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Abstract Background This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR). Methods Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal–Wallis and Dunn. Results Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p

Abstract The marine holothurian-derived fungal strain KMM 4401 has been identified as Paragliomastix luzulae using 28S rDNA, ITS regions and the partial TEF1 gene sequences. The metabolite profile of the fungal culture was studied by UPLC-MS technique. The strain KMM 4401 is a source of various virescenoside-type isopimarane glycosides suggested as chemotaxonomic feature for this fungal species. Also Px. luzulae KMM 4401 was proposed as possible source of new bioactive secondary metabolites especially antimicrobials. Moreover, the co-cultures of Px. luzulae KMM 4401 with another marine fungus Penicillium hispanicum KMM 4689 inoculated simultaneously or after two weeks were investigated by same way. It was shown, that P. hispanicum KMM 4689 suppressed the production of most of Px. luzulae KMM 4401 metabolites. On the other hand, the co-cultivation of P. hispanicum KMM 4689 and Px. luzulae KMM 4401 resulted in increasing of production of main deoxyisoaustamide alkaloids of P. hispanicum KMM 4689 on 50–190%. Graphical Abstract

SGIP1 encodes a protein Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1. It is involved in the regulation of clathrin-mediated endocytosis along with having a role in energy homeostasis in neuronal systems. We generated an isogenic human induced pluripotent stem cell (iPSC) line with a biallelic frameshift variant in SGIP1. This exon has been shown to be subject to alternative splicing, leading to an isoform lacking 24 amino acids that are present in the longest SGIP isoform. The newly generated iPSC line will be helpful to dissect the differential properties of the two SGIP isoforms.

Abstract Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles Penicillium velutinum were analyzed. From the ethyl acetate extract of the P. velutinum were isolated two new piperazine derivatives helvamides B (1) and C (2) together with known saroclazin A (3) (4S,5R,7S)-4,11-dihydroxy-guaia-1(2),9(10)-dien (4). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (1) as 2R,5R was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi Candida albicans were assayed. Graphical Abstract

Data on antibody response (AR) after vaccination against SARS-CoV2 in hematopoietic stem-cell transplantation setting (HSCT) were initially scarce, mainly due to the exclusion of such patients from approval studies. Shortly after the worldwide application of vaccination against SARS-CoV-2 in vulnerable populations such as patients with hematologic malignancies, limited single-center trials, including HSCT patients, were published. However, there was a great heterogeneity between them regarding the type of underlying malignancy, co-current treatment, type of vaccine, method of AR measurement, and time point of AR measurement. Herein, we present the results of a prospective study on AR after vaccination for SARS-CoV-2 using the BNT162b2 vaccine in a cohort of 54 HSCT recipients—mostly autologous from a single Unit—along with a broad review of the current literature. In our cohort, the AR positivity rate at 1 month was 80.8% and remained positive in 85.7% of patients at 3 months after vaccination. There were only nine non-responders, who were more heavily pretreated and more frequently hypogammaglobulinemic compared to responders. High antibody titers (AT), [AT ≥ 1000 U/mL], were detected in 38.5% and 30.6% of the patients at m1 and m3, respectively. A significant decline in AT between m1 and m3 was demonstrated—p < 0.0001; median AT1 and AT3 were 480.5 and 293 U/mL, respectively. A novel finding of our study was the negative impact of IgA hypogammaglobulinemia on response to vaccination. Other negative significant factors were treatment with anti-CD20 antibody at vaccination and vaccination within 18 months from HSCT. Our data indicate that HSCT recipients elicit a positive response to the BNT162b2 vaccine against SARS-CoV-2 when vaccinated at 6 months post-transplant, and vaccination should be offered to this patient population even within the post-pandemic COVID-19 era.

ABSTRACT Objective: The objective of this narrative review is to discuss the current state of research funding in Brazil. Materials and Methods: This study is based on the most recent edition of the course Funding for Research and Innovation in the University of Sao Paulo School of Medicine which was a three-day course with 12 hours of instruction. The course brought together leading experts in the field to comprehensively discuss the current state of research funding in Brazil. Each speaker provided a presentation on a specific topic related to research funding. After the workshop, speakers assembled relevant topics in this manuscript. Results: collaborative research is critical for securing research funding. It optimizes proposal competitiveness, amplifies societal impact, and manages risks effectively. As such, fostering and supporting these collaborations is paramount for both researchers and funding agencies. To maintain the highest integrity in research, investigators involved in these collaborations must disclose any relationships that could potentially influence the outcomes or interpretation of their projects. Conclusions: In Brazil, the mainstay of research funding stems from public entities, with agencies such as CNPq, CAPES, and state bodies like FAPESP, FAPERJ, FAPEMIG and others at the forefront. Concurrently, industry funding offers viable pathways, especially through industry-sponsored studies, investigator-led projects, and collaborative initiatives. The Brazilian funding landscape is further enriched by innovative platforms, including crowdfunding and the contributions of institutions like the Serrapilheira Institute. Internationally, esteemed organizations such as the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation stand out as potential funders.

Background: Current noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. Objective: We investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS’ effects on amygdala-fear circuit resting-state functional connectivity. Methods: Thirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. Results: Compared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F(1,25) = 4.86, p = 0.04, η2 = 0.16) during the fear task, and lower hippocampal (F(1,27) = 4.41, p = 0.05, η2 = 0.14), and dorsal anterior cingulate cortex (F(1,27) = 6.26, p = 0.02; η2 = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F(1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F(1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F(1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F(1,28) = 3.52, p = 0.05) resting-state functional connectivity. Conclusions: tFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS’ therapeutic potential for individuals with clinical levels of anxiety.

Abstract This study aimed to evaluate the influence of combined intermittent fasting (IF) and high‐intensity interval training (HIIT) on morphology, caspase‐independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty‐day‐old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high‐intensity‐interval training (T), and high‐intensity‐interval training and intermittent fasting (T‐IF). The C and T groups received ad libitum chow daily; IF and T‐IF received the same standard chow every other day. Animals from T and T‐IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro‐apoptotic proteins apoptosis‐inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved‐to‐non‐cleaved PARP‐1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved‐to‐total PARP‐1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross‐sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved‐to‐non‐cleaved PARP‐1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase‐independent apoptosis signaling.

