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Background and Objectives Materials and Methods Results Conclusion In Brazil, urban arboviruses, such as dengue virus (DENV), Zika virus (ZIKV) and chikungunya virus (CHIKV), constitute a major public health problem, and due to their endemicity and asymptomatic cases, they pose a potential threat to blood donations. Rio de Janeiro (RJ), Brazil, has been impacted by extensive DENV epidemics over the last 30 years and, after 2015, by CHIKV and ZIKV.Urban arboviruses DENV, ZIKV and CHIKV were investigated in blood donations (n = 778) at the State Institute of Hematology, HEMORIO (RJ) from 2019 to 2022 by serological and molecular methods.An overall arbovirus exposure was observed in 26.1% of the blood donations. Anti‐DENV IgM was detected in 4.0% of samples and two donations were DENV NS1 positive. Positive anti‐CHIKV IgM was observed in 4.7% of the donations. Co‐detection of anti‐CHIKV IgM and anti‐DENV IgM was observed in 1.0% of donors, and CHIKV prevalence was 21.3%. All blood donations tested were negative for the DENV, ZIKV and CHIKV RNA.IgM seroprevalence to the arboviruses analyzed here is an indicator of recent infection in asymptomatic donors, showing that the population of blood donors can be a vehicle for new infections, especially during epidemic periods. [ABSTRACT FROM AUTHOR]

A practicable method is described for the synthesis of 3‐acyl‐pyrazolo[1,5‐a]pyridines from N‐aminopyridines and easily available enaminones via a [3+2] cycloaddition. The reactions proceed well with a broad scope, without using additive (base or oxidant). [ABSTRACT FROM AUTHOR]

Antipsychotic-induced catatonia (AIC) and neuroleptic malignant syndrome (NMS) are life-threatening adverse reactions to antipsychotic medication. We conducted a systematic review of literature following the PRISMA statement guidelines to obtain a description of these syndromes (population, context of occurrence, antipsychotic agents implicated) and draw conclusions about their links. We searched Medline and Web of science databases from January 1951 to May 2019 (further restricted from 2000 to 2019) using search terms including "catatonia", "neuroleptic malignant syndrome" and "antipsychotic agents" for case reports, case series and analytic studies. After screening 4082 records, 410 full-text articles (describing 555 events) were assessed for eligibility. We included events of AIC and/or NMS according to Diagnostic and Statistical Manual (DSM) criteria and extracted data about patients' characteristics, context of occurrence, antipsychotic agent(s) involved and treatment outcomes. We included 165 events (16 AIC, 129 NMS and 20 AIC + NMS) from 144 case reports and case series. The most reported diagnosis was schizophrenia. Comorbid pre-existing conditions such as central nervous system diseases and acute medical events were common. Most of the events (63.3 %) occurred during antipsychotic monotherapy. Second-generation antipsychotics (SGAs, 63.8 %) were overall more implicated than first-generation antipsychotics (FGAs, 36.2 %). Our findings highlight that any antipsychotic medication, even SGA monotherapy prescribed at recommended dose, is at risk for these side effects. FGAs and polypharmacy seem to represent risk factors for malignant catatonia in AIC. The clinical overlap observed between AIC and NMS events in our review suggests a clinical continuum between catatonia and NMS. [ABSTRACT FROM AUTHOR]

Keywords: sulfinate; sulfenylation; iodine; microwave heating; heterocycles; thiolation EN sulfinate sulfenylation iodine microwave heating heterocycles thiolation 1723 1726 4 08/18/23 20230901 NES 230901 Graph Organic sulfur compounds, especially thioethers, are prominent structural motifs in many bioactive natural products, pharmaceuticals, materials, and agrochemicals. [7] In 2018, the Song group developed a difunctionalization of an imidazopyridine by using a sodium sulfinate and iodine (Scheme 1)..[8] With the base and iodine, they obtained the sulfonylated product exclusively, whereas with iodine and a reducing agent (PPh SB 3 sb ), they obtained the sulfenylated product exclusively. However, the reaction of B 1a b with B 2a b in Et SB 2 sb O as a solvent under basic conditions at 100 °C for 20 hours gave the 3-phenylsulfonylated product B 4a b in only 50% conversion, along with 50% of the 3-iodo compound B 5 b (Table 1, entry 1). [Extracted from the article]

Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require combination and double or triple therapies. International guidelines recommend the association of drugs with complementary mechanisms of action and, in particular, the combination of renin-angiotensin system (RAS) inhibitors, calcium channel blockers (CCBs), and diuretics. Among the various angiotensin receptor blockers, olmesartan (OM) is available as a monotherapy and in dual and triple single-pill combinations (SPCs) with amlodipine (AML) and/or hydrochlorothiazide (HCTZ). Several phase III and IV studies, together with real-world studies, have demonstrated the additional benefits of combining OM either with AML or with HCTZ in terms of BP control and target BP achievements both in the general population and in special subgroups of hypertensive patients, such as the elderly, diabetic, chronic kidney disease or obese patients. Ambulatory BP monitoring studies assessing 24h BP have also demonstrated that dual, as well as triple, OM-based SPCs induce a more sustained and smoother BP reduction than placebo and monotherapy. Furthermore, triple OM-based SPC has been shown to improve therapeutic adherence in hypertensive patients compared to free combinations. The availability of OM combined with HCTZ, AML or both at different dosages makes it a valuable option to customize therapy based on the levels of BP and the clinical characteristics of hypertensive patients. [ABSTRACT FROM AUTHOR]

The first nucleophilic selenocyanation from selenium dioxide and malononitrile is described. This methodology produced a wide variety of selenocyanates from halides in moderate to excellent yields under mild conditions, highlighting the versatility and usefulness of this new source of nucleophilic selenocyanation. [ABSTRACT FROM AUTHOR]

