC industrialisation, since all processing steps use low-cost materials and scalable processes at temperatures lower than 120 °C, allowing the cost-effective and high-throughput production of PSC devices. Full article

Microbiota plays a crucial role in intestinal maturation in preterm newborns. The clinical manifestation of the immaturity of the gastro-intestinal tract is called feeding intolerance (FI). This condition may resolve spontaneously or dramatically evolve into necrotizing enterocolitis. One of the most challenging tasks for the neonatologist is to identify those neonates that will develop the disease early in order to adequately provide nutrition to these patients, from the very first hours of life. A close interplay between the maturity of the gastro-intestinal tract and gut microbiota has been described; however, in preterm neonates, this relationship is still undefined. We analyzed the bacterial composition of stool samples, collected early in life, from 30 preterm newborns classified as intolerant or tolerant according to the degree of readiness of the gastro-intestinal tract to receive enteral nutrition. The Pielou evenness index was significantly increased in intolerant compared with tolerant newborns. Data corrected for confounding variables confirmed that the occurrence of gut maturation was independently influenced by Pielou evenness at birth. A lower bacterial diversity very early in life is associated with improved feeding tolerance in preterm newborns. The abundance analysis showed that neonates not ready to receive enteral nutrition for feeding intolerance show, after birth, an increased abundance of Proteobacteria, Lachnospiracae, Enterobacter and Acinetobacter. We can argue that those are the taxa that prevent the establishment of pioneer bacteria. A lower alpha-diversity, in the first days of life, may facilitate the seeding of beneficial pioneer bacteria that, in turn, drive healthy microbial colonization during neonatal life. Full article

Cloud contamination significantly impairs optical remote sensing images (RSIs), reducing their utility for Earth observation. The traditional cloud removal techniques, often reliant on deep learning, generally aim for holistic image reconstruction, which may inadvertently alter the intrinsic qualities of cloud-free areas, leading to image distortions. To address this issue, we propose a multi-stage frequency attention network (MFCRNet), a progressive paradigm for optical RSI cloud removal. MFCRNet hierarchically deploys frequency cloud removal modules (FCRMs) to refine the cloud edges while preserving the original characteristics of the non-cloud regions in the frequency domain. Specifically, the FCRM begins with a frequency attention block (FAB) that transforms the features into the frequency domain, enhancing the differentiation between cloud-covered and cloud-free regions. Moreover, a non-local attention block (NAB) is employed to augment and disseminate contextual information effectively. Furthermore, we introduce a collaborative loss function that amalgamates semantic, boundary, and frequency-domain information. The experimental results on the RICE1, RICE2, and T-Cloud datasets demonstrate that MFCRNet surpasses the contemporary models, achieving superior performance in terms of mean absolute error (MAE), root mean square error (RMSE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM), validating its efficacy regarding the cloud removal from optical RSIs. Full article