Intellectual disability (ID) is a diverse neurodevelopmental condition and almost half of the cases have a genetic etiology. SGIP1 acts as an endocytic protein that influences the signaling of receptors in neuronal systems related to energy homeostasis through its interaction with endophilins. This study focuses on the generation and characterization of induced pluripotent stem cells (iPSC) from two unrelated patients due to a frameshift variant (c.764dupA, NM_032291.4) and a splice donor site variant (c.74 + 1G > A, NM_032291.4) in the SGIP1 gene.

The study considers the medical and socio-pedagogical risks of primary school children using digital devices and social networks, based on the results of a medical and social study, the purpose of which was to assess and systematize these risks. The digital devices, the Internet and activities on social networks have become an integral part of the lives of modern children. However, their use can negatively affect the neuropsychic status of the child and lead to problems with vision and the musculoskeletal system. For this reason, parental control over the use of gadgets and social networks that is safe for children’s health is very important. The methodological basis of the research was social pedagogy, which explores the processes of interaction of a growing person with various objects of society in the main spheres of his/her life: family, educational and social, performing an integrating function in the study of current social problems of children, families and society by various scientific disciplines. A complex of research methods was used, with the main one being a questionnaire survey of parents with children of primary school age and living in the Borovsky district of the Kaluga region (the research base of the Research Institute of Hygiene and Health Protection of Children and Adolescents, National Medical Research Center for Children’s Health of the Ministry of Health of the Russian Federation). It was found that watching videos is a risk of increased irritability, computer games, searching for information on the Internet, uncontrolled use of digital media - a risk of visual impairment, using social networks - complaints for communication difficulties. More than 50% of parents need help from specialists in improving digital literacy and using digital devices safely for children’s health.

Nowadays, plastic contamination worldwide is a concerning reality that can be addressed with appropriate society education as well as looking for innovative polymeric alternatives based on the reuse of waste and recycling with a circular economy point of view, thus taking into consideration that a future world without plastic is quite impossible to conceive. In this regard, in this review, we focus on sustainable polymeric materials, biodegradable and bio-based polymers, additives, and micro/nanoparticles to be used to obtain new environmentally friendly polymeric-based materials. Although biodegradable polymers possess poorer overall properties than traditional ones, they have gained a huge interest in many industrial sectors due to their inherent biodegradability in natural environments. Therefore, several strategies have been proposed to improve their properties and extend their industrial applications. Blending strategies, as well as the development of composites and nanocomposites, have shown promising perspectives for improving their performances, emphasizing biopolymeric blend formulations and bio-based micro and nanoparticles to produce fully sustainable polymeric-based materials. The Review also summarizes recent developments in polymeric blends, composites, and nanocomposite plasticization, with a particular focus on naturally derived plasticizers and their chemical modifications to increase their compatibility with the polymeric matrices. The current state of the art of the most important bio-based and biodegradable polymers is also reviewed, mainly focusing on their synthesis and processing methods scalable to the industrial sector, such as melt and solution blending approaches like melt-extrusion, injection molding, film forming as well as solution electrospinning, among others, without neglecting their degradation processes.

Summary: Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5′ untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5′ UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5′ UTR binding in a cap-dependent and -independent manner. Finally, CMLD012824 led to growth inhibition in MYCN-amplified neuroblastoma models without generalized toxicity. Our studies highlight the key role of eIF4A1 in MYCN-amplified neuroblastoma and demonstrate the therapeutic potential of disrupting its function.

Abstract The introduction of bees for agricultural production in distinct parts of the world and poor management have led to invasion processes that affect biodiversity, significantly impacting native species. Different Bombus species with invasive potential have been recorded spreading in different regions worldwide, generating ecological and economic losses. We applied environmental niche and potential distribution analyses to four species of the genus Bombus to evaluate the similarities and differences between their native and invaded ranges. We found that B. impatiens has an extended environmental niche, going from dry environmental conditions in the native range to warmer and wetter conditions in the invaded range. Bombus ruderatus also exhibited an extended environmental niche with drier and warmer conditions in the invaded range than in its native range. Bombus subterraneus expanded its environmental niche from cooler and wetter conditions in the native range to drier and warmer conditions in the invaded range. Finally, B. terrestris showed the most significant variation in the environmental niche, extending to areas with similar and different environmental conditions from its native range. The distribution models agreed with the known distributions for the four Bombus species, presenting geographic areas known to be occupied by each species in different regions worldwide. The niche analysis indicate shifts in the niches from the native to the invaded distribution area of the bee species. Still, niche similarities were observed in the areas of greatest suitability in the potential distribution for B. ruderatus, B. subterraneus, and B. terrestris, and to a lesser degree in the same areas with B. impatiens. These species require similar environmental conditions as in their native ranges to be established in their introduced ranges. Still, they can adapt to changes in temperature and humidity, allowing them to expand their ranges into new climatic conditions.

AimThe aim of this study was to investigate baseline characteristics and outcome of patients after endovascular therapy (EVT) for acute large vessel occlusion (LVO) in relation to their history of symptomatic vascular disease and sex.MethodsConsecutive EVT-eligible patients with LVO in the anterior circulation admitted to our stroke center between 04/2015 and 04/2020 were included in this observational cohort study. All patients were treated according to a standardized acute ischaemic stroke (AIS) protocol. Baseline characteristics and successful reperfusion, recurrent/progressive in-hospital ischaemic stroke, symptomatic in-hospital intracranial hemorrhage, death at discharge and at 3 months, and functional outcome at 3 months were analyzed according to previous symptomatic vascular disease and sex.Results995 patients with LVO in the anterior circulation (49.4% women, median age 76 years, median admission NIHSS score 14) were included. Patients with multiple vs. no previous vascular events showed higher mortality at discharge (20% vs. 9.3%, age/sex − adjustedOR = 1.43, p = 0.030) and less independency at 3 months (28.8% vs. 48.8%, age/sex − adjustedOR = 0.72, p = 0.020). All patients and men alone with one or multiple vs. patients and men with no previous vascular events showed more recurrent/progressive in-hospital ischaemic strokes (19.9% vs. 6.4% in all patients, age/sex − adjustedOR = 1.76, p = 0.028) (16.7% vs. 5.8% in men, age-adjustedOR = 2.20, p = 0.035). Men vs. women showed more in-hospital symptomatic intracranial hemorrhage among patients with one or multiple vs. no previous vascular events (23.7% vs. 6.6% in men and 15.4% vs. 5.5% in women, OR = 2.32, p = 0.035/age − adjustedOR = 2.36, p = 0.035).ConclusionsPrevious vascular events increased the risk of in-hospital complications and poorer outcome in the analyzed patients with EVT-eligible LVO-AIS. Our findings may support risk assessment in these stroke patients and could contribute to the design of future studies.