The article presents recent discoveries made by the French Archaeological Mission to the Eastern Desert of Egypt in two Ptolemaic forts occupied in the second half of the 3rd century b.c., Bir Samut and Abbad, located along the road leading from Edfu to Berenike on the Red Sea Coast at the southern fringes of the Ptolemaic Empire. These artifacts, three copper-alloy arrowheads marked with the monogram BE and four Ptolemaic coins minted in Joppa, were recovered in contexts securely dated to the last decades of the 3rd century b.c. Due to the sealed stratigraphy and the discovery of thousands of ostraca and dozens of coins in the same deposits, it is clear that the forts and these objects were abandoned on the eve of the Great Theban Revolt in Egypt, around 207–206 b.c. These discoveries offer an occasion to reassess the corpus of similar arrowheads and coins found in the Eastern Mediterranean. The catalog presented here includes 45 BE arrowheads and 18 Joppa coins and a careful reassessment of the corpus suggests that they were probably produced by the Ptolemaic regime in direct association with the Fourth Syrian War, which ended with the Battle of Raphia in 217 b.c. The geographic distribution of the arrowheads and coins discussed in the article demonstrates the mobility of the Ptolemaic troops after this intense period of conflict. [ABSTRACT FROM AUTHOR]

Background: The treatment of patients with headache represents an important part of a neurologist's activity. It requires sufficient training for neurology residents. In France, residents in neurology can complete this training by attending specialized consultations or by participating in a postgraduate training program called "Diplôme Inter‐Universitaire Migraine et Céphalées" (DIUMC). Objective: The objective of this cross‐sectional study was to investigate the French residents' knowledge in headache medicine and the impact of different types of training in headache medicine that are available in France. Methods: An anonymous survey was carried out among 548 French residents in neurology. Results: The questionnaires of 121 residents (22.1%) were analyzed. Among them, 54.5% (66/121) had no complementary training apart from the internship (Group 1), 21.5% (26/121) had attended only specialized consultations (Group 2), and 24% (29/121) had participated in the DIUMC (Group 3). There was no difference between all groups regarding the knowledge of the prevalence of primary or chronic headaches. There was almost no difference between the groups in the management of episodic migraine. In contrast, the management of tension‐type headache and chronic headache was better known by residents of Group 3 than residents of Group 1. In these two diseases, residents of Group 3 offered prophylactic treatment more often. Almost 29% of the residents (35/121) had read the French guidelines for the diagnosis and management of migraine. In Group 3, residents had read them significantly more often (1.6% in Group 1, 38.5% in Group 2 and 62.1% in Group 3, p < 0.001). Conclusion: This study shows the lack of knowledge among French neurology residents regarding headache medicine. It highlights the interest of specific training programs that could improve the practical and theoretical knowledge of future neurologists. [ABSTRACT FROM AUTHOR]

The article presents a case study reporting two instances of severe and transient pain at recent bone fracture sites following subcutaneous sumatriptan (SS) injection in patients with cluster headaches. Topics include the unusual adverse reaction of bone site pain associated with SS injection, the patients' clinical histories, and the proposed hypotheses regarding the pathophysiology, including SS-induced allodynic pain and the stimulation of 5-HT1B and 5-HT1D receptors at the fracture site.

A new method of deborylative selanylation using arylboronic acids and arylseleninic acids gave diaryl selenoethers and diarylselenoxide. The present approach requires only equimolar arylseleninic acid and led selectively to selenoethers or selenoxides depending on the solvent. The method is metal-free, base- or oxidant-free, efficient, and environmentally friendly. [ABSTRACT FROM AUTHOR]

In this paper, a numerical process is presented for predicting the response of vibrating structures excited by a non-homogeneous turbulent boundary layer. This one is based on the synthesis of different realizations of the random pressure fluctuations that can be introduced as loading of a vibroacoustic model. The vibratory response is finally deduced by averaging together the responses of the different loads. As a first approach, the pressure fluctuations of the non-homogeneous turbulent boundary layer can be generated separately for different sub-areas of the structure by using the uncorrelated wall plane waves technique and mean boundary layer parameters. An extension of this basic approach consists in taking into account the interaction between the sub-areas and a refinement of the sub-area decomposition. Wall pressure fluctuations related to a continuous evolution of the boundary layer can then be generated and introduced in the vibroacoustic model. The accuracy of the proposed approach is studied on a rectangular panel excited on one side by a growing fully turbulent boundary layer triggered at one edge of the plate. Comparisons with the spatial approach and the wavenumber approach using the sub-area decomposition technique are proposed. Interests of the proposed approach in terms of accuracy and computing times are discussed. [ABSTRACT FROM AUTHOR]

Alienation is an extremely complex category, difficult to understand, especially when studied from certain works of Marx, such as the Economic--Philosophical Manuscripts of 1844, fragmented and incomplete. Although this notion was not created in the midst of Marxian theory, it is in this aspect that it acquires an understanding more aligned with social reality, with roots in the economic sphere. Using a literature review centered on the theme, this article aims to approach the term, a contribution to its understanding, whose determinants that frame it find their nexus of objectivity under the structural configurations of bourgeois society, dominated by capital. [ABSTRACT FROM AUTHOR]

