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Introduction: Bioinformatics is a relatively recent multidisciplinary research field continuously offering novel opportunities. Although many researchers are actively working in/with bioinformatics, some research centers still face difficulties in hiring bioinformaticians and establishing the appropriate (first) bioinformatics infrastructures and computational resources. In our research center, we started from scratch and established initial bioinformatics infrastructures for common use and also for the specific case of precision/personalized medicine. Case description: Here, we report a case study reflecting our specific needs and circumstances during the implementation of a novel bioinformatics laboratory. This involved the preparation of rooms, computer networks, computational resources novel designs, and upgrades to existing designs. Moreover, this work involved people from diverse areas and institutions, such as companies, institutional projects, informatics, and technical infrastructures services. Discussion and evaluation: The work resulted in the implementation of four novel designs dedicated to genomic medicine and in the adaptation of two existing designs dedicated to common use located in the dry-lab room. This is not an accurate and objective work, as it often depends on the available computer hardware and the target bioinformatics field(s). The four novel designs offered substantial improvements when compared to the upgraded designs, additionally corroborated by performance evaluations, which resulted in an overall highest performance of the novel designs. Conclusions: We present work that was developed over two years until completion with functioning infrastructure. This project enabled us to learn many novel aspects not only related to redundant disk technologies, but also related to computer networks, hardware, storage-management operating systems, file systems, performance evaluation, and also in the management of services. Moreover, additional equipment will be important to maintain and expand the potential and reliability of the bioinformatics laboratory. We hope that this work can be helpful for other researchers seeking to design their bioinformatics equipment or laboratories.

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-β-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.

Tenacibaculum maritimum , the etiological agent of tenacibaculosis in marine fish, constitutively secretes extracellular products (ECPs) in which protein content has not been yet comprehensively studied. In this work, the prevalence of extracellular proteolytic and lipolytic activities related to virulence was analyzed in 64 T. maritimum strains belonging to the O1–O4 serotypes. The results showed the existence of a great intra-specific heterogeneity in the enzymatic capacity, particularly within serotype O4. Thus, the secretome of a strain belonging to this serotype was characterized by analyzing the protein content of ECPs and the possible production of outer membrane vesicles (OMVs). Notably, the ECPs of T. maritimum SP9.1 contain a large amount of OMVs that were characterized by electron microscopy and purified. Thus, ECPs were divided into soluble (S-ECPs) and insoluble fractions (OMVs), and their protein content was analyzed by a high-throughput proteomic approach. A total of 641 proteins were identified in ECPs including some virulence-related factors, which were mainly found in one of the fractions, either OMVs or S-ECPs. Outer membrane proteins such as TonB-dependent siderophore transporters and the type IX secretion system (T9SS)-related proteins PorP, PorT, and SprA appeared to be mainly associated with OMVs. By contrast, putative virulence factors such as sialidase SiaA, chondroitinase CslA, sphingomyelinase Sph, ceramidase Cer, and collagenase Col were found only in the S-ECPs. These findings clearly demonstrate that T. maritimum releases, through surface blebbing, OMVs specifically enriched in TonB-dependent transporters and T9SS proteins. Interestingly, in vitro and in vivo assays also showed that OMVs could play a key role in virulence by promoting surface adhesion and biofilm formation and maximizing the cytotoxic effects of the ECPs. The characterization of T. maritimum secretome provides insights into ECP function and can constitute the basis for future studies aimed to elucidate the full role of OMVs in the pathogenesis of fish tenacibaculosis.

Siderophore production is a key fitness trait for bacteria, particularly in iron-limited environments such as marine ecosystems and host tissues. In this study, we identify the tenABECDC2D2hp1-4 gene cluster as responsible for siderophore biosynthesis in Tenacibaculum maritimum , confirmed through genome analysis and a tenCD -inactivated mutant. This cluster, highly similar to the desferrioxamine biosynthesis system in Streptomyces coelicolor , features a unique tenCD duplication/fusion, essential for siderophore formation. Additionally, accessory genes ( hp1-4 ) encode functions such as nitroreductase and N -acetyltransferase, likely contributing to siderophore diversification. LC/MS analysis of T. maritimum cultures revealed the production of 20 amphiphilic, acylated desferrioxamine-like siderophores. These findings provide new insights into the genetic and metabolic versatility of marine pathogens in iron acquisition.

Aeromonas salmonicida subsp. salmonicida (A. salmonicida), a Gram-negative bacterium causing furunculosis in fish, produces the siderophores acinetobactin and amonabactins in order to extract iron from its hosts. While the synthesis and transport of both systems is well understood, the regulation pathways and conditions necessary for the production of each one of these siderophores are not clear. The acinetobactin gene cluster carries a gene (asbI) encoding a putative sigma factor belonging to group 4 σ factors, or, the ExtraCytoplasmic Function (ECF) group. By generating a null asbI mutant, we demonstrate that AsbI is a key regulator that controls acinetobactin acquisition in A. salmonicida, since it directly regulates the expression of the outer membrane transporter gene and other genes necessary for Fe-acinetobactin transport. Furthermore, AsbI regulatory functions are interconnected with other iron-dependent regulators, such as the Fur protein, as well as with other sigma factors in a complex regulatory network.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T>C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.

