Search

This study was designed to increase our understanding about characteristics and the impact of sensory symptoms (SS) and signs of hyperarousal (HA) in individuals with fragile X syndrome (FXS) from childhood through early adulthood and by gender. Data derived from the Fragile X Online Registry With Accessible Research Database (FORWARD), a natural history study of FXS, were analyzed using descriptive statistics and multivariate linear and logistic regression models to examine SS and signs of HA, their impact on behavioral regulation and limitations on the subject/family. The sample (N = 933) consisted of 720 males and 213 females. More males were affected with SS (87% vs. 68%) and signs of HA (92% vs. 79%). Subjects who were endorsed as having a strong sensory response had more comorbidities, including behavioral problems. The predominant SS was difficulty with eye gaze that increased with age in both genders. As individuals age, there was less use of non-medication therapies, such as occupational therapy (OT)/physical therapy (PT), but there was more use of psychopharmacological medications and investigational drugs for behaviors. Multiple regression models suggested that endorsing SS and signs of HA was associated with statistically significantly increased ABC-C-I subscale scores and limited participation in everyday activities. This study improves our understanding of SS and signs of HA as well as their impact in FXS. It supports the need for more research regarding these clinical symptoms, especially to understand how they contribute to well-known behavioral concerns.

The direct search for dark matter in the form of weakly interacting massive particles (WIMP) is performed by detecting nuclear recoils produced in a target material from the WIMP elastic scattering. The experimental identification of the direction of the WIMP-induced nuclear recoils is a crucial asset in this field, as it enables unmistakable modulation signatures for dark matter. The Recoil Directionality (ReD) experiment was designed to probe for such directional sensitivity in argon dual-phase time projection chambers (TPC), that are widely considered for current and future direct dark matter searches. The TPC of ReD was irradiated with neutrons at the INFN Laboratori Nazionali del Sud. Data were taken with nuclear recoils of known directions and kinetic energy of 72 keV, which is within the range of interest for WIMP-induced signals in argon. The direction-dependent liquid argon charge recombination model by Cataudella et al. was adopted and a likelihood statistical analysis was performed, which gave no indications of significant dependence of the detector response to the recoil direction. The aspect ratio R of the initial ionization cloud is R < 1.072 with 90 % confidence level. [ABSTRACT FROM AUTHOR]

Abstract Background Recovery from acute COVID-19 may be slow and incomplete: cases of Post-Acute Sequelae of COVID (PASC) are counted in millions, worldwide. We aimed to explore if and how the pre-existing Socio-economic-status (SES) influences such recovery. Methods We analyzed a database of 1536 consecutive patients from the first wave of COVID-19 in Italy (February-September 2020), previously admitted to our referral hospital, and followed-up in a dedicated multidisciplinary intervention. We excluded those seen earlier than 12 weeks (the conventional limit for a possible PASC syndrome), and those reporting a serious complication from the acute phase (possibly accounting for symptoms persistence). We studied whether the exposition to disadvantaged SES (estimated through the Italian Institute of Statistics’s model – ISTAT 2017) was affecting recovery outcomes, that is: symptoms (composite endpoint, i.e. at least one among: dyspnea, fatigue, myalgia, chest pain or palpitations); Health-Related-Quality-of-Life (HRQoL, as by SF-36 scale); post-traumatic-stress-disorder (as by IES-R scale); and lung structural damage (as by impaired CO diffusion, DLCO). Results Eight-hundred and twenty-five patients were included in the analysis (median age 59 years; IQR: 50–69 years, 60.2% men), of which 499 (60.5%) were previously admitted to hospital and 27 (3.3%) to Intensive-Care Unit (ICU). Those still complaining of symptoms at follow-up were 337 (40.9%; 95%CI 37.5–42.2%), and 256 had a possible Post-Traumatic Stress Disorder (PTSD) (31%, 95%CI 28.7–35.1%). DLCO was reduced in 147 (19.6%, 95%CI 17.0–22.7%). In a multivariable model, disadvantaged SES was associated with a lower HRQoL, especially for items exploring physical health (Limitations in physical activities: OR = 0.65; 95%CI = 0.47 to 0.89; p = 0.008; AUC = 0.74) and Bodily pain (OR = 0.57; 95%CI = 0.40 to 0.82; p = 0.002; AUC = 0.74). We did not observe any association between SES and the other outcomes. Conclusions Recovery after COVID-19 appears to be independently affected by a pre-existent socio-economic disadvantage, and clinical assessment should incorporate SES and HRQoL measurements, along with symptoms. The socioeconomic determinants of SARS-CoV-2 disease are not exclusive of the acute infection: this finding deserves further research and specific interventions.

