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Background: Trazodone, an antidepressant drug is also largely used in several medical contexts. Insomnia, behavioral disorders, and anxiety may be underlying symptoms for prescribing trazodone. This cross‐sectional study aims to identify reasons for trazodone prescription, assess the efficacy, as well as identify any related side effects in older persons living in long term care facilities (LTCFs). Methods: Older adults aged ≥ 60 years, at risk of or affected with Covid‐19 and enrolled in the GeroCovid Observational study from LTCFs, and using trazodone were included. A structured questionnaire was administered to treating physicians regarding reasons for trazodone prescription, discontinuation, possible adverse events and benefits. Results: Thirty‐seven out 74 LTCFs participating in both the GeroCovid and GeroCovid Vax studies completed the questionnaire regarding trazodone use. Of the 427 participants included in this study analysis, we found that 43% had diagnoses of dementia and depression, 33% had dementia, no behavioral and psychological symptoms of dementia (BPSD) and no depression, 14% had dementia with BPSD and no depression, and < 11% had only depression. The main reasons for trazodone prescription included agitation, insomnia, depression and anxiety. Trazodone use was reported as partially or totally effective in more than 90% of participants using the drug. Falls were the most frequent adverse event (30% of participants). Conclusions: Our data suggest that trazodone behaves as an eclectic antidepressant that, in the clinical practice, may also be used for BPSD and insomnia, especially in older people with dementia. [ABSTRACT FROM AUTHOR]

Noncanonical amino acids (ncAAs) for photo‐ and chemical crosslinking are powerful biochemical tools for studying and manipulating interactions between proteins both in vitro and in intact cells. Since the first crosslinking ncAAs were genetically encoded about 20 years ago, the technology has now ripened beyond the proof‐of‐principle demonstrations and is contributing to the study of relevant biological questions in the frame of modern integrative approaches. Here, we provide an overview of available photo‐activatable ncAAs for photo‐crosslinking and electrophilic ncAAs for genetically encoded chemical crosslinking (GECX), with a major focus on the most recent entries such as ncAAs for SuFEx click chemistry and photo‐activatable ncAAs for chemical crosslinking. We present recent examples of the application of genetically encoded crosslinkers to capture protein–protein interactions and identify interaction partners in live cells, to investigate molecular mechanisms of protein function, to stabilize protein complexes for structural studies, to derive structural information about protein complexes from the physiological cell environment, up to perspective applications of GECX‐ncAAs for the development of covalent drugs. [ABSTRACT FROM AUTHOR]

Small‐Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC‐A and SCLC‐N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E‐box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2, INSM1, MYC, and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles's heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor. Synopsis: SCLCs poorly respond to current treatments, underlying the need for new therapeutic strategies. This study reports how the DNA binder lurbinectedin benefits from the SCLC cells transcription addiction to block the transcriptional program of key transcription factors involved in disease progression. ASCL1 and NEUROD1 target their E‐box cognate sequence and control the expression of a large number of genes in SCLC.Lurbinectedin, a marine alkaloid, targets the central G rich triplets found in CpG islands mainly located downstream from the genes transcription start site.Lurbinectedin binding abolishes the expression of ASCL1 and NEUROD1 target genes, such as INSM1, MYC, MYB and BCL2.Blocking ASCL1 and NEUROD1 transcriptional program drives SCLC cells towards programmed cell death and deeply impacts tumorigenesis. [ABSTRACT FROM AUTHOR]

The binding mode of natural peptide ligands to the Y5 G protein‐coupled receptor (Y5R), an attractive therapeutic target for the treatment of obesity, is largely unknown. Here, we apply complementary biochemical and computational approaches, including scanning of the receptor surface with a genetically encoded crosslinker, Ala‐scanning of the ligand and double‐cycle mutagenesis, to map interactions in the ligand‐receptor interface and build a structural model of the NPY‐Y5R complex guided by the experimental data. In the model, the carboxyl (C)‐terminus of bound NPY is placed close to the extracellular loop (ECL) 3, whereas the characteristic α‐helical segment of the ligand drapes over ECL1 and is tethered towards ECL2 by a hydrophobic cluster. We further show that the other two natural ligands of Y5R, peptide YY (PYY) and pancreatic polypeptide (PP) dock to the receptor in a similar pose. [ABSTRACT FROM AUTHOR]

Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal‐like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic‐type melanoma cells into mesenchymal‐like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal‐type signature, we identify a GATA6‐dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic‐type cells. We show that GATA6 expression is activated in MITF‐low melanoma cells of patient‐derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma. Synopsis: The repressive function of the melanocyte lineage transcription factor MITF participates in a molecular cascade, involving the CDK7 kinase, regulating the activation of a transcriptional program involved in survival and drug resistance of melanoma cells. Inhibition of CDK7 induces dedifferentiation of proliferative melanoma cells and tolerance to targeted therapies.Dedifferentiated cells show GATA6‐dependent gene expression promoting melanoma survival or drug tolerance.CDK7 drives expression of MITF that binds to an intron of GATA6 to repress its expression in melanocytic‐type cells. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to report relief of optokinetic‐triggered vertigo (OKTV) with low‐dose gabapentin in three patients with periodic vestibulocerebellar ataxia [episodic ataxia type 4 (EA4); OMIM 606552]. Methods: Clinical observations and analysis of video‐recorded eye movements were used before and after gabapentin. Results: Gabapentin relieved vertigo of all three treated patients with EA4, particularly during activities that typically would induce vertiginous symptoms. Two patients reported 8–12 hours of sustained relief after the first 100 mg dose. One has benefited from 100–200 mg TID for 7 years. Video analysis of nystagmus revealed improved target tracking on smooth pursuit and a steadier gaze hold. Conclusions: Gabapentin effectively relieved the optokinetic‐triggered vertigo in our patients with EA4. Mechanisms are postulated in terms of known tight gabapentin binding to the Purkinje cell voltage‐gated calcium channel. The observations may offer insight into this rare disease's neuropathology. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Arrestins (arr) are multifunctional cytosolic adaptors that bind to active and phosphorylated G protein‐coupled receptors (GPCRs) via a highly versatile interface. Arrestins stop G protein signaling and trigger other signaling pathways. Recently, 3D structures of arr–GPCR complexes have been solved, which provide a bulk of structural information for understanding the mechanism of arr recruitment and activation. However, many questions about the functional consequences of structural details and the dynamics of the arr–GPCR interaction remain open. A wealth of information about key determinants for the arr–GPCR interaction and their functional relevance, and dynamic insights into the process of arr binding and the functional outcomes of different binding modes have been provided by a series of biochemical methods which we review here. Importantly, most of these methods provide information from the live cell, which is a necessary validation and complement for structural data. With the main focus on the most recent research, we will highlight major findings about arr structure, function, and dynamics derived from mutagenesis studies, cross‐linking studies, conformational probes, and sensors, and we summarize available systems to detect arr recruitment. Furthermore, we discuss recent findings and directions of in silico investigations in arr–GPCR complexes. [ABSTRACT FROM AUTHOR]

2‐iminothiazolidines are important scaffold for pharmaceutical drugs. Herein, we describe a fast and easy procedure for their synthesis by a telescoping reaction integrating an iron‐catalyzed nitrene transfer under mild conditions. The aziridination reaction of olefins is followed by the domino ring‐opening cyclization (DROC) of the aziridine intermediates with organic isothiocyanates catalyzed by a Lewis acid leading to the desired product. This new synthetic route allows time, step and purification economies, which is in agreement with the development of more efficient processes for the synthesis of small molecules. [ABSTRACT FROM AUTHOR]