Data from epidemiological studies show a high prevalence of cardiovascular diseases, including arterial hypertension (AH) and the risk of complications, with changes in AH control and treatment techniques. The review article summarizes the main directions of the new European guidelines on hypertension, which help implement different patient groups in outpatient practice. Secondary risk factors for cardiovascular disease are revised in the new clinical guidelines. The recommendation outlines a diagnostic and therapeutic approach for resistant arterial hypertension, its associated phenotypes, and night-time hypertension. The use and position of renal denervation for antihypertensive treatment have been updated compared with previous recommendations. The new European clinical guidelines reflect a differentiated approach to target indicators of ambulatory blood pressure in different age groups, with functional levels of aging, comorbidity, and AH phenotypes, which is of great clinical importance for a primary care physician and can significantly reduce the risk of heart disease vascular complications.

Ten new decalin polyketides, zosteropenilline M (1), 11-epi-8-hydroxyzosteropenilline M (2), zosteropenilline N (3), 8-hydroxyzosteropenilline G (4), zosteropenilline O (5), zosteropenilline P (6), zosteropenilline Q (7), 13-dehydroxypallidopenilline A (8), zosteropenilline R (9) and zosteropenilline S (10), together with known zosteropenillines G (11) and J (12), pallidopenilline A (13) and 1-acetylpallidopenilline A (14), were isolated from the ethyl acetate extract of the fungus Penicillium yezoense KMM 4679 associated with the seagrass Zostera marina. The structures of isolated compounds were established based on spectroscopic methods. The absolute configurations of zosteropenilline Q (7) and zosteropenilline S (10) were determined using a combination of the modified Mosher’s method and ROESY data. The absolute configurations of zosteropenilline M (1) and zosteropenilline N (3) were determined using time-dependent density functional theory (TD-DFT) calculations of the ECD spectra. A biogenetic pathway for compounds 1–14 is proposed. The antimicrobial, cytotoxic and cytoprotective activities of the isolated compounds were also studied. The significant cytoprotective effects of the new zosteropenilline M and zosteropenillines O and R were found in a cobalt chloride (II) mimic in in vitro hypoxia in HEK-293 cells. 1-Acetylpallidopenilline A (14) exhibited high inhibition of human breast cancer MCF-7 cell colony formation with IC50 of 0.66 µM and its anticancer effect was reduced when MCF-7 cells were pretreated with 4-hydroxitamoxifen. Thus, we propose 1-acetylpallidopenilline A as a new xenoestrogen with significant activity against breast cancer.

The main aim of the present work is to evaluate and characterize the mechanical, morphological and thermal properties of wastes coming from the textile industry, mainly composed of cotton and polyester. These wastes will be thereafter implemented in commodity plastic such as polyamide, in order to develop new formulations of environmentally friendly materials. The composites were produced by extrusion and injection-molded processes in amounts between 15 wt.% and 60 wt.% of textile waste. With the objective of improving the properties of the materials, silanes were used as a compatibilizer between the textile fibers and the polymeric matrix. The effect of the compatibilizer in the composites was studied together with the effect of the amount of textile fiber added to the composites. Mechanical, thermal, morphological and wettability properties were analyzed for each composite. The results show that the use of silanes improves the interaction especially in those composites with a higher amount of textile waste, offering a balanced mechanical behavior with significantly high quantities. On the other hand, the melting temperature does not vary significantly with the introduction of silanes and textile waste content, although the incorporation of textile waste slightly reduces up to 23% the degradation temperature of the resulting composites. The wettability of the composites is also increased up to 16% with the incorporation of textile waste. Finally, the appearance of the composites with textile waste is strongly influenced by the incorporation of the reinforcement, offering shades close to dark brown in the whole range of compositions.

Trichoderma erinaceum is a filamentous fungus that was isolated from decaying sugarcane straw at a Brazilian ethanol biorefinery. This fungus shows potential as a source of plant cell wall-degrading enzymes (PCWDEs). In this study, we conducted a comprehensive multiomics investigation of T. erinaceum to gain insights into its enzymatic capabilities and genetic makeup. Firstly, we performed genome sequencing and assembly, which resulted in the identification of 10,942 genes in the T. erinaceum genome. We then conducted transcriptomics and secretome analyses to map the gene expression patterns and identify the enzymes produced by T. erinaceum in the presence of different substrates such as glucose, microcrystalline cellulose, pretreated sugarcane straw, and pretreated energy cane bagasse. Our analyses revealed that T. erinaceum highly expresses genes directly related to lignocellulose degradation when grown on pretreated energy cane and sugarcane substrates. Furthermore, our secretome analysis identified 35 carbohydrate-active enzymes, primarily PCWDEs. To further explore the enzymatic capabilities of T. erinaceum, we selected a β-glucosidase from the secretome data for recombinant production in a fungal strain. The recombinant enzyme demonstrated superior performance in degrading cellobiose and laminaribiose compared to a well-known enzyme derived from Trichoderma reesei. Overall, this comprehensive study provides valuable insights into both the genetic patterns of T. erinaceum and its potential for lignocellulose degradation and enzyme production. The obtained genomic data can serve as an important resource for future genetic engineering efforts aimed at optimizing enzyme production from this fungus.