Teesid: Tõukudes juba kolmandat aastat käivast sõjast Ukrainas, millele eesti autorid on reageerinud kiiresti ja erksa meelega, võtab artikkel vaatluse alla sõjateema kajastuse eesti algupärases laste- ja noortekirjanduses läbi aegade. Alates kõige varasematest juturaamatutest 18./19. sajandi vahetusel, mis sisaldavad tekste sõjaväeteenistusse saadetud noormeestest, kuni kõige uuemate sõjast rääkivate pildiraamatuteni 2023. aastast annab artikkel kronoloogilise ülevaate lastele ja noortele suunatud teostest, mis kujutavad sõda, okupatsioone, revolutsioone või mõnd muud militaarse iseloomuga sündmust ning nendega seotud aspekte. Artikkel keskendub valdavalt eraldi kaante vahel ilmunud teostele, mis moodustavad vaid ühe osa mahukast tekstikorpusest, toob välja algupärases sõjateemalises laste- ja noortekirjanduses kõige enam kasutatud ainestikud ja motiivid ning loetleb sõjateema edasise uurimise võimalusi. The article gives a historical overview of war-themed texts in Estonian children’s and youth literature. The choice of the research topic is motivated by Russia’s military invasion of Ukraine in February 2022, which also changed the sense of security in our region. It has also prompted children’s and young adult writers to reflect on war and peace, resistance and cooperation, justice and injustice in a form that is appropriate and comprehensible to young readers. From the earliest storybooks at the turn of the 19th century, which include texts about young men conscripted into military service, to the most recent picture books about war from 2023, the article provides a chronological overview of works for children and young people depicting war, occupation, revolution or other events of a military nature and their related aspects. The article looks at works published mainly in book form, covering only part of a large corpus of texts. Texts published in journals, story collections, anthologies, school textbooks and elsewhere have been excluded for reasons of space. The theme of war in Estonian children’s and youth literature has become topical in connection with the turning points in Estonian history (revolutions, wars, occupations), and also bears the ideological signs of the time. However, as early as the 19th century, during the period of national awakening, national mythological and romantic material (the ancient struggle for freedom and the so-called Lembitu line; the so-called Jüriöö text) was introduced into literature, and has remained topical to the present day. The theme of war has been used more in periods when it was important to strengthen the nation’s sense of unity (the Republic of Estonia before the Second World War) or to justify regime change and new ideology (Soviet Estonia). Texts published in these periods stand out for their strong combative or combative-propagandist stance, strong and/or ideologised characters, sharp confrontations, realistic depictions of violence and death. The war texts that have appeared in free society in the last few decades are predominantly childhood memoirs of a long-ago war or occupation, although they are still generally told in an exclusionary, fragmented way through a narrative of silence. The trauma narrative has not been as topical in Estonian children’s and young people’s war literature as it has been in Western literature in recent decades. In Estonian children’s and young adult literature, most of the war stories are realistic, with human characters and real or possible situations, with only a few animal tales. To a large extent, the way a story is presented depends on the theme, genre and the age of the reader of the text. The majority of war stories are written by men, while women’s voices can be heard in memoirs, fairy tales and, to a lesser extent, folk mythological histories. Most of the works have an autobiographical background, i.e. the writers have themselves participated in the war and/or lived under occupation. This leads to a situation in which male characters are in the foreground and the events are characterised by adventures, intense confrontations and action. Girls came to Estonian children and young people’s war literature during the over-militarised Soviet era. Although writing about war is the most difficult and problematic for young children, both from an age and education point of view, there is literature for them (picture books, books about war games). War-themed texts in Estonian children’s and youth literature mainly pursue educational aims (stories of masculinisation, stories of cooperation, presentations of Estonian history in exile, reminiscences of tragic times in contemporary memoirs), but in certain periods political (the period of the Estonian Republic, exile) and ideological aims (Soviet Estonia) have been more prominent. The article outlines the most frequently used themes and motifs in Estonian children’s and young adult literature on war and lists possibilities for further research on war.