β‐arrestins (βarr1 and βarr2) are ubiquitous regulators of G protein‐coupled receptor (GPCR) signaling. Available data suggest that β‐arrestins dock to different receptors in different ways. However, the structural characterization of GPCR‐arrestin complexes is challenging and alternative approaches to study GPCR‐arrestin complexes are needed. Here, starting from the finger loop as a major site for the interaction of arrestins with GPCRs, we genetically incorporate non‐canonical amino acids for photo‐ and chemical crosslinking into βarr1 and βarr2 and explore binding topologies to GPCRs forming either stable or transient complexes with arrestins: the vasopressin receptor 2 (rhodopsin‐like), the corticotropin‐releasing factor receptor 1, and the parathyroid hormone receptor 1 (both secretin‐like). We show that each receptor leaves a unique footprint on arrestins, whereas the two β‐arrestins yield quite similar crosslinking patterns. Furthermore, we show that the method allows defining the orientation of arrestin with respect to the GPCR. Finally, we provide direct evidence for the formation of arrestin oligomers in the cell. Synopsis: Chemical and photo‐crosslinkers genetically incorporated into β‐arrestins allow the mapping of footprints of different receptors on the arrestin surface in living cells, and to identify intermolecular pairs of proximal amino acids in GPCR‐arrestin complexes. Genetically encoded crosslinkers can capture arrestin‐GPCR interactions with high spatial precision.Each G protein‐coupled receptor leaves a unique footprint on arrestins.Arrestins βarr1 and βarr2 may bind to a GPCR in a similar way. [ABSTRACT FROM AUTHOR]

Aim: We investigated the associations of the single‐nucleotide polymorphism rs1080985 of cytochrome P4502D6 (CYP2D6) and the apolipoprotein E (APOE) genotypes with cognitive and functional changes in patients treated with donepezil. Methods: Sixty‐five outpatients with Alzheimer's disease or mixed dementia being treated with donepezil were assessed at baseline and over 27 months. Changes in cognitive status, assessed with the Mini‐Mental State Examination, and in functional status, assessed by the Activities of Daily Living Scale and the Instrumental Activities of Daily Living Scale, were evaluated as a function of CYP2D6 and APOE genotypes by using linear mixed models. Multiplicative interactions between the CYP2D6 and APOE genotypes and time were investigated. Results: Individuals with the mutated CYP2D6 exhibited a slower decline in total Mini‐Mental State Examination scores, orientation, registration, and functional status than those with the wild type. A significant interaction between CYP2D6, APOE, and time was found for changes in the Activities of Daily Living Scale; among the ε4 carriers, those with the mutated CYP2D6 exhibited a slower decline on the Activities of Daily Living Scale than those with the wild type. Conclusion: The CYP2D6 and APOE genotypes may modulate the effectiveness of donepezil on cognitive and functional status. [ABSTRACT FROM AUTHOR]

Palatoschisis (also called cleft palate, CP) is an opening or cleft in the upper lip, the roof of the palate, or both, and is a common defect in both humans and domestic animals (Mossey & Modell, [4]; Mulvihill et al., [5]). Inherited forms of I MYH3 i -related human syndromes, including cleft palate, are known (OMIM 160720). The affected gene, I MYH3 i , encodes the myosin heavy chain 3 protein, which is known to be responsible for muscle contraction. [Extracted from the article]

As part of our effort to improve our understanding of aziridination mechanism, we used tetra substitution of a diphenol ligand to modify the redox properties of corresponding Fe complexes. This allowed us to confirm that aziridination catalysis by Fe‐based complexes is governed by electron affinity of the active species and further show that it correlates with the FeIII/FeII redox potential. [ABSTRACT FROM AUTHOR]

The development of iron catalysts for carbon-heteroatom bond formation, which has attracted strong interest in the context of green chemistry and nitrene transfer, has emerged as the most promising way to versatile amine synthetic processes. A diiron system was previously developed that proved efficient in catalytic sulfimidations and aziridinations thanks to an FeIIIFeIV active species. To deal with more demanding benzylic and aliphatic substrates, the catalyst was found to activate itself to a FeIIIFeIVL. active species able to catalyze aliphatic amination. Extensive DFT calculations show that this activation event drastically enhances the electron affinity of the active species to match the substrates requirements. Overall this process consists in a redox self-adaptation of the catalyst to the substrate needs. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias ( SCA) are autosomal dominant neurodegenerative disorders that affect the cerebellum and its connections, and have a marked clinical and genetic variability. Machado-Joseph disease ( MJD) or spinocerebellar ataxia type 3 ( SCA3)- MJD/ SCA3-is the most common SCA worldwide. MJD/ SCA3 is characterized classically by progressive ataxia and variable other motor and non-motor symptoms. Sleep disorders are common, and include rapid eye movement ( REM) sleep behaviour disorder ( RBD), restless legs syndrome ( RLS), insomnia, excessive daytime sleepiness, excessive fragmentary myoclonus and sleep apnea. This study aims to focus upon determining the presence or not of non- REM ( NREM)-related parasomnias in MJD/ SCA 3, using data from polysomnography ( PSG) and clinical evaluation. Forty-seven patients with clinical and genetic diagnosis of MJD/ SCA3 and 47 control subjects were evaluated clinically and by polysomnography. MJD/ SCA3 patients had a higher frequency of arousals from slow wave sleep ( P < 0.001), parasomnia complaints (confusional arousal/sleep terrors, P = 0.001; RBD, P < 0.001; and nightmares, P < 0.001), REM sleep without atonia ( P < 0.001), periodic limb movements of sleep index ( PLMSi) ( P < 0.001), percentage of N3 sleep ( P < 0.001) and percentage of N1 sleep ( P < 0.001). These data show that NREM-related parasomnias must be included in the spectrum of sleep disorders in MJD/ SCA3 patients. [ABSTRACT FROM AUTHOR]

