CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours

BACKGROUND: Neuroblastoma is a paediatric tumour originated from sympathoadrenal precursors and characterized by its heterogeneity and poor outcome in advanced stages. Intra-tumoral cellular heterogeneity has emerged as an important feature in neuroblastoma, with a potential major impact on tumour aggressiveness and response to therapy. CD44 is an adhesion protein involved in tumour progression, metastasis and stemness in different cancers; however, there has been controversies about the significance of CD44 expression in neuroblastoma and its relationship with tumour progression. METHODS: We have performed transcriptomic analysis on patient tumour samples studying the outcome of patients with high CD44 expression. Adhesion, invasion and proliferation assays were performed in sorted CD44high neuroblastoma cells. Tumoursphere cultures have been used to enrich in undifferentiated stem-like cells and to asses self-renewal and differentiation potential. We have finally performed in vivo tumorigenic assays on cell line-derived or Patient-derived xenografts. FINDINGS: We show that high CD44 expression is associated with low survival in high-grade human neuroblastoma, independently of MYCN amplification. CD44 is expressed in a cell population with neural crest stem-like features, and with the capacity to generate multipotent, undifferentiated tumourspheres in culture. These cells are more invasive and proliferative in vitro. CD44 positive cells obtained from tumours are more tumorigenic and metastatic, giving rise to aggressive neuroblastic tumours at high frequency upon transplantation. INTERPRETATION: We describe an unexpected intra-tumoural heterogeneity within cellular entities expressing CD44 in neuroblastoma, and propose that CD44 has a role in neural crest stem-like undifferentiated cells, which can contribute to tumorigenesis and malignancy in this type of cancer. FUNDING: Research supported by grants from the "Asociación Española contra el Cáncer" (AECC), the Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P), and the European Research Council (ERC Starting Grant to RP).Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

Zika virus (ZIKV) is a mosquito-borne flavivirus in which human infection became relevant during recent outbreaks in Latin America due to its unrecognized association with fetal neurological disorders. Currently, there are no approved effective antivirals or vaccines for the treatment or prevention of ZIKV infections. Amantadine and rimantadine are approved antivirals used against susceptible influenza A virus infections that have been shown to have antiviral activity against other viruses, such as dengue virus (DENV). Here, we report the in vitro effectiveness of both amantadine and rimantadine hydrochlorides against ZIKV replication, resulting in a dose-dependent reduction in viral titers of a ZIKV clinical isolate and two different ZIKV reference strains. Additionally, we demonstrate similar in vitro antiviral activity of these drugs against DENV-1 and yellow fever virus (YFV), although at higher drug concentrations for the latter. ZIKV replication was inhibited at drug concentrations well below cytotoxic levels of both compounds, as denoted by the high selectivity indexes obtained with the tested strains. Further work is absolutely needed to determine the potential clinical use of these antivirals against ZIKV infections, but our results suggest the existence of a highly conserved mechanism across flavivirus, susceptible to be blocked by modified more specific adamantane compounds.Centro de Investigación en Enfermedades Tropicales, Facultad de Microbiología, Universidad de Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

The UlaG protein family defines novel structural and functional motifs grafted on an ancient RNase fold

Background: Bacterial populations are highly successful at colonizing new habitats and adapting to changing environmental conditions, partly due to their capacity to evolve novel virulence and metabolic pathways in response to stress conditions and to shuffle them by horizontal gene transfer (HGT). A common theme in the evolution of new functions consists of gene duplication followed by functional divergence. UlaG, a unique manganese-dependent metallo-b-lactamase (MBL) enzyme involved in L-ascorbate metabolism by commensal and symbiotic enterobacteria, provides a model for the study of the emergence of new catalytic activities from the modification of an ancient fold. Furthermore, UlaG is the founding member of the so-called UlaG-like (UlaGL) protein family, a recently established and poorly characterized family comprising divalent (and perhaps trivalent)metal-binding MBLs that catalyze transformations on phosphorylated sugars and nucleotides. Results: Here we combined protein structure-guided and sequence-only molecular phylogenetic analyses to dissect the molecular evolution of UlaG and to study its phylogenomic distribution, its relatedness with present-day UlaGL protein sequences and functional conservation. Phylogenetic analyses indicate that UlaGL sequences are present in Bacteria and Archaea, with bona fide orthologs found mainly in mammalian and plant-associated Gramnegative and Gram-positive bacteria. The incongruence between the UlaGL tree and known species trees indicates exchange by HGT and suggests that the UlaGL-encoding genes provided a growth advantage under changing conditions. Our search for more distantly related protein sequences aided by structural homology has uncovered that UlaGL sequences have a common evolutionary origin with present-day RNA processing and metabolizing MBL enzymes widespread in Bacteria, Archaea, and Eukarya. This observation suggests an ancient origin for the UlaGL family within the broader trunk of the MBL superfamily by duplication, neofunctionalization and fixation. Conclusions: Our results suggest that the forerunner of UlaG was present as an RNA metabolizing enzyme in the last common ancestor, and that the modern descendants of that ancestral gene have a wide phylogenetic distribution and functional roles. We propose that the UlaGL family evolved new metabolic roles among bacterial and possibly archeal phyla in the setting of a close association with metazoans, such as in the mammalian gastrointestinal tract or in animal and plant pathogens, as well as in environmental settings. Accordingly, the major evolutionary forces shaping the UlaGL family include vertical inheritance and lineage-specific duplication and acquisition of novel metabolic functions, followed by HGT and numerous lineage-specific gene loss events