This paper presents a technique that can potentially help to determine the receptivity stage of the endometrium from histology images by automatically measuring the stromal nuclear changes. The presented technique is composed of an image segmentation model and the statistical evolution of segmented areas in hematoxylin and eosin (HE)-stained histology images. Three different endometrium receptivity stages, namely pre-receptive, post-receptive, and receptive, were compared. An ensemble-based AI model was proposed for histology image segmentation, which is based on individual UNet++, UNet, and ResNet34-UNet segmentation models. The performance of the ensemble-based technique was assessed using the Dice score and intersection over unit (IoU) values. In comparison to alternative segmentation architectures that were applied singly, the current ensemble-based method obtained higher Dice score (0.95) and IoU (0.90) values. The statistical comparison highlighted a noticeable difference in the number of nuclei and the size of the stroma tissue. The proposed technique demonstrated the positive potential for practical implementation for automatic endometrial tissue analysis.

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.

Background: The SCN5A gene polymorphism histidine-558-to-arginine (H558R) has been associated with atrial fibrillation (AF) and may affect the therapeutic effects of flecainide. This study aimed to assess the prevalence of the H558R polymorphism in a European cohort of patients with AF and examine its association with flecainide's effects on AF recurrence and toxicity., Methods: This cohort study included patients diagnosed with AF and prescribed flecainide between 2017 and 2021 in a regional health area. Patients without the polymorphism (H558R-/-) were compared with heterozygous patients (H558R+/-) for a primary outcome of combined 6-month AF recurrence or toxicity. Secondary analyses evaluated the long-term outcomes and compared the prevalence of H558R in the AF cohort to a general population sample (n=3401)., Results: A total of 104 patients were enrolled, with 57% H558R-/-, 37% H558R+/- and 6% H558R+/+. The prevalence of the H558R polymorphism was significantly higher in the AF cohort than in the general population (43.27% vs 24.37%, prevalence ratio 1.78, 95% CI 1.41 to 2.23, p<0.01). H558R+/- patients had a significantly lower risk of 6-month AF recurrence or toxicity (p=0.023, risk ratio 0.423, 95% CI 0.189 to 0.947), corresponding to an absolute risk difference of 21.5%. These findings were similar in the multivariable analysis. In long-term follow-up, H558R+/- patients continued to demonstrate a lower risk of AF recurrence or toxicity (p=0.039, HR 0.53, 95% CI 0.276 to 0.999)., Conclusions: The H558R polymorphism is more prevalent in patients with AF compared with the general population and its presence is associated with a more favourable response to flecainide treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Covering: 1970 through June of 2023Verticillins are epipolythiodioxopiperazine (ETP) alkaloids, many of which possess potent, nanomolar-level cytotoxicity against a variety of cancer cell lines. Over the last decade, their in vivo activity and mode of action have been explored in detail. Notably, recent studies have indicated that these compounds may be selective inhibitors of histone methyltransferases (HMTases) that alter the epigenome and modify targets that play a crucial role in apoptosis, altering immune cell recognition, and generating reactive oxygen species. Verticillin A (1) was the first of 27 analogues reported from fungal cultures since 1970. Subsequent genome sequencing identified the biosynthetic gene cluster responsible for producing verticillins, allowing a putative pathway to be proposed. Further, molecular sequencing played a pivotal role in clarifying the taxonomic characterization of verticillin-producing fungi, suggesting that most producing strains belong to the genus Clonostachys ( i.e. , Bionectria ), Bionectriaceae. Recent studies have explored the total synthesis of these molecules and the generation of analogues via both semisynthetic and precursor-directed biosynthetic approaches. In addition, nanoparticles have been used to deliver these molecules, which, like many natural products, possess challenging solubility profiles. This review summarizes over 50 years of chemical and biological research on this class of fungal metabolites and offers insights and suggestions on future opportunities to push these compounds into pre-clinical and clinical development.

