Depolymerization of SUMO chains induces slender to stumpy differentiation in T. brucei bloodstream parasites.

Trypanosoma brucei are protozoan parasites that cause sleeping sickness in humans and nagana in cattle. Inside the mammalian host, a quorum sensing-like mechanism coordinates its differentiation from a slender replicative form into a quiescent stumpy form, limiting growth and activating metabolic pathways that are beneficial to the parasite in the insect host. The post-translational modification of proteins with the Small Ubiquitin-like MOdifier (SUMO) enables dynamic regulation of cellular metabolism. SUMO can be conjugated to its targets as a monomer but can also form oligomeric chains. Here, we have investigated the role of SUMO chains in T. brucei by abolishing the ability of SUMO to polymerize. We have found that parasites able to conjugate only SUMO monomers are primed for differentiation. This was demonstrated for monomorphic lines that are normally unable to produce stumpy forms in response to quorum sensing signaling in mice, and also for pleomorphic cell lines in which stumpy cells were observed at unusually low parasitemia levels. SUMO chain mutants showed a stumpy compatible transcriptional profile and better competence to differentiate into procyclics. Our study indicates that SUMO depolymerization may represent a coordinated signal triggered during stumpy activation program.

Structured Tandem Repeats in Protein Interactions.

Tandem repeats (TRs) in protein sequences are consecutive, highly similar sequence motifs. Some types of TRs fold into structural units that pack together in ensembles, forming either an (open) elongated domain or a (closed) propeller, where the last unit of the ensemble packs against the first one. Here, we examine TR proteins (TRPs) to see how their sequence, structure, and evolutionary properties favor them for a function as mediators of protein interactions. Our observations suggest that TRPs bind other proteins using large, structured surfaces like globular domains; in particular, open-structured TR ensembles are favored by flexible termini and the possibility to tightly coil against their targets. While, intuitively, open ensembles of TRs seem prone to evolve due to their potential to accommodate insertions and deletions of units, these evolutionary events are unexpectedly rare, suggesting that they are advantageous for the emergence of the ancestral sequence but are early fixed. We hypothesize that their flexibility makes it easier for further proteins to adapt to interact with them, which would explain their large number of protein interactions. We provide insight into the properties of open TR ensembles, which make them scaffolds for alternative protein complexes to organize genes, RNA and proteins.

The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model, the Ts65Dn, through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem brain tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of DG in the memory deficits observed in Down syndrome.

Plantar keratoderma-like crusted scabies in an immunocompetent infant after topical steroids.

A healthy 6-month-old girl presented with plantar keratoderma-like lesions unresponsive to topical corticosteroids. Nocturnal pruritus in 13 relatives, presence of burrows on clinical exam, and the positive scabies preparation led to the diagnosis of crusted scabies. She was successfully treated with topical and oral scabicides. Crusted scabies is a severe form of Sarcoptes scabiei infection uncommon in immunocompetent subjects, in whom previous corticosteroid use may favor its occurrence.

A Systematic Review of Lipid-Focused Cardiovascular Disease Research: Trends and Opportunities.

Lipids are important modifiers of protein function, particularly as parts of lipoproteins, which transport lipophilic substances and mediate cellular uptake of circulating lipids. As such, lipids are of particular interest as blood biological markers for cardiovascular disease (CVD) as well as for conditions linked to CVD such as atherosclerosis, diabetes mellitus, obesity and dietary states. Notably, lipid research is particularly well developed in the context of CVD because of the relevance and multiple causes and risk factors of CVD. The advent of methods for high-throughput screening of biological molecules has recently resulted in the generation of lipidomic profiles that allow monitoring of lipid compositions in biological samples in an untargeted manner. These and other earlier advances in biomedical research have shaped the knowledge we have about lipids in CVD. To evaluate the knowledge acquired on the multiple biological functions of lipids in CVD and the trends in their research, we collected a dataset of references from the PubMed database of biomedical literature focused on plasma lipids and CVD in human and mouse. Using annotations from these records, we were able to categorize significant associations between lipids and particular types of research approaches, distinguish non-biological lipids used as markers, identify differential research between human and mouse models, and detect the increasingly mechanistic nature of the results in this field. Using known associations between lipids and proteins that metabolize or transport them, we constructed a comprehensive lipid-protein network, which we used to highlight proteins strongly connected to lipids found in the CVD-lipid literature. Our approach points to a series of proteins for which lipid-focused research would bring insights into CVD, including Prostaglandin G/H synthase 2 (PTGS2, a.k.a. COX2) and Acylglycerol kinase (AGK). In this review, we summarize our findings, putting them in a historical perspective of the evolution of lipid research in CVD.