Background: Indomethacin (IMC) as a prophylactic treatment is considered to be ineffective in cluster headache (CH). However, small series suggested the interest of IMC in CH. Some authors support that an IMC test is useful in all trigeminal autonomic cephalalgias. We described clinical features of IMC responders in a retrospective cohort of chronic cluster headache (CCH). Methods: This single-center and retrospective study was conducted in a tertiary care specialist headache center in France. Patients were selected between January 2007 and December 2008. We included all patients fulfilling CCH criteria (ICHD-3-beta). Data were collected from medical records. We recorded all the prescriptions of IMC as a prophylactic treatment. Responders were defined by 50% reduction in attack frequency; complete response was defined by disappearance of the attacks. The non-responders must have received at least 100 mg daily during 7 days. Results: The study consisted of 324 CCH, 121 female (37%) and 203 males (63%) with an average age at onset of 33.93 (± 14.71) years. Of the patients, 105 were treated with IMC. Thirty patients (29%) were responders. Thirty-four patients (32%) were non-responders. Responding status was undefined for 41 patients (39%). Twelve patients (11%) had a complete response. Responders were composed by 18 women (60%) and 12 men (40%) and had on average 44.89 (± 12.88) years. The minimal effective dose was 86.11 mg daily (± 48.72). Discussion: This study shows the interest of IMC in CCH patients. We recommend an IMC test as a third-line treatment in CCH. [ABSTRACT FROM AUTHOR]

The presence of endolymphatic hydrops has been studied in many neurological disorders. The pathophysiological mechanisms may involve CSF pressure variations, transmitted to the innear ear. This hydrops could play a role in vestibular or cochlear symptoms. For the ENT specialist, the etiological diagnosis of endolymphatic hydrops is a challenge, and neurological etiologies must be known. The treatment of these neurological causes could be effective on cochleo-vestibular symptoms. The knowledge of endolymphatic hydrops could also be a target for noninvasive tests, able to estimate CSF pressure variations. For the neurologist, this could represent a useful tool for the diagnosis and follow-up, in some of these neurological disorders, related to a CSF pressure imbalance. The purpose of this paper is to summarize literature data on endolymphatic hydrops in neurological disorders. We define some neurological conditions, for which there is a particular interest in noninvasive investigations of endolymphatic hydrops. [ABSTRACT FROM AUTHOR]

The cell cycle is modulated by ubiquitin ligases, including CRL4, which facilitate degradation of the chromatin-bound substrates involved in DNA replication and chromosome segregation. One of the members of the CRL4 complex, RepID (DCAF14/PHIP), recognizes kinetochore-localizing BUB3, known as the CRL4 substrate, and recruits CRL4 to the chromatin/chromosome using the WD40 domain. Here, we show that the RepID WD40 domain provides different platforms to CRL4 and BUB3. Deletion of the H-box or exon 8 located in the RepID WD40 domain compromises the interaction between RepID and CRL4, whereas BUB3 interacts with the exon 1–2 region. Moreover, deletion mutants of other exons in the WD40 domain lost chromatin binding affinity. Structure prediction revealed that the RepID WD40 domain has two beta-propeller folds, linked by loops, which are possibly crucial for chromatin binding. These findings provide mechanistic insights into the space occupancy of the RepID WD40 domain to form a complex with CRL4, BUB3, or chromatin. • RepID WD40 domain is crucial for binding to chromatin and proteins. • WD40 domain of RepID forms a two-β propeller configuration connected by a loop. • RepID WD40 domain provides different platforms for proteins and chromatin. [ABSTRACT FROM AUTHOR]

Deciphering how DCAFs (DDB1‐CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin‐Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery ("catalytic DCAFs"). However, recent studies have suggested that some DCAFs might play a different role by targeting CRL4 complexes to distinct cellular compartments ("structural DCAFs"). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate‐specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time. [ABSTRACT FROM AUTHOR]

Resulting from a university extension action, the article presents elements and characteristics of Xapuri, State of Acre, Brazil, birthplace of the rubber tapper leader, Francisco Alves Mendes Filho, best known as Chico Mendes, from a historical and cultural trail conducted during the Vale do Acre Operation, part of the Rondon Project, coordinated by the Ministry of Defense. The town comprises a series of historic-cultural, identity and social particularities, which, at first, may go unnoticed by its visitors or even by natives. Considering the potential of Xapuri regarding tourism, the trail can be an attractive proposal for the sector and a tool for heritage education, as it is a hiking path that allows participants to identify and interpret the landscapes and the material and immaterial elements of the visited route, which contribute to its visibility, preservation and memory. [ABSTRACT FROM AUTHOR]

Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial. Keywords: Finerenone; Type 2 diabetes; Chronic kidney disease; Heart failure; FIGARO-DKD EN Finerenone Type 2 diabetes Chronic kidney disease Heart failure FIGARO-DKD e36 e37 2 05/20/22 20220401 NES 220401 Diabetes is the main cause of chronic kidney disease (CKD) and a risk factor for their progression to end-stage renal disease. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. [Extracted from the article]

The NonNegative Canonical Polyadic Decomposition (NN-CPD) is used in many fields such as in chemistry, biology and medicine. The data coming from these fields can be dynamic which lead to use real-time or "online" decomposition. Even though there are a variety of online tensor decomposition algorithms, the main assumption of all these algorithms is that the rank of the decomposition is known and/or does not vary over time. However this should not be the case in experimental conditions. In this work, we propose three algorithms to compute the online NN-CPD based on sparse dictionary learning for tracking chemical components in water by using a set of Emission and Excitation Matrices (EEMs) of fluorescence. The methods developed in this work is not limited to this application field and it addresses the major challenges posed by the variation of the CPD rank in real-time. First, the algorithms take into account the unknown factors and the variation of tensor rank. Second, previous extracted information are used to decompose upcoming new tensors. In addition to the development of these algorithms, one of the contributions of this paper is the real-time acquisition of fluorescence data in a semi-controlled environment. These algorithms were applied on these real datasets and compared to state of the art algorithms. • New online approaches for Canonical Polyadic Decomposition with nonnegative and sparsity constraint. • Application on experimental data. • Automatic and continuous rank determination taking into account its variation. • The role of overlapping two consecutive tensors on online decomposition. [ABSTRACT FROM AUTHOR]

The article presents the study of Treatment of medication overuse headache, and effect and predictors after 1 year. Topics discussed include Medication overuse headache (MOH) is a chronic secondary headache caused by medication overuse; and the condition is a common clinical problem that should be managed in an effective manner because these patients are highly impaired.