Eupenifeldin (1) is a fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A series of ester (2-6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-30) analogues of 1 were generated via 22 reactions. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained. The cytotoxic activities of 1-30 were evaluated against human melanoma and ovarian cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of 1 (i.e., 2-8) maintained cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue (6), which was acylated on the secondary hydroxy at the 11 position., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicholas Oberlies reports a relationship with Mycosynthetix Inc that includes: board membership. Nicholas Oberlies reports a relationship with Clue Genetics Inc that includes: board membership. Nicholas Oberlies reports a relationship with Ionic Pharmaceuticals LLC that includes: board membership. Cedric Pearce reports a relationship with Clue Genetics Inc that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The many diverse polymorphic behaviors observed in organic electronic materials offer opportunities to modulate electronic properties through reversibly switching crystal structures. Here, we access the prolific polymorphism observed in two-dimensional quinoidal terthiophene via laser writing to locally heat and direct the phase transitions. We access a metastable polymorph IV through rapid cooling and observe distinct symmetry as well as packing through grazing incidence X-ray diffraction (GIXD). Using our open-source PolyChemPrint patterning platform, we direct laser heating to initiate the IV-I transition, switching the conductance by >2 orders of magnitude. This is confirmed via a combination of GIXD and Raman spectroscopy. Finally, we demonstrate switching of transistor devices as well as discrete tuning of conductance via laser writing.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms of dementia. The limited efficacy of drugs for the treatment of neurodegenerative diseases reflects their complex etiology and pathogenesis. A novel in vitro model may help to bridge the gap between existing preclinical animal models and human clinical trials, thus identifying promising therapeutic targets that can be explored in upcoming clinical trials. By assisting in the identification of the mechanism of action and potential dangers, in vitro testing can also shorten the time and expense of translation., Aim: As a result of these factors, our objective is to develop a powerful and informative cellular model of AD within a short period of time. Through triggering the MAPK and NF-κβ signaling pathways with the aid of small chemical compounds (PAF C-16 and BetA), respectively, in mouse microglial (SIM-A9) and neuroblast Neuro-2a (N2a) cell lines., Results: PAF C-16, initiated an activation effect at a concentration of 3.12 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. BetA, activated the NF-κβ pathway with a concentration of 12.5 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. The combination of the activator chemicals provided suitable activation for MEK1/2-ERK and NF-κβ in more than three subcultures. Activators significantly initiate APP and MAPT gene expression, as well as the expression of proteins APP, β. Amyloid, tau, and p-tau. The activation of the targeted pathways leads to significant morphological changes., Conclusion: We can infer that the MEK1/2-ERK and NF-κβ pathways, respectively, are directly activated by the PAF C-16 and BetA chemicals. The activation of MEK1/2-ERK pathway results in the activation of the APP gene, which in turn activates the β. Amyloid protein, which in turn results in plaque. Furthermore, NF-κβ activation results in the activation of the MAPT gene, which leads to Tau and p-Tau protein activation, which ultimately results in tangles. This can be put into practice in just three days, with a high level of activity and stability that is passed down to the next three generations (subculture), with significant morphological changes. In microglial and neuroblast cell lines, we were successful in creating a novel AD-cell model., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This work focused on the translation and evaluation of the psychometric properties of two widely used scales for assessing sense of purpose in life - the Revised Sense of Purpose Scale (SOPS-2) and the Specific Purpose Orientations (SPO) scale - in the Ukrainian language. The SOPS-2 consisted of 14 items measuring three dimensions of purpose: awakening to purpose, awareness of purpose, and altruistic purpose. Meanwhile, the SPO included 12 items assessing three types of purpose: others-growth, self-growth, and career-focused purpose orientations. Renamed as the Revised Sense of Purpose Scale - Ukrainian Version (SOPS-2U) and the Specific Purpose Orientations - Ukrainian Version (SPO-U), these two scales underwent a thorough translation process by two multilingual scholars proficient in both Ukrainian and English languages, employing the committee approach. Then through analyses of two datasets, the factorial validity, construct validity, and reliability of the SOPS-2U and SPO-U were established. These translated scales provide reliable and valid tools for assessing life purpose among Ukrainian-speaking adults.•Recognizing the profound impact of life purpose on adult wellbeing, the availability of a psychometrically robust measurement tool for assessing this construct in the Ukrainian language becomes crucial; thus, we translated and validated two such tools.•The Revised Sense of Purpose Scale - Ukrainian Version (SOPS-2U) is valid for assessing awakening to purpose, awareness of purpose, and altruistic purpose dimensions in Ukrainian adults.•The Specific Purpose Orientations - Ukrainian Version (SPO-U) can be used with Ukrainian adults to further examine the specific types of purpose, such as others-growth, self-growth, and career-focused purpose orientations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Type 2 diabetes (T2D) is a widespread health condition both in the United States and around the world, with insulin resistance playing a critical role in its development. Effective treatment strategies are essential for managing T2D and mitigating associated risks. Adiponectin (APN), secreted by adipocytes, exhibits an inverse correlation with obesity-related adiposity, and its levels are negatively associated with insulin resistance and body mass index. This study aimed to enhance endogenous APN levels in a diet-induced obese (DIO) mouse model using lipid nanoparticles (LNP) as safe delivery agents for APN mRNA conjugates. The results indicate that APN-mRNA-LNP administration successfully induced APN synthesis in various tissues, including muscle, liver, kidney, pancreas, and adipose cells. This induction was associated with several positive outcomes, such as preventing diet-induced body weight gain, improving hyperglycemia by promoting Glut-4 expression, alleviating diabetic nephropathy symptoms by blocking the EGFR pathway, and reducing pro-inflammatory cytokine production. In addition, the treatment demonstrated enhanced insulin sensitivity by activating DGKd and inhibiting PKCε. This resulted in reactivation of insulin receptors in insulin target tissues and stimulation of insulin secretion from pancreatic beta cells. The findings of the present study highlight the potential of APN-mRNA-LNP-based nucleic acid therapy as a treatment for type 2 diabetes, offering a comprehensive approach to addressing its complexities.

The aim of this study was to translate the Flourishing Scale, which is a brief 8-item measure, into Ukrainian and examine its construct validity. The Flourishing Scale has been previously validated into various languages, including Russian. While Ukrainian is a distinct language with its unique characteristics, it shares some similarities with Russian due to historical and geographical connections. These similarities encompass words with similar or related meanings, comparable sentence structures, and certain cultural references and idiomatic expressions. Accordingly, the Ukrainian version of the Flourishing Scale was developed based on the Russian version. The translation process involved two proficient researchers fluent in Ukrainian, English, and Russian. Following the committee approach, one researcher conducted the initial translation, while the other ensured the accuracy and linguistic equivalence of the translated items. The eight items were pilot-tested with Ukrainian-speaking adult participants. Results from confirmatory factor analysis indicated that the Ukrainian version of the Flourishing Scale showed evidence of construct validity and reliability, thereby resulting in a tool that can be used with Ukrainian adults to further examine their flourishing.•The Flourishing Scale was translated into Ukrainian and pilot-tested to assess it psychometric properties.•Results indicated good construct validity and reliability of the Ukrainian version of the Flourishing Scale., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Some of the most complex surgical interventions to treat trauma and cancer include the use of locoregional pedicled and free autologous tissue transfer flaps. While the techniques used for these reconstructive surgery procedures have improved over time, flap complications and even failure remain a significant clinical challenge. Animal models are useful in studying the pathophysiology of ischemic flaps, but when repeatability is a primary focus of a study, conventional in-vivo designs, where one randomized subset of animals serves as a treatment group while a second subset serves as a control, are at a disadvantage instigated by greater subject-to-subject variability. Our goal was to provide a step-by-step methodological protocol for creating an alternative standardized, more economical, and transferable pre-clinical animal research model of excisional full-thickness wound healing following a simulated autologous tissue transfer which includes the primary ischemia, reperfusion, and secondary ischemia events with the latter mimicking flap salvage procedure., Results: Unlike in the most frequently used classical unilateral McFarlane's caudally based dorsal random pattern skin flap model, in the herein described bilateral epigastric fasciocutaneous advancement flap (BEFAF) model, one flap heals under normal and a contralateral flap-under perturbed conditions or both flaps heal under conditions that vary by one within-subjects factor. We discuss the advantages and limitations of the proposed experimental approach and, as a part of model validation, provide the examples of its use in laboratory rat (Rattus norvegicus) axial pattern flap healing studies., Conclusions: This technically challenging but feasible reconstructive surgery model eliminates inter-subject variability, while concomitantly minimizing the number of animals needed to achieve adequate statistical power. BEFAFs may be used to investigate the spatiotemporal cellular and molecular responses to complex tissue injury, interventions simulating clinically relevant flap complications (e.g., vascular thrombosis) as well as prophylactic, therapeutic or surgical treatment (e.g., flap delay) strategies in the presence or absence of confounding risk factors (e.g., substance abuse, irradiation, diabetes) or favorable wound-healing promoting activities (e.g., exercise). Detailed visual instructions in BEFAF protocol may serve as an aid for teaching medical or academic researchers basic vascular microsurgery techniques that focus on precision, tremor management and magnification., (© 2024. The Author(s).)