Objective Both glucagon-like peptide-1 ( GLP-1) and peptide YY ( PYY) are gut hormones involved in energy homoeostasis. Obesity, insulin resistance and hyperglycaemia are significant confounders when GLP-1 and PYY secretion is assessed. Thus, we evaluated GLP-1 and PYY response after fat load in morbidly obese patients with different degrees of insulin resistance and glycemic status. Design We studied 40 morbidly obese subjects (mean age, 40·6 ± 1·3 years; mean BMI, 53·1 ± 1·2 kg/m2) divided into groups according to their glycemic status: normal fasting glucose ( NFG) group, impaired fasting glucose ( IFG) group and type 2 diabetes mellitus ( T2 D) group. NFG patients were additionally subclassified, according to the homoeostasis model assessment of insulin resistance ( HOMAIR), into a low insulin-resistance ( LIR) group ( HOMAIR <3·9) or a high insulin-resistance ( HIR) group ( HOMAIR ≥3·9). Measurements Lipid emulsion was administered orally and measurements made at baseline and 180 min postprandially of levels of GLP-1, PYY, insulin, glucose, free fatty acids, triglycerides and leptin. Results At the 180-minute postprandial reading, GLP-1 and PYY had increased in LIR- NFG subjects (41·84%, P = 0·01; 35·7%, P = 0·05; respectively), whereas no changes were observed in HIR- NFG, IFG or T2 D subjects. Conclusions These results suggest that in morbidly obese subjects, both insulin resistance and abnormal glucose metabolism ( IFG or T2 D) impair the GLP-1 and PYY response to fat load. The implications of this attenuated enteroendocrine response should be elucidated by further studies. [ABSTRACT FROM AUTHOR]

Nucleotide excision repair (NER) is a precisely coordinated process essential to avoid DNA damage-induced cellular malfunction and mutagenesis. Here, we investigate the mechanistic details and effects of the NER machinery when it is compromised by a pathologically significant mutation in a subunit of the repair/transcription factor TFIIH, namely XPD. In contrast to previous studies, we find that no single- or double-strand DNA breaks are produced at early time points after UV irradiation of cells bearing a specific XPD mutation, despite the presence of a clear histone H2AX phosphorylation (?H2AX) signal in the UV-exposed areas. We show that the observed ?H2AX signal can be explained by the presence of longer single-strand gaps possibly generated by strand displacement. Our in vivo measurements also indicate a strongly reduced TFIIH-XPG binding that could promote single-strand displacement at the site of UV lesions. This finding not only highlights the crucial role of XPG's interactions with TFIIH for proper NER, but also sheds new light on how a faulty DNA repair process can induce extreme genomic instability in human patients. [ABSTRACT FROM AUTHOR]