Contribución al alcance estratigráfico de la Formación Agueguexquite (Mioceno), Veracruz, México

La Formación Agueguexquite aflora en el sureste de México, en el sur de Veracruz y norte de Chiapas. Su edad aún no ha sido determinada formalmente, estudios previos han considerado su depósito entre el Mioceno y el Plioceno. Moluscos y muestras de roca de tres localidades de la Formación Agueguexquite en el estado de Veracruz, fueron recolectados a fin de establecer el alcance estratigráfico de la formación por medio de edades relativas utilizando foraminíferos bentónicos y nanoplancton calcáreo, así como estratigrafía isotópica (Sr87/Sr86). La datación con foraminíferos bentónicos mostró un alcance estratigráfico amplio (Mioceno-Plioceno). La nanofauna calcárea muestra una edad de depósito del Mioceno medio-tardío, que fue corroborada con los resultados de la estratigrafía isotópica con (Sr87/ Sr86). Con base a los resultados obtenidos se sugiere que la Formación Agueguexquite fue depositada entre el Mioceno medio y tardío.The Agueguexquite Formation crops out in southeastern Mexico, in southern Veracruz and northern Chiapas; its age has not been formally determined, but previous studies consider that it was deposited between the Miocene and Pliocene. Mollusks and rock samples from three localities of the Agueguexquite Formation in Veracruz were collected in order to define the stratigraphic range of this formation by means of relative ages using benthic forams and calcareous nannoplankton, as well as isotopic stratigraphy (87Sr/86Sr). Dating with benthic forams indicates a broad stratigraphic range (Miocene-Pliocene); calcareous nannoplankton yielded a middle-late Miocene age, which is supported by the results of isotopic stratigraphy (87Sr/86Sr). Based on our stratigraphic results, it is suggested that the Agueguexquite Formation was deposited between the middle and late Miocene.Facultad de Ciencias Naturales y Muse

Tropical agroindustrial biowaste revalorization through integrative biorefineries—review part II: pineapple, sugarcane and banana by-products in Costa Rica

Biorefineries are a model for greener production processes, based on the concept of bioeconomy. Instead of targeting first-generation biofuels—that compete with food supply—the focus relies on lignocellulosic material, considering many aspects, such as sustainable fuel production, as well as valorization of waste, as an alternative to the traditional petrochemical approach of goods production. Especially, in tropical countries agricultural activities lead to tremendous amounts of biomass, resulting in waste that has to be dealt with. In the case of Costa Rica, the five major crops cultivated for export are coffee, oil palm, pineapple, sugarcane, and banana. Traditional ways of waste treatment cannot cope with the increasing amount of biomass produced and therefore, bear various challenges often related to increased pollution. This review aims to bring up the recent state of waste treatment but even more, stress potential opportunities of adding value to not used residues; thus, improve sustainability in the agro industrial sector. Part I of the review already highlighted the potential of producing promising bioactive chemical compounds by novel biorefinery concepts from agricultural waste originating from coffee and oil palm cultivation. This second part focuses on the lignocellulose-rich biowaste from pineapple, sugarcane, and banana, showing biorefinery concepts, where fuel and energy production, as well as establishment of novel products and new applications, play an important role. © 2022, The Author(s)

Efficacy of Physiotherapy Treatment in Primary Dysmenorrhea: A Systematic Review and Meta-Analysis