Iron acquisition is critical for bacterial survival and virulence, especially under the iron-limited conditions encountered in host environments. This study uncovers unexpected siderophore diversification within the piscibactin pathway, including two novel catecholate analogs and fluorinated derivatives produced via precursor-directed biosynthesis. We identify Irp5 as a versatile salicylate-activating enzyme that drives this metabolic flexibility. Moreover, the piscibactin and vanchrobactin systems interact at both biosynthetic and uptake levels, forming a resilient and adaptable iron acquisition network that supports virulence. These findings advance our understanding of siderophore-mediated iron acquisition and illustrate how enzymatic promiscuity and system interplay can be leveraged for synthetic biology and antimicrobial development. Given the widespread distribution of irp -HPI in Vibrionaceae , including human pathogens, our study provides a foundation for the rational design of antimicrobial strategies.

Accumulation of amyloid-beta (Aβ) in the brain is thought to derive from the impairment of Aβ clearance mechanisms rather than from its overproduction, which consequently contributes to the development of Alzheimer’s disease. The choroid plexus epithelial cells constitute an important clearance route for Aβ, either by facilitating its transport from the cerebrospinal fluid to the blood, or by synthesizing and secreting various proteins involved in Aβ degradation. Impaired choroid plexus synthesis, secretion, and transport of these Aβ-metabolizing enzymes have been therefore associated with the disruption of Aβ homeostasis and amyloid load. Factors such as aging, female gender, and circadian rhythm disturbances are related to the decline of choroid plexus functions that may be involved in the modulation of Aβ-clearance mechanisms. In this study, we investigated the impact of age, sex hormones, and circadian rhythm on the expression of Aβ scavengers such as apolipoprotein J, gelsolin, and transthyretin at the rat choroid plexus. Our results demonstrated that mRNA expression and both intracellular and secreted protein levels of the studied Aβ scavengers are age-, sex-, and circadian-dependent. These data suggest that the Aβ-degradation and clearance pathways at the choroid plexus, mediated by the presence of Aβ scavengers, might be compromised as a consequence of aging and circadian disturbances. These are important findings that enhance the understanding of Aβ-clearance-regulating mechanisms at the blood–cerebrospinal fluid barrier.

ABSTRACT Rhipicephalus ticks are competent vectors of several pathogens, such as Spotted Fever Group Rickettsiae (SFGR) and many Babesia species. Within this genus, different R. sanguineus s.l. lineages show an unequal vector competence and resistance regarding some pathogenic strains. Current literature supports that tick endosymbionts may play an essential role in the transmission ability of a vector. Indeed, the microbial community of Rhipicephalus seems to be dominated by Coxiella-like endosymbionts (CLE). Still, their co-evolutionary associations with the complicated phylogeny of Rhipicephalus lineages and their transmissible pathogens remain unclear. We performed a phylogenetic congruence analysis to address whether divergent R. sanguineus s.l. lineages had a different symbiont composition. For that, we applied a PCR based approach to screen part of the microbial community present in 279 Rhipicephalus ticks from the Iberian Peninsula and Africa. Our analyses detected several qPCR-positive signals for both SFGR and Babesia species, of which we suggest R. sanguineus-tropical lineage as a natural vector of Babesia vogeli and R. sanguineus-temperate lineage of SFGR. The acquisition of 190 CLE sequences allowed to evaluate co-phylogenetic associations between the tick and the symbiont. With this data, we observed a strong but incomplete co-cladogenesis between CLE strains and their Rhipicephalus tick lineages hosts. Coxiella and Rhipicephalus mitochondrial lineages revealed an almost complete co-cladogenesis signature between ixodid lineages and endosymbiont strains, evidencing the strong co-evolutionary history between these taxa.

The World Food Programme, in collaboration with the Mozambique National Meteorology Institute, is partnering with several governmental and non-governmental organizations to establish an advanced early warning system for droughts in pilot districts across Mozambique. The “Ready, Set & Go!” system is operational in Mozambique for activating anticipatory action (AA) against droughts based on predefined thresholds, triggers and pre-allocated financing. The system uses bias-corrected and downscaled seasonal forecasts from the European Centre for Medium-Range Weather Forecasts (ECMWF) as core information to anticipate severe reductions in rainfall during the rainy season. This information guides the implementation of actions to reduce the impacts of rainfall deficits in the critical window between a forecast and the onset of the drought event. Within this window of opportunity, the system releases an alert for readiness (Ready) and activation (Set) preceding the mobilization of anticipatory action on the ground (Go). With the recent adoption of the Southern African Development Community “Maputo Declaration on Bridging the Gap between Early Warning and Early Action”, member states have committed to enhancing the reach of early warning system by leaving no one behind. Therefore, there is a need to assess the opportunities and limitations of the Ready, Set & Go! system to scale up drought AA information to all districts in Mozambique. This study describes the Ready, Set & Go! system, which uses ensemble forecasts of the Standardized Precipitation Index to trigger anticipatory action against droughts on a seasonal timescale. The Ready, Set & Go! optimizes the use of seasonal forecast information by choosing triggers for anticipatory action based on verification statistics and on a double-confirmation process, which combines longer lead times with shorter lead time forecasts for issuing drought alerts. In this study, we show the strengths of the system by benchmarking it against three simpler triggering approaches. Our findings indicate that the Ready, Set & Go! system has significant potential to scale up AA activities against severe droughts throughout the entire rainy season, covering on average 76 % of the Mozambican districts. This approach outperforms the three benchmarked methods, demonstrating higher hit rates, extended lead times and a lower false alarm. If efforts are concentrated on the first part of the rainy season, national coverage against severe droughts could be expanded to 87 % of all districts. By aligning with the objectives outlined in the “Maputo Declaration” and the “Early Warning for All” initiative, this research contributes to safeguarding communities against the adverse impacts of climate-related events, aligning with the ambitious goal of universal protection by 2027.