We undertook a candidate locus study of the HIN200 gene cluster on 1q21-23 in UK systemic lupus erythematosus (SLE) families. To date, despite mounting evidence demonstrating the importance of these proteins in autoimmune disease, cancer, apoptosis, inflammation, and cell cycle arrest, there has been a dearth of data with respect to the genetic characterisation of the HIN200 locus in SLE or any other disease. We typed 83 single nucleotide polymorphisms (SNPs) across 317 kb of the HIN200 cluster in 428 UK SLE families and sought replication from a European-American lupus cohort. We do not find strong evidence of SNP association in either cohort. Interestingly, we do observe a trend for association with certain HIN200 SNPs and serologic subphenotypes in UK SLE that parallels the association of lupus antibodies with the orthologous murine locus. Furthermore, we find the HIN200 locus to be unexpectedly complex in terms of genetic structural organisation. We have identified a number of copy number variants (CNVs) in this region in healthy French males, HapMap samples, and UK SLE families. In summary, candidate interferon signalling genes show evidence of common CNV in human SLE and healthy subjects. The impact of these CNVs in health and disease remains to be determined. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a common and often misdiagnosed entity among the general population and it may be more common among dialysis patients, with an estimated prevalence of 6.6 to 21.5%. The treatment for uremic RLS has been controversial and therefore a systematic synthesis of the evidence is needed in order to evaluate the effectiveness and safety of treatments for uremic RLS. This was a systematic review of randomized or quasi-randomized double-blind trials on treatments for uremic RLS. The outcomes considered were relief of RLS symptoms marked on a validated scale, subjective sleep quality, sleep quality measured using night polysomnography and actigraphy, quality of life measured subjectively, and adverse events associated with these treatments. Six eligible clinical trials were included. The results from subjective analyses in these studies were divergent, although objective analyses in one trial showed that there was a statistically significant improvement in periodic leg movement while asleep in the treatment group. No combined analysis (meta-analysis) was performed. The most common adverse event seen was gastrointestinal symptoms. Only a few therapeutic trials on patients with uremia with RLS have been published, and there is insufficient scientific evidence to favor any specific therapeutic regimen for uremic-associated RLS. Therapy using levodopa, dopaminergic agonists, anticonvulsants, and clonidine tend to be effective, but further studies are needed. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]

After about one century of peptide chemistry, the main limitation to the accessibility of peptides and proteins via chemosynthesis is the arising of folding and aggregation phenomena. This is true not only for sequences above a critical length but also for several biologically relevant substrates that are relatively short yet form either highly folded structures (e.g. WW domains) or fibrils and aggregates after final deprotection (β-amyloid peptide). Such so-called difficult sequences may be more easily obtained via their corresponding depsipeptides ( O-acyl isopeptides), ester isomers that are often easier to assemble and purify, and are smoothly converted to the parent amides under mild conditions. The depsipeptide method is the most recent technique to improve the outcome of difficult syntheses, applicable to sequences containing residues of serine or threonine. A brief overview is presented about chemical aspects of the method, the steps that have been undertaken for its optimization, and the evaluation of its efficiency. Further applications of analogous principles to other critical topics in peptide synthesis such as condensation of peptide segments and solid-phase synthesis of naturally occurring cyclodepsipeptides are addressed as well. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

XPB and XPD subunits of TFIIH are central genome caretakers involved in nucleotide excision repair (NER), although their respective role within this DNA repair pathway remains difficult to delineate. To obtain insight into the function of XPB and XPD, we studied cell lines expressing XPB or XPD ATPase-deficient complexes. We show the involvement of XPB, but not XPD, in the accumulation of TFIIH to sites of DNA damage. Recruitment of TFIIH occurs independently of the helicase activity of XPB, but requires two recently identified motifs, a R-E-D residue loop and a Thumb-like domain. Furthermore, we show that these motifs are specifically involved in the DNA-induced stimulation of the ATPase activity of XPB. Together, our data demonstrate that the recruitment of TFIIH to sites of damage is an active process, under the control of the ATPase motifs of XPB and suggest that this subunit functions as an ATP-driven hook to stabilize the binding of the TFIIH to damaged DNA. [ABSTRACT FROM AUTHOR]