Intranuclear inclusions of polyQ-expanded ATXN1 sequester RNA molecules.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in the ATXN1 gene. It is characterized by the presence of polyglutamine (polyQ) intranuclear inclusion bodies (IIBs) within affected neurons. In order to investigate the impact of polyQ IIBs in SCA1 pathogenesis, we generated a novel protein aggregation model by inducible overexpression of the mutant ATXN1(Q82) isoform in human neuroblastoma SH-SY5Y cells. Moreover, we developed a simple and reproducible protocol for the efficient isolation of insoluble IIBs. Biophysical characterization showed that polyQ IIBs are enriched in RNA molecules which were further identified by next-generation sequencing. Finally, a protein interaction network analysis indicated that sequestration of essential RNA transcripts within ATXN1(Q82) IIBs may affect the ribosome resulting in error-prone protein synthesis and global proteome instability. These findings provide novel insights into the molecular pathogenesis of SCA1, highlighting the role of polyQ IIBs and their impact on critical cellular processes.

The nucleotide landscape of polyXY regions.

PolyXY regions are compositionally biased regions composed of two different amino acids. They are classified according to the arrangement of the two amino acid types 'X' and 'Y' into direpeats (composed of alternating amino acids, e.g. 'XYXYXY'), joined (composed of two consecutive stretches of each amino acid, e.g. 'XXXYYY') and shuffled (other arrangements, e.g., 'XYXXYY'). They have been characterized at the amino acid level in all domains of life, and are described as often found within intrinsically disordered regions. Since DNA replication slippage has been proposed as a driver of repeat variation, and given that some polyXY have a repetitive nature, we hypothesized that characterizing the nucleotide coding of various types of polyXY could give hints about their origin and evolution. To test this, we obtained all polyXY regions in the human transcriptome, categorized them, and studied their coding nucleotide sequences. We observed that polyXY exacerbates the codon biases, and that the similarity between the X and Y codons is higher than in the background proteome. Our results support a general mechanism of emergence and evolution of polyXY from single-codon polyX. PolyXY are revealed as hotspots for replication slippage, particularly those composed of repeats: joined and direpeat polyXY. Inter-conversion to shuffled polyXY disrupts nucleotide repeats and restricts further evolution by replication slippage, a mechanism that we previously observed in polyX. Our results shed light on polyXY composition and should simplify the determination of their functions.

Corrigendum: Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

[This corrects the article DOI: 10.3389/fmicb.2023.1149145.].

Structure-function relationships in protein homorepeats.

Homorepeats (or polyX), protein segments containing repetitions of the same amino acid, are abundant in proteomes from all kingdoms of life and are involved in crucial biological functions as well as several neurodegenerative and developmental diseases. Mainly inserted in disordered segments of proteins, the structure/function relationships of homorepeats remain largely unexplored. In this review, we summarize present knowledge for the most abundant homorepeats, highlighting the role of the inherent structure and the conformational influence exerted by their flanking regions. Recent experimental and computational methods enable residue-specific investigations of these regions and promise novel structural and dynamic information for this elusive group of proteins. This information should increase our knowledge about the structural bases of phenomena such as liquid-liquid phase separation and trinucleotide repeat disorders.

The importance of planning CT-based imaging features for machine learning-based prediction of pain response.

Patients suffering from painful spinal bone metastases (PSBMs) often undergo palliative radiation therapy (RT), with an efficacy of approximately two thirds of patients. In this exploratory investigation, we assessed the effectiveness of machine learning (ML) models trained on radiomics, semantic and clinical features to estimate complete pain response. Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomics, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation. The best radiomics classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01). We could demonstrate that radiomics and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results.

The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of the DG in the memory deficits observed in Down syndrome.

Selection of Multi-Drug Targets against Drug-Resistant Mycobacterium tuberculosis XDR1219 Using the Hyperbolic Mapping of the Protein Interaction Network.

Tuberculosis remains the leading cause of death from a single pathogen. On the other hand, antimicrobial resistance (AMR) makes it increasingly difficult to deal with this disease. We present the hyperbolic embedding of the Mycobacterium tuberculosis protein interaction network (mtbPIN) of resistant strain (MTB XDR1219) to determine the biological relevance of its latent geometry. In this hypermap, proteins with similar interacting partners occupy close positions. An analysis of the hypermap of available drug targets (DTs) and their direct and intermediate interactors was used to identify potentially useful drug combinations and drug targets. We identify rpsA and rpsL as close DTs targeted by different drugs (pyrazinamide and aminoglycosides, respectively) and propose that the combination of these drugs could have a synergistic effect. We also used the hypermap to explain the effects of drugs that affect multiple DTs, for example, forcing the bacteria to deal with multiple stresses like ethambutol, which affects the synthesis of both arabinogalactan and lipoarabinomannan. Our strategy uncovers novel potential DTs, such as dprE1 and dnaK proteins, which interact with two close DT pairs: arabinosyltransferases (embC and embB), Ser/Thr protein kinase (pknB) and RNA polymerase (rpoB), respectively. Our approach provides mechanistic explanations for existing drugs and suggests new DTs. This strategy can also be applied to the study of other resistant strains.