Abstract Copper is an essential trace element for human health and, at the same time, a major industrial metal widely used both in its elemental form and in compounds. We conducted a dose-dependent assessment of the response of outbred albino male rats to subchronic low-dose exposure to copper oxide nanoparticles administered intraperitoneally at cumulative doses of 18 and 36 mg/kg during 6 weeks to exposure groups 1 and 2, respectively. We observed disorders at different levels of organization of the body in the exposed animals, from molecular to organismal. The observed decrease in the activity of succinate dehydrogenase in nucleated blood cells gave evidence of impaired bioenergetics processes. In view of the results of the metabolomics analysis, we assume mitochondrial damage and contribution of apoptotic processes to the pathology induced by copper poisoning. We also assume neurodegenerative effects based on the assessed morphological parameters of the nervous system, results of behavioral tests, and a decreased level of expression of genes encoding NMDA receptor subunits in the hippocampus. The hepatotoxic effect noted by a number of metabolomics-based, biochemical, and cytological indicators was manifested by the impaired protein-synthesizing function of the liver and enhanced degenerative processes in its cells. We also observed a nephrotoxic effect of nanosized copper oxide with a predominant lesion of proximal kidney tubules. At the same time, both doses tested demonstrated such positive health effects as a statistically significant decrease in the activity of alkaline phosphatase and the nucleated blood cell DNA fragmentation factor. Judging by the changes observed, the cumulative dose of copper oxide nanoparticles of 18 mg/kg body weight administered intraperitoneally approximates the threshold one for rats. The established markers of health impairments may serve as a starting point in the development of techniques of early diagnosis of copper poisoning.

ABSTRACT: Introduction. Used tire rubber cracking with organic solvents leads to rubber devulcanization and dispersion of the material to nanosized particles. The process can be carried out in a flow reactor. The obtained nanomodifiers are compatible with bitumen and predictably change the bituminous binder technical characteristics. Various practical solutions have been proposed for the use of the resulting modified bituminous binders in the road construction and strengthening soil foundations. Methods and materials. It has been proposed to use a method of joint cracking of rubber with organic solvents to obtain a nanostructured modifier of bitumen. The obtained nanostructural modifier has been studied by the methods of analyzing the sizes of nanoparticles and solubility in toluene. For the bituminous binders obtained with the use of nanomodifiers, standard characteristics for bitumen, such as needle penetration depth, softening temperature, brittleness temperature and extensibility have been determined. Results and discussion. It is established that during the proposed process, a nanostructural modifier compatible with bitumen is formed. It is shown that the addition of a nanomodifier to bitumen makes it possible to purposefully change the properties of the resulting bitumen binder, improve the consumer properties of the bitumen binder and expand its application areas. It is proposed to use the obtained product as a component of waterproofing mastics for waterproofing the underground parts of buildings and structures. Conclusion. Joint cracking of rubber with organic solvents in a flow reactor allows obtaining a nanostructural modifier compatible with bitumen. The resulting product has improved properties compared to the original bitumen, which expands its scope of application. It is proposed to use the resulting product for the manufacture of waterproofing mastics. The proposed technical solutions make it possible to reduce the environmental load of automobile tires wastes

Introduction: The post-prostatectomy incontinence is influenced by multiple elements, anatomic components and biological factors. The bladder neck preservation, more accurate during robot assisted radical prostatectomy, works on two anatomic components responsible for post-prostatectomy continence. The bladder neck preservation spares the internal sphincter, which is responsible for passive continence, and results in earlier return to continence and lower rates of post-prostatectomy incontinence. Moreover, this surgical technique spares the zone of urothelium coaptation and provides primary resistance to the urine to maintain postprostatectomy continence. The potential risk of bladder neck positive surgical margins (PSM) may prevent the usage of the bladder neck preservation. Aim: The purpose of this study is to evaluate the surgical and pathological outcome in prostate cancer patients underwent robot assisted radical prostatectomy with bladder neck preservation. Materials and methods: Prospectively, we have collected demographic, clinical, surgical and pathological data of prostate cancer patients underwent robot assisted radical prostatectomy with bladder neck preservation, from January 2014 to December 2016, in Urological Clinic of the University of Padua. Moreover, it was valued the presence of alterations or continuous solutions of specimen external capsule, attributable to the surgical technique of bladder neck preservation, by microscopic and macroscopic pathological analysis. Results: According to D'Amico risk classification, 40 patients (45.4%) had a low risk neoplasia, 35 patients (39.8%) had an intermediate risk neoplasia, 13 patients (14.8%) had an high risk neoplasia. The median prostatic volume, valued on specimen, was 30.84 cc (21.5-44.75 cc). The median prostatic weight, valued on specimen, was 51 gr (36-67 gr). The pathological stage of disease was pT2a in 11 cases (12.5%), pT2b in 37 cases (42.1%), pT3a in 28 cases (31.8%), pT3b in 12 cases (13.6%). The pathological stage of lymph node involvement was pNx in 17 cases (19.3%), pN0 in 66 cases (75%), pN1 in 5 cases (5.7%). The prostate cancers diagnosed had a Gleason score at specimen of 6 in 10 cases (10.4%), 7 (3+4) in 30 cases (34.1%), 7 (4+3) in 20 cases (22.7%), 8 in 19 cases (21.6%) and 9 in 9 cases (10.2%). The prostatic base was involved by neoplasia in 14 patients (15.9%); of these, 5 patients (35.7%) had bladder neck PSM. The patients with bladder neck PSM had: a pathological stage of disease as pT3a in 2 cases (40%) and pT3b in 3 cases (60%); a pathological stage of lymph node involvement as pN0 in 2 cases (40%) and pN1 in 3 cases (60%); a Gleason score at specimen of 8 in 3 cases (60%) and 9 in 2 cases (40%); multiple PSM. Nobody had alterations or continuous solutions of specimen external capsule, attributable to surgical technique of bladder neck preservation. Conclusions: The bladder neck preservation, during robot assisted radical prostatectomy, is a safe oncological procedure resulting in a good functional outcome, about post-prostatectomy continence, working on two anatomic components responsible for post-prostatectomy continence. The bladder neck PSM are linked to neoplasia with adverse pathological features, rather than the bladder neck preservation.

Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.

Antimicrobial peptides (AMPs) are short polypeptide molecules produced by multicellular organisms that are involved in host defense and microbiome preservation. In recent years, AMPs have attracted attention as novel drug candidates. However, their successful use requires detailed knowledge of the mode of action and identification of the determinants of biological activity. In this review, we focused on structure-function relationships in the thionins, α-hairpinins, hevein-like peptides, and the unique Ib-AMP peptides isolated from Impatiens balsamina. We summarized the available data on the amino acid sequences and 3D structure of peptides, their biosynthesis, and their biological activity. Special attention was paid to the determination of residues that play a key role in the activity and the identification of the minimal active cores. We have shown that even subtle changes in amino acid sequences can affect the biological activity of AMPs, which opens up the possibility of creating molecules with improved properties, better therapeutic efficacy, and cheaper large-scale production.

Abstract Background Although clinical practice guidelines recommend pain education as the first-line option for the management of chronic musculoskeletal pain, there is a lack of pain education programmes in healthcare. Thus, digital health programmes can be an effective tool for implementing pain education strategies for public health. This trial will aim to analyse the implementation and effectiveness outcomes of three online pain science education strategies in the Brazilian public health system (SUS) for individuals with chronic musculoskeletal pain. Methods We will conduct a hybrid type III effectiveness-implementation randomised controlled trial with economic evaluation. We will include adult individuals with chronic musculoskeletal pain, recruited from primary healthcare in the city of Guarapuava, Brazil. Individuals will be randomised to three implementation groups receiving a pain science education intervention (EducaDor) but delivered in different modalities: group 1) synchronous online; group 2) asynchronous videos; and group 3) interactive e-book only. Implementation outcomes will include acceptability, appropriateness, feasibility, adoption, fidelity, penetration, sustainability, and costs. We will also assess effectiveness outcomes, such as pain, function, quality of life, sleep, self-efficacy, and adverse effects. Cost-effectiveness and cost-utility analyses will be conducted from the SUS and societal perspectives. The evaluations will be done at baseline, post-intervention (10 weeks), and 6 months. Discussion This study will develop and implement a collaborative intervention model involving primary healthcare professionals, secondary-level healthcare providers, and patients to enhance self-management of chronic pain. In addition to promoting better pain management, this study will also contribute to the field of implementation science in public health by generating important insights and recommendations for future interventions. Trial registration ClinicalTrials.gov (NCT05302180; 03/29/2022).

An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and the formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is the reduction of free Aβ levels by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) in HSA to improve its affinity for Aβ. Here we develop this approach through a bioinformatic search for the clinically approved AD-related LMWLs in HSA, followed by classification of the candidates according to the predicted location of their binding sites on the HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA–Aβ40 interaction: prednisone favors HSA–Aβ interaction, mefenamic acid shows the opposite effect, and levothyroxine exhibits bidirectional effects. Overall, the LMWLs in HSA chosen here provide a basis for drug repurposing for AD prevention, and for the search of medications promoting AD progression.

Peptides play an essential role in plant development and immunity. Filipendula ulmaria, belonging to the Rosaceae family, is a medicinal plant which exhibits valuable pharmacological properties. F. ulmaria extracts in vitro inhibit the growth of a variety of plant and human pathogens. The role of peptides in defense against pathogens in F. ulmaria remains unknown. The objective of this study was to explore the repertoire of antimicrobial (AMPs) and defense-related signaling peptide genes expressed by F. ulmaria in response to infection with Bipolaris sorokiniana using RNA-seq. Transcriptomes of healthy and infected plants at two time points were sequenced on the Illumina HiSeq500 platform and de novo assembled. A total of 84 peptide genes encoding novel putative AMPs and signaling peptides were predicted in F. ulmaria transcriptomes. They belong to known, as well as new, peptide families. Transcriptional profiling in response to infection disclosed complex expression patterns of peptide genes and identified both up- and down-regulated genes in each family. Among the differentially expressed genes, the vast majority were down-regulated, suggesting suppression of the immune response by the fungus. The expression of 13 peptide genes was up-regulated, indicating their possible involvement in triggering defense response. After functional studies, the encoded peptides can be used in the development of novel biofungicides and resistance inducers.

Expanded polystyrene will account for 5.3% of total global plastic production in 2021 and is widely used for food packaging due to its excellent moisture resistance and thermal insulation. However, some of these packages are often used only once before being discarded, generating large amounts of environmentally harmful plastic waste. A very attractive alternative to the conventional methods used for polymer processing is the use of supercritical carbon dioxide (scCO2) since it has mass-transfer properties adapted to the foam morphology, generating different path lengths for the diffusion of active compounds within its structure and can dissolve a wide range of organic molecules under supercritical conditions. The objective of this research was to evaluate the effect of operational variables on the process of caffeic acid (CA) impregnation and subsequent foaming of polylactic acid (PLA) as well as two PLA/poly(butylene-co-terephthalate-adipate) (PBAT) blends using scCO2. The results showed an increase in the degree of crystallinity of the CA-impregnated samples due to the nucleation effect of the active compound. On the other hand, SEM micrographs of both films and foams showed significant differences due to the presence of PBAT and its low miscibility with PLA. Finally, the results obtained in this work contribute to the knowledge of the important parameters to consider for the implementation of the impregnation and foaming process of PLA and PLA/PBAT blends with potential use in food packaging.

In the last decade, among the emerging technologies in the area of bioplastics, additive manufacturing (AM), commonly referred to as 3D printing, stands out. This technology has gained great interest in the development of new products, mainly due to its capability to easily produce customized and low-cost plastic products. This work aims to evaluate the effect of supercritical foaming of 3D-printed parts based on a commercial PLA matrix loaded with calcium carbonate, for single-use sustainable food contact materials. 3D-printed PLA/CaCO3 parts were obtained by 3D printing with a 20% and 80% infill, and two infill patterns, rectilinear and triangular, were set for each of the infill percentages selected. Supercritical fluid foaming of PLA/CaCO3 composite printed parts was performed using a pressure of 25 MPa, a temperature of 130 °C for 23 min, with a fast depressurization rate (1 s). Closed-cell foams were achieved and the presence of CaCO3 did not influence the surface of the foams or the cell walls, and no agglomerations were observed. Foam samples with 80% infill showed subtle temperature fluctuations, and thermogravimetric analysis showed that samples were thermally stable up to ~300 °C, while the maximum degradation temperature was around 365 °C. Finally, tensile test analysis showed that for lower infill contents, the foams showed lower mechanical performance, while the 80% infill and triangular pattern produced foams with good mechanical performance. These results emphasize the interest in using the supercritical CO2 process to easily produce foams from 3D-printed parts. These materials represent a sustainable alternative for replacing non-biodegradable materials such as Expanded Polystyrene, and they are a promising option for use in many industrial applications, such as contact materials.

Summary: Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES −1.18 years [95% CI −2.05, −0.32]), had fewer respiratory symptoms (RD −0.15 [95% CI −0.33, −0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD −0.35 [95% CI −0.64, −0.07]), lower lymphocyte count (ES −0.16 × 109/uL [95% CI −0.30, −0.01]), lower C-reactive protein (ES −28.5 mg/L [95% CI −46.3, −10.7]), and lower troponin (ES −0.14 ng/mL [95% CI −0.26, −0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES −1.6 years [95% CI −2.5, −0.8]), had less frequent SIRS (RD −0.18 [95% CI −0.30, −0.05]), lower lymphocyte count (ES −0.39 × 109/uL [95% CI −0.52, −0.25]), lower troponin (ES −0.16 ng/mL [95% CI −0.30, −0.01]) and less frequently received anticoagulation therapy (RD −0.19 [95% CI −0.37, −0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (−1.3 days [95% CI −2.3, −0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.

Summary: Background: Characterizing Post-Acute Sequelae of COVID (SARS-CoV-2 Infection), or PASC has been challenging due to the multitude of sub-phenotypes, temporal attributes, and definitions. Scalable characterization of PASC sub-phenotypes can enhance screening capacities, disease management, and treatment planning. Methods: We conducted a retrospective multi-centre observational cohort study, leveraging longitudinal electronic health record (EHR) data of 30,422 patients from three healthcare systems in the Consortium for the Clinical Characterization of COVID-19 by EHR (4CE). From the total cohort, we applied a deductive approach on 12,424 individuals with follow-up data and developed a distributed representation learning process for providing augmented definitions for PASC sub-phenotypes. Findings: Our framework characterized seven PASC sub-phenotypes. We estimated that on average 15.7% of the hospitalized COVID-19 patients were likely to suffer from at least one PASC symptom and almost 5.98%, on average, had multiple symptoms. Joint pain and dyspnea had the highest prevalence, with an average prevalence of 5.45% and 4.53%, respectively. Interpretation: We provided a scalable framework to every participating healthcare system for estimating PASC sub-phenotypes prevalence and temporal attributes, thus developing a unified model that characterizes augmented sub-phenotypes across the different systems. Funding: Authors are supported by National Institute of Allergy and Infectious Diseases, National Institute on Aging, National Center for Advancing Translational Sciences, National Medical Research Council, National Institute of Neurological Disorders and Stroke, European Union, National Institutes of Health, National Center for Advancing Translational Sciences.

Abstract This article documents enu, a freely-downloadable, open-source and stand-alone program written in C++ for the enumeration of the constitutional isomers and stereoisomers of a molecular formula. The program relies on graph theory to enumerate all the constitutional isomers of a given formula on the basis of their canonical adjacency matrix. The stereoisomers of a given constitutional isomer are enumerated as well, on the basis of the automorphism group of this matrix. The isomer list is then reported in the form of canonical SMILES strings within files in XML format. The specification of the molecule family of interest is very flexible and the code is optimized for computational efficiency. The algorithms and implementations underlying enu are described, and simple illustrative applications are presented. The enu code is freely available on GitHub at https://github.com/csms-ethz/CombiFF .

Abstract Background Given the rapid advances in communication technology and the need that emerged from the COVID-19 pandemic, telehealth initiatives have been widely used worldwide. This masterclass aims to provide an overview of telerehabilitation for musculoskeletal conditions, synthesizing the different terminologies used to describe telehealth and telerehabilitation, its effectiveness and how to use it in clinical practice, barriers and facilitators for the implementation in health services, and discuss the need of a curriculum education for the near future. Main body Telerehabilitation refers to the use of information and communication technologies provided by any healthcare professionals for rehabilitation services. Telerehabilitation is a safe and effective option in the management of musculoskeletal conditions in different models of delivery. There are many technologies, with different costs and benefits, synchronous and asynchronous, that can be used for telerehabilitation: telephone, email, mobile health, messaging, web-based systems and videoconferences applications. To ensure a better practice of telerehabilitation, the clinician should certify safety and access, and appropriateness of environment, communication, technology, assessment, and therapeutic prescription. Despite the positive effect of telerehabilitation in musculoskeletal disorders, a suboptimal telerehabilitation implementation may have happened due to the COVID-19 pandemic, especially in countries where telehealth was not a reality, and clinicians lacked training and guidance. This emphasizes the need to identify the necessary curriculum content to guide future clinicians in their skills and knowledge for telerehabilitation. There are some challenges and barriers that must be carefully accounted for to contribute to a health service that is inclusive and relevant to health professionals and end users. Conclusions Telerehabilitation can promote patient engagement in health care and plays an important role in improving health outcomes in patients with musculoskeletal conditions. Digital health technologies can also offer new opportunities to educate patients and facilitate the process of behavior change to a healthy lifestyle. Currently, the main needs in telerehabilitation are the inclusion of it in health curriculums in higher education and the development of cost-effectiveness and implementation trials, especially in low- and middle-income countries where access, investments and digital health literacy are limited.

ABSTRACT: Introduction. Polymer-bitumen binders are innovative nano-binders for asphalt concrete pavement. Introduction of a polymer modifier improves the characteristics of bitumen and asphalt concrete. The use of waste tires rubber for bitumen modification is considered to be an environmentally friendly solution, but it is limited due to the poor cosite of rubber with bitumen. Various methods based on activation of the rubber surface, dispersion of rubber to nanosized particles, and thermochemical transformations of rubber into individual organic compounds are known to overcome this limitation. Methods and materials. The method of joint pyrolysis of rubber with oxygen-containing oil under pressure is proposed to be used for converting it into a nanostructural bitumen modifier. The resulting product is studied by the methods of thermogravimetry, NMR-spectroscopy, chromatomasspectrometry, scanning electron microscopy and solubility in toluene. Results and discussion. It has been established that during joint pyrolysis rubber undergoes devulcanization, cracking and dispersion to nanosized particles, and as a result the product becomes compatible with bitumen. Thermochemical reprocessing of waste automobile tires can be considered to be a promising method for the production of a nanostructured bitumen modifier. Conclusion. The use of thermochemical pressure treatment of waste tire rubber in the presence of oxygen-containing oil makes it possible to obtain a nanostructured product compatible with bitumen for further use of the resulting modifier in the production of asphalt concrete.

The review discusses the relationship between chronic heart failure and diabetes mellitus type 2, metabolic phenotypes of patients w ith chronic heart failure with preserved left ventricular ejection fraction (HFpEF), features of the pathophysiological interaction between diabetes mellitus and HFpEF. Chronic inflammatory condition, metabolic disorders and comorbidities are the pathophysiological basis of HFpEF. The review discusses the concept of diabetic cardiomyopathy, its molecular mechanism and current possibilities of treating this pathology, considering the impact on the prognosis.

Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice. Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an intravenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%). Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 substance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C

Abstract White outbred female rats were exposed intranasally to 50-µL of suspension of lead oxide nanoparticles (PbO NPs) at a concentration of 0.5 mg/mL thrice a week during six weeks. A control group of rats was administered deionized water in similar volumes and conditions. The developed intoxication was manifested by altered biochemical and cytochemical parameters, as well as behavioral reactions of animals. Using electron microscopy and energy-dispersive X-ray spectroscopy techniques, we revealed deposition of PbO NPs in the olfactory bulb, but not in basal ganglia, and an increase in the number of axons with damage to the myelin sheath in the tissues of olfactory bulb and basal ganglia, changes in the ultrastructure of mitochondria of neurons in the tissues of olfactory bulb and basal ganglia of the brain, and differences in the mitochondrial profile of neurons in different regions of the rat brain. Our results collectively suggest that the central nervous system may be a target of low-level toxicity of lead oxide nanoparticles.

Biomarkers of age and frailty may aid in understanding the aging process, predicting lifespan or health span and in assessing the effects of anti-aging interventions. Here, the authors show that combining physics-based models and deep learning may enhance understanding of aging from big biomedical data, observe effects of anti-aging interventions in laboratory animals, and discover signatures of longevity.

The article presents the results of an online survey conducted among the volunteers of the Olympic and/or Paralympic Games 2022 (Beijing, China). The text discusses the experience of participation of Chinese Olympic volunteers in relevant activities before the Games, their motivation for participating in the Olympic / Paralympic volunteer program, the level of satisfaction from participating in the organization and conduct of the Games, life and value orientations and attitudes towards further participation in volunteer activities. The results of the research show that more than half of the respondents had previous experience of participating in volunteer activities, as a rule, organized ones. Olympic volunteers have not only altruistic, but also selfish reasons in their motivation. Most of the volunteers of the Olympic and Paralympic Games in Beijing are satisfied with participation in this program, the largest proportion of respondents expressed a desire to participate in it again. Participants of the Olympic/Paralympic volunteer programs have demonstrated positive attitudes towards their current position and future, and a significant part of them plan to continue volunteering. Olympic volunteers, based on data on the level of satisfaction and future plans, represent a valuable resource for volunteering and can form a personnel reserve for professional volunteering and providing quality volunteer services.

The article is devoted to the participants of volunteer programs of major sporting events that were implemented in the BRICS countries. The main attention in the text is given to the life priorities of volunteers, their idea of happiness. The empirical basis of the article is an online survey of volunteers who have experience of participating in programs to work with volunteers at major sporting events in Brazil, Russia, India, China and South Africa (BRICS countries). The survey was conducted from January to March 2022. 2,638 respondents took part in the study. Based on the results of a survey of volunteers, we determined that volunteers are more likely to set goals in life. Also, volunteers participating in major sporting events tend to make plans for the distant and near future. The most frequently mentioned priorities in life among the volunteers were: family; health; helping those in need; education and selfdevelopment. At the same time, more than half of the volunteers consider themselves unconditionally happy people, and consider their loved ones happy. For volunteers, often inner feelings are more important for understanding happiness. About half of the volunteers participating in major sporting events from the BRICS countries would like to devote more time to volunteering in the next three years.

The article is devoted to the study of the issue of ethnic and civic identity of student youth, the education of a culture of interethnic relations in an educational institution. The article presents an analysis of the literature on the problem under consideration, considers state approaches to solving issues of ethnicity and citizenship. The relevance of the study is due to the reasons that require a timely response to the changes taking place in the modern multi-ethnic space. The multinationality of the Russian Federation, the ambiguity of historically established interethnic relations, the active development in the minds of modern youth of attitudes not only towards material, but also spiritual globalization, allow us to pay special attention to the process of forming ethnic and civic identity of the individual. The purpose of the article is to study the features of the formation of ethnic and civic identity and to identify their relationship in the student environment. The author cites the results of his own empirical studies of the general civic and ethnic identity of university students. The use of the methods of questioning, interviewing, observation and generalization of pedagogical experience helped the author in determining the main directions of ethno-cultural education of students. Ethnic identity is a necessary step in the formation of citizenship of student youth, it makes it easier and faster to interact with representatives of other ethnic groups, unites and helps to adapt to new cultural conditions.

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a‐/− and Epm2b−/− mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a−/− knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.

Sulfated polysaccharides of brown algae, fucoidans, are known for their anticoagulant properties, similar to animal heparin. Their complex and irregular structure is the main bottleneck in standardization and in defining the relationship between their structure and bioactivity. Fucoidan-active enzymes can be effective tools to overcome these problems. In the present work, we identified the gene fwf5 encoding the fucoidan-active endo-fucanase of the GH168 family in the marine bacterium Wenyingzhuangia fucanilytica CZ1127T. The biochemical characteristics of the recombinant fucanase FWf5 were investigated. Fucanase FWf5 was shown to catalyze the endo-type cleavage of the 1→4-O-glycosidic linkages between 2-O-sulfated α-L-fucose residues in fucoidans composed of the alternating 1→3- and 1→4-linked residues of sulfated α-L-fucose. This is the first report on the endo-1→4-α-L-fucanases (EC 3.2.1.212) of the GH168 family. The endo-fucanase FWf5 was used to selectively produce high- and low-molecular-weight fucoidan derivatives containing either regular alternating 2-O- and 2,4-di-O-sulfation or regular 2-O-sulfation. The polymeric 2,4-di-O-sulfated fucoidan derivative was shown to have significantly greater in vitro anticoagulant properties than 2-O-sulfated derivatives. The results have demonstrated a new type specificity among fucanases of the GH168 family and the prospects of using such enzymes to obtain standard fucoidan preparations with regular sulfation and high anticoagulant properties.