A promising application of the depsipeptide technique has recently been proposed to provide ideal conditions for segment condensation, in that coupling of peptides bearing a C-terminal depsipeptide unit occurs without giving rise to epimerization at the activated amino acid. This is due to the low tendency of the activated depsipeptide units, in contrast to the corresponding peptide segments, to form optically labile oxazolones. In this work we demonstrate that coupling of depsipeptides via base-assisted activation using HBTU occurs not only without loss of configuration, but even much faster than the coupling of the corresponding all-amide segments. Nevertheless, when the coupling of long depsipeptide segments proceeds slowly, we uncovered the occurrence of β-elimination at the activated depsipeptide unit, in an extent dependent on the presence of base in the system and on the type of the solvent. Beta-elimination was completely suppressed by using carbodiimide/HOBt activation in a non-polar solvent (DCM), and in more polar media it was limited by substituting TMP for DIEA during HBTU activation, or using particular solvent mixtures (such as DMSO/toluene) for activation via carbodiimide. Finally, we show the application of C-terminal pseudoprolines, in comparison with that of depsipeptide units, to segment coupling. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To test the association between body mass index (BMI) and lower extremity motor performance in elderly people. DESIGN: Multicenter, cross-sectional, observational study. SETTING: A sample of individuals aged 65 and older recruited for the baseline survey of the Italian Longitudinal Study on Aging. PARTICIPANTS: Two thousand six hundred seventy-two individuals (1,436 men, 1,236 women) independent with transfers and toileting and independent or requiring assistance for bathing or dressing. MEASUREMENTS: Motor function was assessed using a Motor Performance Test (MPT), with a set of six tasks exploring lower extremity performance (LEP): rising once from a chair, turning in a half circle, tandem walking, standing on one leg, stair climbing, and walking 5 m. RESULTS: The highest prevalence rates of difficulty in performing the tasks occurred in men and women, respectively, in tandem walking (14%, 28%), stair climbing (17.0%, 43%) and walking 5 m (15%, 30%). In both sexes, moderate (men: odds ratio (OR)=1.99, 95% confidence interval (CI)=1.16–3.43; women OR=2.07, 95% CI=1.18–3.65) and severe obesity (men: OR=3.45, 95% CI=1.21–9.89; women: OR=3.16, 95% CI=1.43–6.95) were each independently associated with overall motor performance impairment after adjusting for age, smoking, and comorbidity. Best performance was generally observed in the normal-weight and overweight groups. CONCLUSION: The results confirm that, in both sexes, overweight is not related to motor impairment. Only in women, low BMI is associated with higher probability of overall motor performance impairment. These data suggest that moderate obesity should be distinguished from severe obesity when assessing the relationship between BMI and LEP. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a sensory motor disorder characterized by a distressing urge to move the legs and sometimes also other parts of the body usually accompanied by a marked sense of discomfort or pain in the leg or other affected body part. The prevalence of RLS is estimated at 2.7 to 5% of adults and it is more common in women. The treatment of RLS with levodopa has been reported thus a systematic synthesis of evidence is necessary to evaluate the effectiveness and safety of levodopa for RLS. Systematic review of randomized or quasi-randomized, double blind trials on levodopa. Relief of restless legs symptoms marked on a validated scale, subjective sleep quality, sleep quality measured by night polysomnography and actigraphy, quality of life measured by subjective measures, adverse events associated with the treatments. Nine eligible clinical trials were included. The subjective analyses of these studies showed contradictory results, although the objective analyses showed that treatment group had a statistically significant improvement of periodic leg movement (PLM) index, favoring the treatment group. The most commonly adverse event seen was gastrointestinal symptoms. The short-term treatment with levodopa was demonstrated effective and safety for PLM, but there was only few trials assessing long-term treatment and the augmentation phenomenon in RLS. Further long-term randomized controlled trials using standard follow-up measurements as the International RLS Study Group Rating Scale are necessary. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Nucleotide excision repair (NER) removes damage from DNA in a tightly regulated multiprotein process. The xeroderma pigmentosum group B (XPB) helicase subunit of TFIIH functions in NER and transcription. The serine 751 (S751) residue of XPB was found to be phosphorylated in vivo. This phosphorylation inhibits NER and the microinjection of a phosphomimicking XPB-S751E mutant is unable to correct the NER defect of XP-B cells. Conversely, XPB-S751 dephosphorylation or its substitution with alanine (S751A) restores NER both in vivo and in vitro. Surprisingly, phospho/dephosphorylation of S751 spares TFIIH-dependent transcription. Finally, the phosphorylation of XPB-S751 does not impair the TFIIH unwinding of the DNA around the lesion, but rather prevents the 5'incision triggered by the ERCC1-XPF endonuclease. These data support an additional role for XPB in promoting the incision of the damaged fragment and reveal a point of NER regulation on TFIIH without interference in its transcription activity. [ABSTRACT FROM AUTHOR]