The Use of Crystal Violet Degradation Products for Ballpoint Pen Ink Manuscript Dating.

Determining the approximate dates that written documents were drawn up based on the chemical composition of the ink is not a simple process. It is very demanding in terms of legal requirements. Various studies have succeeded in dating manuscripts by analyzing the temporal evolutions of the concentrations of dyes and solvents in documents based on the original formulations of the ink pens. These analyses were carried out simultaneously by HPLC-DAD for dyes and by GC-MS for solvents. This study aims, for the first time, to evaluate novel ink compounds and the temporal evolution of the concentrations of the degradation products of the dyes used by most suppliers and which are present in almost all types of ballpoint inks, i.e., Crystal Violet (CV). CV degrades through two parallel pathways: on the one hand, it undergoes progressive demethylation until it becomes pararosaniline, and on the other, it undergoes a breakdown of the molecule obtaining, among other by-products, the compound N,N'-Dimethyl-4-aminophenol (NNAPH), that was experimentally verified using four different inks (e.g., Inoxcrom® and Sigma® brands, in blue and black). For the NNAPH compound, we observed that four of the inks under analysis displayed the same temporary behavior despite having different initial chemical compositions. These initial results show the high potential for both CV and NNAPH, together with the rest of the pararosaniline family, as age tracers for dated/old documents. These techniques may potentially open up new avenues for universal dating tools, regardless of the brands of ink employed for use in different ballpoint pen types.

One Step Closer to the Understanding of the Relationship IDR-LCR-Structure.

Intrinsically disordered regions (IDRs) in protein sequences are emerging as functionally important elements for interaction and regulation. While being generally flexible, we previously showed, by observation of experimentally obtained structures, that they contain regions of reduced sequence complexity that have an increased propensity to form structure. Here we expand the universe of cases taking advantage of structural predictions by AlphaFold. Our studies focus on low complexity regions (LCRs) found within IDRs, where these LCRs have only one or two residue types (polyX and polyXY, respectively). In addition to confirming previous observations that polyE and polyEK have a tendency towards helical structure, we find a similar tendency for other LCRs such as polyQ and polyER, most of them including charged residues. We analyzed the position of polyXY containing IDRs within proteins, which allowed us to show that polyAG and polyAK accumulate at the N-terminal, with the latter showing increased helical propensity at that location. Functional enrichment analysis of polyXY with helical propensity indicated functions requiring interaction with RNA and DNA. Our work adds evidence of the function of LCRs in interaction-dependent structuring of disordered regions, encouraging the development of tools for the prediction of their dynamic structural properties.

Strasseriolides display in vitro and in vivo activity against trypanosomal parasites and cause morphological and size defects in Trypanosoma cruzi.

Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates. We recently reported the discovery and bioassay-guided isolation of a novel family of macrolides with antiplasmodial activity. The novel family of four potent antimalarial macrolides, strasseriolides A-D, was isolated from cultures of Strasseria geniculata CF-247251, a fungal strain obtained from plant tissues. In the present study, we analyze these strasseriolides for activity against kinetoplastid protozoan parasites, namely, Trypanosoma brucei brucei, Leishmania donovani and Trypanosoma cruzi. Compounds exhibited mostly low activities against T. b. brucei, yet notable growth inhibition and selectivity were observed for strasseriolides C and D in the clinically relevant intracellular T. cruzi and L. donovani amastigotes with EC50 values in the low micromolar range. Compound C is fast-acting and active against both intracellular and trypomastigote forms of T. cruzi. While cell cycle defects were not identified, prominent morphological changes were visualized by differential interference contrast microscopy and smaller and rounded parasites were visualized upon exposure to strasseriolide C. Moreover, compound C lowers parasitaemia in vivo in acute models of infection of Chagas disease. Hence, strasseriolide C is a novel natural product active against different forms of T. cruzi in vitro and in vivo. The study provides an avenue for blocking infection of new cells, a strategy that could additionally contribute to avoid treatment failure.

Effects of high-intensity interval training with an eccentric hamstring exercise program in futsal players: A randomized controlled trial.