Abstract Identifying deforested areas with high potential for natural forest recovery can be used as an aid for ecological restoration projects at large‐scale. However, accurate predictions that infer the resilience (i.e. recovery rate after deforestation) and stability (i.e. the ability of the ecosystem to maintain its functions) of early second‐growth forests are scarce at a regional scale. Here, we investigated the effect of climate, soil and topography on the resilience and stability of 165 early second‐growth forests throughout the Brazilian Atlantic Forest. We also built prediction maps of potential resilience and stability to identify where reforestation could be optimized in the early stages of forest succession. We assessed the resilience and stability through an interannual plant primary productivity time series using a normalized difference vegetation index. Our analysis reveals that resilience was mainly associated with isothermality (i.e. diurnal temperature oscillation relative to the annual temperature oscillation) and precipitation of the warmest quarter. In turn, stability was mainly associated with the probability of bedrock occurrence, annual precipitation and precipitation seasonality. The prediction maps show a spatial pattern in which potential resilience and stability increase from north to south of the Atlantic Forest. Forest restoration can be optimized in regions with high potential resilience and stability, such as an isolated area on the north coast in the Bahia state and the southern region. However, restoration may require active practices and management in regions with low potential for both ecosystem properties, such as the north inland in the Bahia and Minas Gerais states. This ecosystemic approach can help achieve Atlantic Forest restoration commitments.

Introduction A number of epidemiologic and experimental studies have demonstrated that cadmium exposure increases the risk of cardiovascular diseases. However, it has not been investigated so far whether the cardiotoxicity of cadmium ions and cadmium oxide nanoparticles are similar. Methods Subchronic cadmium poisoning was modelled on outbred white male rats by repeated intraperitoneal injections of cadmium chloride (CdCl 2 ) solution or cadmium oxide nanoparticles (CdO NPs) 3 times a week for 6 weeks. Single doses of Cd were 0.38 and 0.22 mg Cd per kg of body weight, respectively. Results In rats of both Cd-exposed groups were found signs of hepatotoxicity and nephrotoxicity accompanied by cardiotoxic effects manifested by changes in hemodynamic parameters and myocardial contractility. The force of contractions decreased while the muscle isometric contraction–relaxation cycle of isolated myocardial preparations shortened. The change in the maximum velocity of isotonic shortening of papillary muscles correlated with change in the content of α- or β-myosin heavy chains following the exposure to CdCl 2 or CdO NPs, respectively. In the NPs-exposed rats, the mechanical work performed by cardiac muscles was found to be decreased. Conclusions We established that moderate subchronic cadmium exposure weakened the pumping function of the heart due to the cardiotoxic effects at the cellular and molecular levels. At the same time, we observed not only quantitative, but also certain qualitative differences in the cardiotoxic effects of CdCl 2 and CdO NPs, probably associated with a more expressed oxidative stress induced by nanoparticles.

The text of this article analyzes the processes of managing volunteers at social enterprises in Russia and India. Social enterprises are becoming more popular, but this type of organization remains poorly understood. Social entrepreneurship is a form of business that differs from an ordinary commercial enterprise in that. The goal of a social enterprise is not only to make a profit, but also to solve social problems. It is known that social enterprises involve volunteers in their work, however, the problems faced by representatives of social enterprises when working with volunteers are unknown. The empirical basis of the work was an online survey of representatives of social enterprises from Russia and India. These countries were chosen due to the fact that it is in Russia and India that the sector of social entrepreneurship is currently developing. The focus of our article concerned such issues: what stages of working with volunteers are implemented in social enterprises, what problems they face when working with volunteers, and what processes can help minimize difficulties in working with volunteers. Analysis of the data obtained showed that representatives of social enterprises in Russia and India are actively implementing the selection of volunteers, education and training of volunteers, and discussion of the results of work with volunteers. Among the most significant problems in working with volunteers, representatives of Russian social enterprises consider a high level of volunteer turnover and distrust of volunteers. Representatives of Indian social enterprises consider the insufficient level of training of volunteers, the high turnover of volunteers as significant problems in working with volunteers. Despite the differences in the processes of working with volunteers, representatives of social Russian and Indian enterprises believe that the training and education of specialists working with volunteers and the education and training of volunteers themselves can improve the quality of work with volunteers. The analysis of work and management of volunteers is an extremely broad topic, the text of the article covers only some of its aspects, which were studied based on the results of the survey. The results of the study can be used by researchers for further work in the field of studying the processes of working with volunteers, and the results of the study can also be useful to those who are practitioners in the field of social entrepreneurship and social enterprises.

Aim. Study the impact of various combinations of comorbid original diseases in patients infected with COVID-19 later on the disease progression and outcomes of the new coronavirus infection. Materials and methods. The ACTIV registry was created on the Eurasian Association of Therapists initiative. 5,808 patients have been included in the registry: men and women with COVID-19 treated at hospital or at home. ClinicalTrials.gov ID NCT04492384. Results. Most patients with COVID-19 have original comorbid diseases (oCDs). Polymorbidity assessed by way of simple counting of oCDs is an independent factor in negative outcomes of COVID-19. Search for most frequent combinations of 2, 3 and 4 oCDs has revealed absolute domination of cardiovascular diseases (all possible variants). The most unfavorable combination of 2 oCDs includes atrial hypertension (AH) and chronic heart failure (CHF). The most unfavorable combination of 3 oCDs includes AH, coronary heart disease (CHD) and CHF; the worst combination of 4 oCDs includes AH, CHD, CHF and diabetes mellitus. Such combinations increased the risk of lethal outcomes 3.963, 4.082 and 4.215 times respectively. Conclusion. Polymorbidity determined by way of simple counting of diseases may be estimated as a factor in the lethal outcome risk in the acute phase of COVID-19 in real practice. Most frequent combinations of 2, 3 and 4 diseases in patients with COVID-19 primarily include cardiovascular diseases (AH, CHD and CHF), diabetes mellitus and obesity. Combinations of such diseases increase the COVID-19 lethal outcome risk.