Genuine leather is produced from animal skin by chemical tanning using chemical or vegetable agents, while synthetic leather is a combination of fabric and polymer. The replacement of natural leather by synthetic leather is becoming more difficult to identify. In this work, Laser Induced Breakdown Spectroscopy (LIBS) is evaluated to separate between very similar materials: leather, synthetic leather, and polymers. LIBS is now widely employed to provide a specific fingerprint from the different materials. Animal leathers processed with vegetable, chromium, or titanium tanning were analyzed together with polymers and synthetic leather from different origins. The spectra exhibited typical signatures from the tanning agents (Cr, Ti, Al) and the dyes and pigments, but also from polymer characteristic bands. The principal factor analysis allowed to discriminate between four main groups of samples representing the tanning processes and the polymer or synthetic leather character. [ABSTRACT FROM AUTHOR]

H2A.J is a poorly studied mammalian-specific variant of histone H2A. We used immunohistochemistry to study its localization in various human and mouse tissues. H2A.J showed cell-type specific expression with a striking enrichment in luminal epithelial cells of multiple glands including those of breast, prostate, pancreas, thyroid, stomach, and salivary glands. H2A.J was also highly expressed in many carcinoma cell lines and in particular, those derived from luminal breast and prostate cancer. H2A.J thus appears to be a novel marker for luminal epithelial cancers. Knocking-out the H2AFJ gene in T47D luminal breast cancer cells reduced the expression of several estrogen-responsive genes which may explain its putative tumorigenic role in luminal-B breast cancer. [ABSTRACT FROM AUTHOR]

• MeSA can be assayed in wines at concentrations over its olfactory detection threshold. • MeSA is extracted during alcoholic fermentation from V.vinifera grape skins and stems. • MeSA in wines can be related to grapevine alteration level by several pathogens. Methyl salicylate (MeSA) is a plant metabolite that induces plant defence resistance and an odorous volatile compound presenting green nuances. This volatile compound was shown to be present in wine samples, sometimes at concentrations above its olfactory detection threshold. MeSA is localized in grapes, particularly in the skins and stems, and is extracted during red wine vinification. It was detected at the highest concentrations in wines of several grape varieties, made from grapes affected by cryptogamic diseases, namely downy mildew caused by Plasmopara viticola , and black rot caused by Guignardia bidwellii. It has also been detected in wines from vines affected by Esca, a Grapevine Trunk Disease. MeSA can also be considered to be a chemical marker in grapes and wine indicative of the level of development of several vine cryptogamic diseases. [ABSTRACT FROM AUTHOR]

Non- Saccharomyces yeasts have been used for many years due to their technological potential, particularly as a "booster" of wine fruity aroma in mixed fermentations with Saccharomyces cerevisiae. Recently, a new application has emerged, bioprotection, which consists in colonizing the environment in the context of sulfite reduction in wines. The chemical and sensory impact of non- Saccharomyces yeast according to different modes of application in a context of fermentation without addition of SO 2 was evaluated through trial with Merlot N. (Vitis vinifera L.). An effective niche occupation by non- Saccharomyces yeasts was highlighted during the prefermentary stages by Quantitative-PCR and MALDI-TOF MS identification. Chemical analysis (GC-MS and GC MS/MS) of finish wine showed the significant impact of the dose applications, with bioprotection characterized by linear esters and sequential application by acetates of higher alcohol contents. Moreover, a separation according to the species used in bioprotection was revealed. Finally, using a panel trained, the sensory analysis confirmed that the use of non- Saccharomyces yeast was a fruity booster in sequential inoculation and, to a less extent, when used as bioprotection. This study shows for the first time that the use of non- Saccharomyces yeast as a bioprotection has a significant impact on the aromatic profile of wines. • Occupying the niche by T. delbrueckii as a bioprotection, unlike S. cerevisiae. • The dosage of non- Saccharomyces significantly impact the chemical composition of red wine. • Impact of bioprotection on the chemical and aromatic profile red wine in low SO 2. [ABSTRACT FROM AUTHOR]

Objectives: Electroconvulsive therapy (ECT) is one of the most effective treatments in mood disorders, mainly in major depressive episode (MDE) in the context of either unipolar (MDD) or bipolar disorder (BD). However, ECT remains a neglected and underused treatment. Older people are at high risk patients for the development of adverse drug reactions. In this context, we sought to determine the duration of MDEs and the number of lines of treatment before the initiation of ECT in patients aged 65 years or over according to the presence or absence of first-line indications for using ECT from international guidelines. Methods: In this multicenter, retrospective study including patients aged 65 years or over with MDEs in MDD or BD who have been treated with ECT for MDEs, data on the duration of MDEs and the number of lines of treatment received before ECT were collected. The reasons for using ECT, specifically first-line indications (suicidality, urgency, presence of catatonic and psychotic features, previous ECT response, patient preference) were recorded. Statistical comparisons between groups used standard statistical tests. Results: We identified 335 patients. The mean duration of MDEs before ECT was about 9 months. It was significantly shorter in BD than in MDD- about 7 and 10 months, respectively. The co-occurrence of chronic medical disease increased the duration before ECT in the MDD group. The presence of first-line indications for using ECT from guidelines did not reduce the duration of MDEs before ECT, except where there was a previous response to ECT. The first-line indications reduced the number of lines of treatment before starting ECT. Conclusion: Even if ECT seems to be a key treatment in the elderly population due to its efficacity and safety for MDEs, the delay before this treatment is still too long. Key points: • The mean duration of depression before ECT was 8.8 months. • The duration before ECT for Bipolar Disorder (vs Major Depressive Disorder) is shorter. • The co-occurrence of chronic medical disease increased the duration before ECT in the MDD group. • Focusing on the first-line indications for using ECT, only a previous response reduces the duration of depression before ECT. [ABSTRACT FROM AUTHOR]