BACKGROUND: Physiotherapy protocols based on high-intensity interval training (HIIT) or eccentric hamstring exercises like Nordic Curl (NC) have been scarcely studied in futsal players. The objective of this study was to compare the effectiveness of a HIIT combined with an NC exercise program versus a HIIT-only program in futsal players. METHODS: Twenty-one futsal players were divided into (1) HIIT + NC group (n = 11, mean age = 21.55 [4.25]); and (2) HIIT group (n = 10, mean age = 20.90 [1.29]). The HIIT + NC group performed a HIIT circuit combined with 3 sets of 10 NC repetitions for 4 weeks, while the HIIT group performed the same protocol without NC exercise. Body mass index, intermittent work performance, vertical jump performance without and with arms, isometric strength of quadriceps and hamstrings, and the isometric hamstrings/quadriceps (H/Q) ratio, were assessed before and after the interventions. RESULTS: The HIIT + NC group and the HIIT group showed a significant improvement in intermittent work performance after the intervention (P = .04 and P = .01, respectively). Also, both groups showed a trend of increasing quadriceps and hamstring isometric strength, although no significant changes were found (P > .05). In addition, neither the HIIT + NC protocol nor the HIIT protocol was sufficient to yield changes in body mass index nor to improve the vertical jump performance (P > .05). CONCLUSION: Both an isolated HIIT protocol and HIIT in combination with NC exercise improved intermittent work performance in futsal players. The present study's findings may guide futsal players' physical preparation and injury prevention programs.

A STRP-ed definition of Structured Tandem Repeats in Proteins.

Tandem Repeat Proteins (TRPs) are a class of proteins with repetitive amino acid sequences that have been studied extensively for over two decades. Different features at the level of sequence, structure, function and evolution have been attributed to them by various authors. And yet many of its salient features appear only when looking at specific subclasses of protein tandem repeats. Here, we attempt to rationalize the existing knowledge on Tandem Repeat Proteins (TRPs) by pointing out several dichotomies. The emerging picture is more nuanced than generally assumed and allows us to draw some boundaries of what is not a "proper" TRP. We conclude with an operational definition of a specific subset, which we have denominated STRPs (Structural Tandem Repeat Proteins), which separates a subclass of tandem repeats with distinctive features from several other less well-defined types of repeats. We believe that this definition will help researchers in the field to better characterize the biological meaning of this large yet largely understudied group of proteins.

Evolutionary Study of Protein Short Tandem Repeats in Protein Families.

Tandem repeats in proteins are patterns of residues repeated directly adjacent to each other. The evolution of these repeats can be assessed by using groups of homologous sequences, which can help pointing to events of unit duplication or deletion. High pressure in a protein family for variation of a given type of repeat might point to their function. Here, we propose the analysis of protein families to calculate protein short tandem repeats (pSTRs) in each protein sequence and assess their variability within the family in terms of number of units. To facilitate this analysis, we developed the pSTR tool, a method to analyze the evolution of protein short tandem repeats in a given protein family by pairwise comparisons between evolutionarily related protein sequences. We evaluated pSTR unit number variation in protein families of 12 complete metazoan proteomes. We hypothesize that families with more dynamic ensembles of repeats could reflect particular roles of these repeats in processes that require more adaptability.

Circulating microRNAs predict recurrence and death following venous thromboembolism.

BACKGROUND: Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating microRNAs (miRNAs) has yet to be explored in detail. OBJECTIVES: To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement. METHODS: Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses. RESULTS: A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HRSD, 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (ORSD for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis. CONCLUSION: Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.

Complications associated with vertical bone augmentation techniques in implant dentistry: A systematic review of clinical studies published in the last ten years.

Vertical bone augmentation procedures are increasingly necessary in daily practice. However, it has been reported that vertical ridge augmentation is one of the least predictable techniques in terms of complications. The aim of this systematic review was to evaluate and compare complications in relation to the different procedures used for vertical bone augmentation prior to implant placement. This review was conducted according to PRISMA guidelines. An electronic search was carried out in four databases: The National Library of Medicine (MEDLINE/PubMed); Web of Science; SCOPUS; and Cochrane Central Register of Controlled Trials (CENTRAL). The Newcastle-Ottawa Quality Assessment Scale, the Cochrane Collaboration tool for assessing risk of bias, and The Joanna Briggs Institute Critical Appraisal tool were used to assess the quality of evidence in the studies reviewed. Twenty-five studies with a total of 749 vertically augmented sites were included in the review. Complication rates varied among the different procedures: 51.02% for distraction osteogenesis, 38.01% for bone blocks, and 16.80% for guided bone regeneration. Vertical bone augmentation procedures prior to implant placement are associated with frequent surgical complications and should be approached with caution due to their possible impact on clinical treatment success.