Summary Obesity is increasing in middle-aged adults and in elderly subjects (over 65 years), owing to the concurrence of different factors: inactivity, wrong nutritional habits, and basal metabolism and nutritional need reduction. This condition is becoming a serious problem because of the increasing numbers of the aged population all over the world. In the past, obesity was considered as a ‘secondary’ pathology of no medical importance in old age; but nowadays, obesity is increasingly being studied in Geriatrics too, because it causes disability and because of its quality-of-life impairment consequences. The Euronut-Seneca study has confirmed the presence of obesity in both men and women in Europe. The definition of obesity, the reference values of body mass index and obesity as a mortality factor in elderly persons are still under discussion. Even when overweight does not represent a serious problem in old age, obese elderly people are certainly at risk of disability, morbidity and mortality. This review focuses on the potential risks of overweight and obesity in the aged population. [ABSTRACT FROM AUTHOR]

Investigates the effect of apatite, transforming growth factor (TGF) beta, bone morphogenetic protein-2 (BMP-2) and interleukin-7 on in vitro ameloblast differentiation. Culture of molar enamel organs with synthetic apatite; Inducement of apatite functional cell differentiation by BMP-2; Presence of transcripts for TGF and BMP-2 in odontoblasts.

As part of TFIIH, XPB and XPD helicases have been shown to play a role in nucleotide excision repair (NER). Mutations in these subunits are associated with three genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The strong heterogeneous clinical features observed in these patients cannot be explained by defects in NER alone. We decided to look at the transcriptional activity of TFIIH from cell lines of XP individuals. We set up an immunopurification procedure to isolate purified TFIIH from patient cell extracts. We demonstrated that mutations in two XP-B/CS patients decrease the transcriptional activity of the corresponding TFIIH by preventing promoter opening. The defect of XPB in transcription can be circumvented by artificial opening of the promoter. Western blot analysis and enzymatic assays indicate that XPD mutations affect the stoichiometric composition of TFIIH due to a weakness in the interaction between XPD­CAK complex and the core TFIIH, resulting in a partial reduction of transcription activity. This work, in addition to clarifying the role of the various TFIIH subunits, supports the current hypothesis that XP-B/D patients are more likely to suffer from transcription repair syndromes rather than DNA repair disorders alone. [ABSTRACT FROM AUTHOR]

A connection between transcription and DNA repair was demonstrated previously through the characterization of TFIIH. Using filter binding as well as in vitro transcription challenge competition assays, we now show that the promoter recognition factor TATA box-binding protein (TBP)/TFIID binds selectively to and is sequestered by cisplatin- or UV-damaged DNA, either alone or in the context of a larger protein complex including TFIIH. Computer-assisted 3D structural analysis reveals a remarkable similarity between the structure of the TATA box as found in its TBP complex and that of either platinated or UV-damaged oligonucleotides. Thus, cisplatin-treated or UV-irradiated DNA could be used as a competing binding site which may lure TBP/TFIID away from its normal promoter sequence, partially explaining the phenomenon of DNA damage-induced inhibition of RNA synthesis. Consistent with an involvement of damaged DNA-specific binding of TBP in inhibiting transcription, we find that microinjection of additional TBP in living human fibroblasts alleviates the reduction in RNA synthesis after UV irradiation. Future anticancer drugs could be designed with the consideration of lesion recognition by TBP and their ability to reduce transcription. [ABSTRACT FROM AUTHOR]

A tubular photobioreactor for outdoor cultivation of Spirulina platensis was successfully operated for the last two years. The reactor was made of transparent 2.4-cm diameter tubes with a total length of approximately 101-m and a volume of 124-liter. Flow was induced using an airlift pumping system. To optimize the system further, a larger tube diameter was also tested. Preliminary results have suggested that a larger tube diameter might provide increased output with reduced surface area requirements. Results of experiments comparing the productivity of the same culture volume in tubes of 2.4 cm and 5.0 cm will be presented which show a small decrease in productivity by volume, but a large increase in areal productivity. This suggests that the larger tube diameter would be an appropriate choice for larger scale systems. Additionally, data will be presented demonstrating the effectiveness of an on-line surface scatter turbidimeter for accurate measurement of Spirulina density when correlated to manual dry weight measurements. [ABSTRACT FROM AUTHOR]

Background The COVID-19 pandemic forced Veterans Health Administration facilities to rapidly adopt and deploy telehealth alternatives to provide continuity of care to veterans while minimizing physical contact. The impact of moving to virtual visits on patients with congestive heart failure (HF) is unknown. The goal of this study was to understand how patients with HF and their providers experienced the shift to telehealth for managing a chronic condition, and to inform best practices for continued telehealth use. Methods and Results We identified Veterans Health Administration Medical Centers with high telehealth use before COVID-19 and sites that were forced to adopt telehealth in response to COVID-19, and interviewed cardiology providers and veterans with HF about their experiences using telehealth. Interviews were recorded, transcribed, and analyzed using team-based rapid content analysis. We identified 3 trajectory patterns for cardiology telehealth use before and during COVID-19. They were the low-use class (low to low), high-use class (relatively high to higher), and increased-use class (low to high). The high-use and increased-use classes fit the criteria for sites that had high telehealth use before COVID-19 and sites that rapidly adopted telehealth in response to COVID-19. There were 12 sites in the high-use class and 4 sites in the increased-use class. To match with the number of sites in the increased-use class, we selected the top 4 sites by looking at the months before COVID-19. We identified 3 themes related to telehealth use among patients with HF and cardiology providers: (1) technology was the primary barrier for both patients and providers; (2) infrastructural support was the primary facilitator for providers; and (3) both patients and providers had largely neutral opinions on how telehealth compares to in-person care but described situations in which telehealth is not appropriate. Conclusions Only 12 sites fit the criteria of high telehealth use in cardiology before COVID-19, and 4 fit the criteria of low use that increased in response to COVID-19. Patients and providers at both site types were largely satisfied using telehealth to manage HF. Understanding best practices for managing ambulatory care-sensitive conditions through virtual visits can help the Veterans Health Administration prepare for long-term impacts of COVID-19 on in-person visits, as well as improve access to care for veterans who live remotely or who have difficulty traveling to in-person appointments.

Studies on attempted suicide in transgender populations, particularly those in resource-limited settings, are scarce. We examined the relationships between stigma, trauma, and suicide attempts in a national sample of transgender women from the Dominican Republic. Bivariate analysis examined differences between suicide attempters and nonattempters (n = 298). Multivariate analysis reported odds ratios with attempted suicide as the outcome (n = 260). About a quarter of respondents (23.9%) experienced sexual abuse, 12.3% were tortured, and 20.3% experienced a murder attempt. More than a quarter reported using illegal drugs. Independent sample t tests found significant differences between suicide attempters and nonattempters. Attempters were more likely to have experienced sexual abuse, psychological abuse, torture, and a murder attempt (p < .001 for all). Respondents who experienced psychological abuse had over three times higher odds of attempting suicide, compared to respondents who had not (OR = 3.203, p < .01). Experience with torture and attempted murder were associated with higher odds of attempting suicide (OR = 2.967, p < .05 and OR = 2.894, p < .05, respectively). Although some nations have implemented antidiscrimination policies protecting transgender citizens, these policies are often not consistently enforced. Eliminating stigmatizing policies may reduce rates of negative health outcomes and subsequently improving population health., (© 2017 The American Association of Suicidology.)

Correlates of past-year suicidal ideation and lifetime suicide risk among a national sample of transgender veterans were examined. An online, convenience sample of 212 U.S. transgender veterans participated in a cross-sectional survey in February-May 2014. We evaluated associations between sociodemographic characteristics, stigma, mental health, and psychosocial resources with past-year suicidal ideation and lifetime suicide plans and attempts. Participants reported high rates of past-year suicidal ideation (57%) as well as history of suicide plan or attempt (66%). Transgender-related felt stigma during military service and current posttraumatic stress disorder and depressive symptoms were associated with suicide outcomes as were economic and demographic factors., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)