Cells activate distinctive regulatory pathways that prevent excessive initiation of DNA replication to achieve timely and accurate genome duplication. Excess DNA synthesis is constrained by protein–DNA interactions that inhibit initiation at dormant origins. In parallel, specific modifications of pre-replication complexes prohibit post-replicative origin relicensing. Replication stress ensues when the controls that prevent excess replication are missing in cancer cells, which often harbor extrachromosomal DNA that can be further amplified by recombination-mediated processes to generate chromosomal translocations. The genomic instability that accompanies excess replication origin activation can provide a promising target for therapeutic intervention. Here we review molecular pathways that modulate replication origin dormancy, prevent excess origin activation, and detect, encapsulate, and eliminate persistent excess DNA. Cells have evolved specialized mechanisms to avoid the deleterious effects of excess initiation from replication origins. During unperturbed proliferation, most potential replication origins are dormant and do not initiate replication but are prepared for activation to facilitate complete genome duplication if cells encounter replication stress. Cells prevent initiation at dormant origins by adjusting chromatin structure to constrain the assembly and activation of pre-replication complexes, targeting components of the replication machinery for degradation or modulating specific protein–DNA interactions at origins. Cancer cells often lack the controls that prevent excess activation of replication origins, resulting in the amplification of extrachromosomal DNA that can persist if they contain genes that can confer a selective growth advantage. Cells activate metabolic and inflammatory responses to sense and encapsulate and eliminate excess DNA. Because excess replication origin activation can directly or indirectly lead to genomic instability, targeting the pathways that prevent excess replication or eliminate excess DNA is a promising avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Dielectric constants of Al 2 O 3 (alumina) ceramic samples have been measured with non-destructive terahertz time-domain spectroscopy. Using an effective medium approximation, we demonstrated that the relative permittivity can be used to evaluate the porous alumina samples, with porosity fractions ranging from 0% to 20% per volume. This result makes it possible to control sample porosity, a key material parameter related to mechanical strength under compression load, hardness and wear resistance, or thermal stability. We also employed terahertz time-domain spectroscopy to differentiate alumina samples fabricated with different grain sizes, or reveal a small fraction of impurities, such as 5% vol of ZrO 2 , embedded in non-porous alumina. These results demonstrated the potential of terahertz radiation for non-destructive characterization of low loss high dielectric constant ceramics. [ABSTRACT FROM AUTHOR]

Several urban canopy models now incorporate urban vegetation to represent local urban cooling related to natural soil and plant evapotranspiration. Nevertheless, little is known about the realism of simulating these processes and turbulent exchanges within the urban canopy. Here, the coupled modeling of thermal and hydrological exchanges was investigated for a lawn located in an urban environment and for which soil temperature and water content measurements were available. The ISBA diffusive (ISBA-DF) surface–vegetation–atmosphere transfer model is inline coupled to the Town Energy Balance urban canopy model to model mixed urban environments. For the present case study, ISBA-DF was applied to the lawn and first evaluated in its default configuration. Particular attention was then paid to the parameterization of turbulent exchanges above the lawn and to the description of soil characteristics. The results highlighted the importance of taking into account local roughness related to surrounding obstacles for computing the turbulent exchanges over the lawn and simulating realistic surface and soil temperatures. The soil nature and texture vertical heterogeneity are also key properties for simulating the soil water content evolution and water exchanges. [ABSTRACT FROM AUTHOR]

The discrimination of humidity in exhaled breath is of utmost importance to turn breath analysis into an efficient noninvasive tool for early diagnosis or treatment monitoring of several diseases. Herein, by assembling different ratios of the conductive poly(3,4‐ethylenedioxythiophene): polystyrene sulfonate with the polymer matrix polyethylene oxide (PEO), humidity chemiresistor‐based sensors are designed and investigated. The testing results display a broad relative humidity detection range (6–92%), repeatability, reproducibility, and good reversibility. Meanwhile, the sensors possess good reliability for distinct temperatures and in the presence of typical volatile organic compounds found in human exhaled air. The hygroscopic idiosyncrasy of PEO is attributed to be the main responsible for the high sensibility toward humidity. In a proof‐of‐principle for detection of respiration humidity, the outcome shows the ability of the chemiresistors to detect the humidity variation in a real case of breath exposure up to 2 s intervals. The 30 d trial of stability readings shows a standard deviation of only 2.6%. These sensing devices appear as a new array component able to distinguish moisture from biomarkers of diagnosed diseases in breath analysis. [ABSTRACT FROM AUTHOR]

Modern condensed matter physics relies on the concept of topology to classify matter, from quantum Hall systems to topological insulators. Engineered systems, benefiting from synthetic dimensions, can potentially give access to topological states predicted in dimensions D > 3. We report the realization of an atomic quantum Hall system evolving in four dimensions (4D), with two spatial dimensions and two synthetic ones encoded in the large spin of dysprosium atoms. We measure the nontrivial topological index of the ground band through a full characterization of the nonlinear electromagnetic response and observe the associated anisotropic hyperedge modes. We also excite nonplanar cyclotron motion, in contrast to the planar orbits in D ≤ 3. Our work may enable the investigation of strongly correlated topological liquids in 4D, generalizing fractional quantum Hall states. [ABSTRACT FROM AUTHOR]

As part of our ongoing attempt to broaden the applications of the amidoxime moiety as a potential source of new antileishmanial agents, this study focuses on the product 4-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-2-nitrobenzamide. This unexpected amide was obtained in an 85% yield as the major product with a conventional amidoxime synthesis protocol (Ethanol/Na2CO3) involving the reaction of hydroxylamine and a nitrile group. The formation of this amide derivative instead of the expected amidoxime can be attributed to two complementary effects: the strong electron effect of the nitro group and the influence of ethanol, a polar protic solvent. Alternatively, the desired amidoxime derivative, 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N′-hydroxy-2-nitrobenzimidamide, was obtained in an 80% yield by an alternative protocol (DMSO/KOtBu). This original compound, featuring a nitro group in the ortho position to the amidoxime, will be further evaluated, both in the field of medicinal chemistry and in other relevant areas, highlighting an unusual method to access amidoximes from hindered substrates. [ABSTRACT FROM AUTHOR]

As part of our ongoing research into the antileishmanial properties of amidoxime derivatives, we report a preliminary assessment of the antiparasitic properties of a novel compound, diethyl (5-benzyl-2-(4-(N′-hydroxycarbamimidoyl)phenyl)-5-methyl-4,5-dihydrofuran-3-yl)phosphonate. This compound was evaluated in vitro for the first time against the promastigote form of Leishmania amazonensis. Compounds containing both amidoxime and phosphonyl functional groups in dihydrofuran scaffolds are relatively rare, despite the extensive study of this heterocycle in various biological applications. Therefore, this work makes a valuable contribution to the fight against Leishmania spp. as a neglected disease. The cyclized 4,5-dihydrofuran intermediate scaffold was obtained via a three-step synthetic route that had previously been developed for accessing other derivatives, including the sulfone moiety. This synthesis was performed using a manganese-based free radical oxidative method under microwave irradiation. The intermediary 4,5-dihydrofuran, which included a nitrile group, tolerated the subsequent reaction with hydroxylamine hydrochloride, resulting in the formation of the target product. The target compound showed moderate activity in vitro against the promastigote form of L. amazonensis (IC50 = 91.1 µM). [ABSTRACT FROM AUTHOR]

In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication, and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant origins). We studied the effects of aging and SIRT1 activity on replication origin usage and the incidence of transcription–replication collisions (creating R-loop structures) in adult human cells obtained at different time points during chronological aging and in cancer cells. In primary, untransformed cells, SIRT1 activity declined and the prevalence of R-loops rose with chronological aging. Both the reduction in SIRT1 activity and the increased abundance of R-loops were also observed during the passage of primary cells in culture. All cells, regardless of donor age or transformation status, reacted to the short-term, acute chemical inhibition of SIRT1 with the activation of excessive replication initiation events coincident with an increased prevalence of R-loops. However, cancer cells activated dormant replication origins, genome-wide, during long-term proliferation with mutated or depleted SIRT1, whereas, in primary cells, the aging-associated SIRT1-mediated activation of dormant origins was restricted to rDNA loci. These observations suggest that chronological aging and the associated decline in SIRT1 activity relax the regulatory networks that protect cells against excess replication and that the mechanisms protecting from replication–transcription collisions at the rDNA loci manifest as differentially enhanced sensitivities to SIRT1 decline and chronological aging. [ABSTRACT FROM AUTHOR]

Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP -related disease to include neurodevelopmental disease presenting in childhood. Valosin-containing protein (VCP) is an ATPase that assists in cellular recycling pathways. Pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), affecting the brain, muscle, and bone. This article describes 13 individuals with VCP variants associated with childhood-onset neurodevelopmental disorder, possibly mediated by a loss-of-function mechanism. [ABSTRACT FROM AUTHOR]

The objective was to identify the chronic impact of SARS-CoV-2 virus infection in new diagnostics, pharmacological prescriptions, and use of healthcare resources in patients after acute infection in a case-control study. Methods: Case-control study with observation of new diagnostics codified in the Electronic Health Recordings, with a total population of 604,000 subjects. Cases included patients diagnosed with acute infection. Matched controls in the absence of infection using a Propensity Score were also included. Observational period was 6 months. New diagnostic (CIE10), prescriptions and visits to Health Care Resources were identified. Results: 38,167 patients with a previous COVID infection and the same number of controls were analyzed. Population included < 18 years old, 7586 (mean age 10.2 years, girls 49%), and 30,581 adults (mean age 46.6 years, females 53%). In adults, 25% presented new diagnoses, while the prevalence was 16% in youth. A total of 40 new diagnostics were identified. The most frequent were diagnostics in the neuropsychiatric sphere, with older age, female, and previous admission in the Critical Care Unit being the factors related in adults, while in youth higher age was also a factor. Prescription of psychoanaleptic, psycholeptic and muscle relaxants had increased. An increment of around 20% in visits to Primary Care Physicians, Specialists and Emergency Departments was registered. Conclusion: Compared with a control group, an increment in the number of new diagnostics, new prescriptions and higher use of Health Care resources were observed. Many of the new diagnoses also occur in non-infected subjects, supporting the complex origin of so-called Long-COVID. [ABSTRACT FROM AUTHOR]

Aminoquinolinium salts, aminoquinazolinium salts, N, N '-bridging alkylation, amination, nucleophilic aromatic substitution An attempted I N i , I N i '-alkylation of two molecules of 4-chloro-6,7-dimethoxyquinoline ( B 2 b ) with a propyl bridge resulted in an inseparable mixture of the expected dimer B 26 b , the monosubstituted I N i -(3-halopropyl)quinolinium salts B 24 b and B 25 b , and the protonated 4-halo-6,7-dimethoxyquinolinium salt B 23 b , in addition to halogen-exchange products. Keywords: aminoquinolinium salts; aminoquinazolinium salts; N, N '-bridging alkylation; amination; nucleophilic aromatic substitution EN aminoquinolinium salts aminoquinazolinium salts N, N '-bridging alkylation amination nucleophilic aromatic substitution 1685 1688 4 08/18/23 20230901 NES 230901 Graph Most drugs available on the market, as well as pharmacologically active molecules in development, have heterocyclic pharmacophoric structures, often with quinoline or quinazoline nuclei. [Extracted from the article]

Background: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. Methods: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. Results: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. Conclusion: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. EhctJ7T1-GG5oU5fji2odB Video Abstract [ABSTRACT FROM AUTHOR]

• A renewed interest exists in miRNAs as biomarkers in cardiovascular disease. • miR-126–3p is associated with albuminuria, a marker of endothelial dysfunction, in hypertension. • High miR-126–3p levels are associated with cardiovascular events in general population. Endothelial dysfunction is a forerunner of atherosclerosis, leading to cardiovascular disease, and albuminuria is a marker of endothelial dysfunction. Circulating levels of microRNAs are emerging as potential biomarkers for cardiovascular disease. Here we estimate the predictive value of a plasma microRNAs signature associated with albuminuria in the incidence of cardiovascular events. Plasma microRNAs quantified in hypertensive patients by next generation sequencing were validated in a cohort of patients and controls by real-time quantitative PCR. The microRNAs found to be associated with albuminuria were analysed for their prognostic value in predicting cardiovascular events incidence on a retrospective, population-based study (Hortega Study), using Cox proportional hazard models. A plasma microRNA profile was identified in the discovery cohort (n = 48) associated with albuminuria and three microRNAs (miR-126–3p, miR-1260b and miR-374a-5p) were confirmed in the validation cohort (n = 98). The microRNA signature discriminates urinary albumin excretion at baseline (n = 1025), and predicts the incidence of cardiovascular events and coronary heart disease and stroke in a general population retrospective study within a 14-year follow-up (n = 926). High miR-126–3p levels were associated with a shorter time free of both cardiovascular events (HR=1.48, (1.36–1.62), p < 0.0001), as well as coronary artery disease and stroke combined (HR=2.49, (2.19–2.83), p < 0.0001). An increased plasma microRNAs profile was identified in hypertensive patients with albuminuria. Increased miR-126–3p suggest it may serve as a prognostic marker for cardiovascular events in a long-term general population. Further studies will assess the potential role of miR-126–3p as a guide for the status of endothelial dysfunction. Circulating miR-126–3p as a prognostic marker of MACE and combined CAD and stroke in a long-term general population cohort. A signature of 4 miRNAs is associated with albuminuria in the discovery and validation cohorts of hypertensive patients and controls. in a general population cohort (Hortega testing cohort) followed during 14 years, increased levels of plasma circulating miR-126–3p are associated with the incidence of MACE (major adverse cardiovascular events) and combined CAD (coronary artery disease) and stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein's impact was confirmed on the patient's cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients' genetic explorations as well as functional tests to assess a variant's pathogenicity. [ABSTRACT FROM AUTHOR]

Simple Summary: In diabetic nephropathy, the injury of renal cells such as podocytes worsens the glomerular filtration process due to the cells' loss and detachment from the basal membrane. Intra- and intercellular communications in cells are partially mediated by the Rab3A/Rab27A system. We have observed that silencing the Rab3A/Rab27A system in podocytes experiencing glucose overload has a differential impact on differentiation, cytoskeleton organisation, apoptosis, CD63 distribution, and miRNA levels. Generally, when cells are subjected to glucose stress and the Rab system is silenced, we observed a reduction in the detrimental cell processes. These results suggest that the Rab3A/Rab27A system is a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy. Diabetic nephropathy is a major complication in diabetic patients. Podocytes undergo loss and detachment from the basal membrane. Intra- and intercellular communication through exosomes are key processes for maintaining function, and the Rab3A/Rab27A system is an important counterpart. Previously, we observed significant changes in the Rab3A/Rab27A system in podocytes under glucose overload, demonstrating its important role in podocyte injury. We investigated the implication of silencing the Rab3A/Rab27A system in high glucose-treated podocytes and analysed the effect on differentiation, apoptosis, cytoskeletal organisation, vesicle distribution, and microRNA expression in cells and exosomes. For this, we subjected podocytes to high glucose and transfection through siRNAs, and we isolated extracellular vesicles and performed western blotting, transmission electron microscopy, RT-qPCR, immunofluorescence and flow cytometry assays. We found that silencing RAB3A and RAB27A generally leads to a decrease in podocyte differentiation and cytoskeleton organization and an increase in apoptosis. Moreover, CD63-positive vesicles experienced a pattern distribution change. Under high glucose, Rab3A/Rab27A silencing ameliorates some of these detrimental processes, suggesting a differential influence depending on the presence or absence of cellular stress. We also observed substantial expression changes in miRNAs that were relevant in diabetic nephropathy upon silencing and glucose treatment. Our findings highlight the Rab3A/Rab27A system as a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. Methods: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25–30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. Results: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7–13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73–6.28] for normal weight, 2.50 [95% CI: 1.34–4.66] for overweight, and 3.42 [95% CI: 1.81–6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36–3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10–1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). Conclusions: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention. [ABSTRACT FROM AUTHOR]

The potential joint influence of metabolites on bone fragility has been rarely evaluated. We assessed the association of plasma metabolic patterns with bone fragility endpoints (primarily, incident osteoporosis-related bone fractures, and, secondarily, bone mineral density BMD) in the Hortega Study participants. Redox balance plays a key role in bone metabolism. We also assessed differential associations in participant subgroups by redox-related metal exposure levels and candidate genetic variants. In 467 participants older than 50 years from the Hortega Study, a representative sample from a region in Spain, we estimated metabolic principal components (mPC) for 54 plasma metabolites from NMR-spectrometry. Metals biomarkers were measured in plasma by AAS and in urine by HPLC-ICPMS. Redox-related SNPs (N = 341) were measured by oligo-ligation assay. The prospective association with incident bone fractures was inverse for mPC1 (non-essential and essential amino acids, including branched-chain, and bacterial co-metabolites, including isobutyrate, trimethylamines and phenylpropionate, versus fatty acids and VLDL) and mPC4 (HDL), but positive for mPC2 (essential amino acids, including aromatic, and bacterial co-metabolites, including isopropanol and methanol). Findings from BMD models were consistent. Participants with decreased selenium and increased antimony, arsenic and, suggestively, cadmium exposures showed higher mPC2-associated bone fractures risk. Genetic variants annotated to 19 genes, with the strongest evidence for NCF4, NOX4 and XDH, showed differential metabolic-related bone fractures risk. Metabolic patterns reflecting amino acids, microbiota co-metabolism and lipid metabolism were associated with bone fragility endpoints. Carriers of redox-related variants may benefit from metabolic interventions to prevent the consequences of bone fragility depending on their antimony, arsenic, selenium, and, possibly, cadmium, exposure levels. • Several metabolic patterns, so-called mPCs, were associated with bone fragility endpoints. • For mPC2, the bone fracture risk was higher with high exposure to Sb, As and, suggestively, Cd, and low Se. • Carriers of genetic variants in NCF4, NOX4 and XDH showed differential metabolic-related bone fracture risk. • Identified gene-environment statistical interactions may be relevant for metabolic bone fragility prevention. [ABSTRACT FROM AUTHOR]

Previous studies focused on the relationships between Serum Uric Acid (SUA) and lipids have found an association mainly with triglycerides. Furthermore, previous studies on adiposity indices have been focused on the evaluation of the Visceral Adiposity Index (VAI). The present study was aimed at providing within the same population a systematic evaluation of lipids and adiposity indices with SUA, employing both the classic cutoff for hyperuricemia and the newly one identified by the Uric Acid Right for Heart Health (URRAH) study. We analyzed data collected in 1892 subjects of the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) study with available SUA, lipid profile and variables necessary to calculate VAI, Cardio‐Metabolic Index (CMI) and Lipid Accumulation Product (LAP). At linear regression model (corrected for confounders) SUA correlated with all the lipids values (with the strongest β for triglycerides) and adiposity indices. When the two different cutoffs were compared, the URRAH one was significantly related to atherogenic lipids profile (OR 1.207 for LDL and 1.33 for non‐HDL, P < 0.001) while this was not the case for the classic one. Regarding adiposity indices the classic cutoff displays highest OR as compared to the URRAH one. In conclusions, newly reported URRAH cutoff for hyperuricemia better relate to atherogenic lipoprotein (LDL and non‐HDL) when compared to the classic one. The opposite has been found for adiposity indexes where the classic cut‐off seems to present highest performance. Among adiposity indexes, LAP present the highest OR for the relationship with hyperuricemia. [ABSTRACT FROM AUTHOR]

Cullin-RING ubiquitin E3 ligase (CRLs) composed of four components including cullin scaffolds, adaptors, substrate receptors, and RING proteins mediates the ubiquitination of approximately 20% of cellular proteins that are involved in numerous biological processes. While CRLs deregulation contributes to the pathogenesis of many diseases, including cancer, how CRLs deregulation occurs is yet to be fully investigated. Here, we demonstrate that components of CRL3 and its transcriptional regulators are possible prognosis marker of neuroendocrine (NE) cancer. Analysis of Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal revealed that expression of CRL3 scaffold Cullin 3 (CUL3) highly correlates with NE signature, and CUL3 silencing inhibited NE cancer proliferation. Moreover, subset of 151 BTB (Bric-a-brac, Tramtrack, Broad complex) domain-containing proteins that have dual roles as substrate receptors and adaptor subunits in CRL3, as well as the expression of transcription factors (TFs) that control the transcription of BTB genes were upregulated in NE cancer. Analysis using published ChIP-sequencing data in small cell lung cancer (SCLC), including NE or non-NE SCLC verified that gene promoter of candidates which show high correlation with NE signature enriched H3K27Ac. These observations suggest that CRL3 is a master regulator of NE cancer and knowledge of specifically regulated CRL3 genes in NE cancer may accelerate new therapeutic approaches. • Cullin 3 is highly expressed in neuroendocrine cancer. • Subgroups of BTBs are highly expressed in neuroendocrine cancer. • Multiple modules in the transcription factors-BTBs-CRL3 axis are promising novel biomarkers in neuroendocrine cancer. [ABSTRACT FROM AUTHOR]

Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves. We then identified a regulatory network of more than 23,000 activation and inhibition links between 216 TFs. Within this network, we observed previously unknown inferred transcriptional activations linking IRX3 and IRX5 TFs to three master cardiac TFs: GATA4, NKX2-5 and TBX5. Luciferase and co-immunoprecipitation assays demonstrated that these five TFs could (1) activate each other's expression; (2) interact physically as multiprotein complexes; and (3) together, finely regulate the expression of SCN5A, encoding the major cardiac sodium channel. Altogether, these results unveiled thousands of interactions between TFs, generating multiple robust hypotheses governing human cardiac development. [ABSTRACT FROM AUTHOR]