Primary dysmenorrhea (PD) refers to painful cramps before and/or during menstruation. There is a need for emphasis on alternative methods of conservative treatment, so as to reduce the dependence on drugs for alleviating the symptoms. The aim was to find out the effectiveness of some physiotherapy techniques in the treatment of PD. A systematic review and meta-analysis was conducted according to PRISMA standards. The descriptors were “dysmenorrhea”, “physical the-rapy”, “physiotherapy”, and “manual therapy”. The search was performed in five databases: Scopus, PubMed, PEDro, Web of Science, and Medline, in February 2021. The inclusion criteria were randomized controlled trials over the last six years. Articles not related to the treatment of PD or using pharmacology as the main treatment were excluded. Nine articles met the objectives and criteria, with a total of 692 participants. The most used scale to measure pain was the VAS (visual analogue scale). The main techniques were isometric exercises, massage therapy, yoga, electrotherapy, connective tissue manipulation, stretching, kinesio tape, progressive relaxation exercises and aerobic dance. Meta-analysis shows benefits of physiotherapy treatment for pain relief compared with no intervention or placebo (MD: −1.13, 95% CI: −1.61 to −0.64, I2: 88%). The current low-quality evidence suggests that physiotherapy may provide a clinically significant reduction in menstrual pain intensity. Given the overall health benefits of physiotherapy and the low risk of side effects reported, women may consider using it, either alone or in conjunction with other therapeutic modalities

Treatment of Dysphagia in Parkinson’s Disease: A Systematic Review

The incidence of oropharyngeal dysphagia in Parkinson’s disease (PD) is very high. It is necessary to search for effective therapies that could prevent pneumonia. Previous results should be interpreted cautiously as there is a lack of evidence to support the use of compensatory or rehabilitative approaches to dysphagia. We reviewed the scientific literature to describe the treatments of dysphagia in PD. A systematic review was performed in PubMed, Scopus, Elsevier, and Medline according to PRISMA standards in 2018. The articles that did not mention dysphagia secondary to PD or used surgical treatment were excluded. Eleven articles met the criteria with information from 402 patients. The review relates to different protocols, such as training in expiratory muscle strength, postural techniques, oral motor exercises, video-assisted swallowing therapy, surface electrical stimulation, thermal stimulation, touch, compensatory interventions, training regime for swallowing, neuromuscular electrical stimulation, Lee Silverman voice treatment, swallow maneuver, airway protection, and postural compensation maneuvers. This review identifies the rationing interventions in each trial, if they are efficient and equitable. Several rehabilitative therapies have been successful. An improvement was seen in the degenerative function (coordination, speed, and volume), quality of life, and social relationships of people with PD. Further investigations concerning the clinical applicability of these therapies based on well-designed randomized controlled studies are needed. Larger patient populations need to be recruited to evaluate the effectiveness, long-term effects, and new treatment techniques

Epidemiological characterization of incident cases of Rickettsia infection in rural areas of Urabá region, Colombia

Introduction Most of the studies related to rickettsial infection in Colombia are cross-sectional because of the challenge in conducting prospective studies on infectious disease that may have a difficult diagnosis. Although cross-sectional studies are essential to detect people exposed to rickettsiae, they are not suited to demonstrate the recent circulation of this pathogen in areas at risk of transmission. Objective To characterize the epidemiology of incident cases of Spotted fever group (SFG) rickettsial infection in humans and equines from rural areas of Uraba´ region in Colombia where outbreaks of rickettsiae previously occurred. Materials and methods A prospective study was conducted in the Alto de Mulatos and Las Changas in the Uraba´ region. Serum samples and socio-ecological information were collected from 597 people enrolled in 2015, and a second sample was collected from 273 people a year later. Indirect immune-fluorescence assays for detection of IgG antibody against rickettsiae were done using slides with Rickettsia rickettsii antigens. A titer 128 was considered positive. Incident cases were defined as (i) serological conversion of IgG titers from seronegative to seropositive or (ii) at least a four-fold increase in IgG end point titers in the second sample. Results The cumulative incidence of rickettsial infection was 6.23% (95%CI 3.67–9.78) in humans and 32.31% (21/65) of incident cases in equines. Incident cases were mostly females (82.35%), the median age of cases was 41.02 years (IQR 18.62–54.1), and 29.41% reported tick bites during the study period. Results from multivariate analysis showed that removal of ticks after working outdoors is a protective factor for rickettsial infection (RR 0.26, 95%CI 0.08–0.84) and that a higher incidence of infection occurred in people who reported fever in the last year (RR 4.26, 95%CI 1.15–9.31). Conclusions These results showed recent circulation of SFG rickettsiae in areas where previous lethal outbreaks have been reported, supporting the implementation of preventive measures to halt rickettsial transmission in the studied communities.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET