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Hypertensive ulcer, also known as Martorell ulcer, comprises cutaneous lesions induced by microvascular arteriolitis, which leads to ischaemia and subsequent ulceration in patients with long‐standing hypertension. These lesions predominantly affect women and have traditionally been considered rare; however, recent studies suggest that their prevalence may be significantly higher than previously assumed. Early and accurate diagnosis is crucial, as these ulcers are often mistaken for lesions of alternative aetiologies, such as venous ulcers or pyoderma gangrenosum, thereby contributing to their frequent underdiagnosis. Moreover, this pathology is associated with pronounced painful symptomatology and exhibits a suboptimal response to both analgesic regimens and conventional wound care protocols, potentially necessitating alternative management strategies. This diagnostic delay or misdiagnosis consequently escalates the utilisation of healthcare resources. The primary objective of this study was to develop a predictive model for the differential diagnosis of Martorell ulcers. The investigation entailed a systematic case review, during which the most prevalent signs and symptoms, medical histories and demographic characteristics associated with these lesions were scrutinised. A comprehensive descriptive and inferential analysis of the various variables was performed, followed by a binomial logistic regression to construct the predictive model. In this logistic regression analysis, systolic blood pressure (SBP) emerged as the principal predictor among the cases examined. Additionally, pain intensity was incorporated into the predictive model as a clinically relevant variable, thereby confirming its utility in conjunction with SBP for the identification of this pathology. These findings underscore the importance of integrating key variables, such as elevated SBP and severe pain, into diagnostic tools to enhance early detection and clinical management of Martorell ulcers.

VGF (non-acronymic)is a secreted chromogranin/secretogranin that gives rise to a number of bioactive peptides by a complex proteolysis mechanism. VGF-derived peptides exert an extensive array of biological effects in energy metabolism, mood regulation, pain, gastric secretion function, reproduction and, perhaps, cancer. It is therefore surprising that very little is known about receptors and binding partners of VGF-derived peptides and their downstream molecular mechanisms of action. Here, using affinity chromatography and mass spectrometry-based protein identification, we have identified the heat shock cognate 71 kDa protein A8 (HSPA8)as a binding partner of human TLQP-21 on the surface of human neuroblastomaSH-SY5Y cells. Binding of TLQP-21 to membrane associated HSPA8 in live SH-SY5Y cells was further supported by cross-linking to live cells. Interaction between HSPA8 and TLQP-21 was confirmed in vitro by label-free Dynamic Mass Redistribution (DMR) studies. Furthermore, molecular modeling studies show that TLQP-21 can be docked into the HSPA8 peptide binding pocket. Identification of HSPA8 as a cell surface binding partner of TLQP-21 opens new avenues to explore the molecular mechanisms of its physiological actions, and of pharmacological modulation thereof.

The structure of the infectious prion protein (PrPSc), which is responsible for Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, has escaped all attempts at elucidation due to its insolubility and propensity to aggregate. PrPSc replicates by converting the non-infectious, cellular prion protein (PrPC) into the misfolded, infectious conformer through an unknown mechanism. PrPSc and its N-terminally truncated variant, PrP 27-30, aggregate into amorphous aggregates, 2D crystals, and amyloid fibrils. The structure of these infectious conformers is essential to understanding prion replication and the development of structure-based therapeutic interventions. Here we used the repetitive organization inherent to GPI-anchorless PrP 27-30 amyloid fibrils to analyze their structure via electron cryomicroscopy. Fourier-transform analyses of averaged fibril segments indicate a repeating unit of 19.1 Å. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 Å3, predicted the height of each PrP 27-30 molecule as ~17.7 Å. Together, the data indicate a four-rung β-solenoid structure as a key feature for the architecture of infectious mammalian prions. Furthermore, they allow to formulate a molecular mechanism for the replication of prions. Knowledge of the prion structure will provide important insights into the self-propagation mechanisms of protein misfolding.

The biological activity of 2 isolates of Spodoptera frugiperda multiple nucleopolyhedrovirus (Sf-YUC and Sf-CHI) obtained from the states of Yucatán and Chiapas, Mexico, on second instar fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) from Michoacán State, Mexico, was determined and compared with that of a Nicaraguan isolate (Sf-NIC). Response of third and fourth instar S. frugiperda to the most active isolate, Sf-YUC, also was determined. Sublethal effects caused by this isolate and its intergenerational persistence were evaluated. The most pathogenic isolates on second instar S. frugiperda were Sf-NIC and Sf-YUC. No significant differences were detected in the speed of kill between the Sf-NIC (146 h) and Sf-YUC (149 h) isolates, whereas that of the Sf-CHI (158 h) isolate was slower significantly. The lethal concentration that kills 50% of the insects (LC50) values of the Sf-YUC isolate increased with larval stage from 9.45 × 104 to 1.25 × 106 occlusion bodies per mL. Statistically significant reductions in pupal weight, fecundity, fertility, and adult longevity were associated in individuals derived from third instar (generation F0) treated with 4.8 × 104 occlusion bodies per mL of the Sf-YUC isolate. A viral mortality of 15.83 ± 1.43% in larvae as well as a significant reduction in pupal weight of generation F1 was recorded. In conclusion, the Mexican isolates may prove suitable as the basis for biological insecticides for regional control of S. frugiperda. Sublethal infections that persist between generations could incur developmental costs and decrease reproductive capacity of the host insect. En el presente estudio, se determinó la actividad biológica de dos aislados mexicanos del nucleopolyhedrovirus múltiple de Spodoptera frugiperda (Sf-YUC y Sf-CHI) sobre larvas de segundo instar del gusano cogollero, Spodptera frugiperda (J. E. Smith), y se compararon con un aislado nicaragüense (Sf-NIC). También se determinó la respuesta de tercer y cuarto instar de S. frugiperda al aislado mexicano más activo, Sf-YUC. Finalmente, se evaluaron los efectos subletales causados por este aislado y su persistencia intrageneracional. Los aislados más patogénicos sobre el segundo instar de S. frugiperda fueron Sf-NIC y Sf-YUC. No se detectaron diferencias significativas en la velocidad de muerte entre los aislados Sf-NIC (146 h) y Sf-YUC (149 h), mientras que la del aislado Sf-CHI (158 h) fue significativamente mayor. Los valores de la concentración letal que matan el 50% de los insectos (CL50) se incrementaron con el estado larval desde 9.45 × 104 a 1.25 × 106 cuerpos de oclusión por mL del segundo al cuarto instar. Reducciones estadísticamente significativas en el peso pupal, la fecundidad, la fertilidad y la longevidad de adultos se asociaron con individuos derivados de tercer estadio (generación F0) tratados con 4,8 × 104 cuerpos de oclusión por mL del aislado Sf-YUC. observó una reducción significativa en el peso pupal. En conclusión, los aislados mexicanos pueden ser adecuados como la base de insecticidas biológicos para el control de S. frugiperda. Las infecciones subletales que persisten entre generaciones pueden generar costos de desarrollo y disminuir la capacidad reproductiva del insecto huésped.

The efficacy of two selected Metarhizium rileyi Mexican isolates (T9-21 and L8-22) against Spodoptera frugiperda was evaluated under greenhouse conditions. To this end, a suspension (1 × 108 conidia/mL) of these isolates was sprayed on maize plants previously infested with six second-instar larvae. No significant differences were observed between the survival curves of the T9-21 and L8-22 isolates. Cadaver sporulation was significantly higher, and the lethal time was significantly lower with the T9-21 isolate compared with those of the L8-22 isolate (97% and 8 days vs. 70% and 10 days, respectively). Based on these results, a small-scale field trial on maize was performed to evaluate the degree of pest control achieved by the T9-21 isolate and compare it with the insecticide spinetoram, applied at a rate of 1 × 1013 conidia/ha and 75 mL/ha, respectively. No significant differences were observed in the proportion of larval mortality between the T9-21 isolate (0.49) and spinetoram (0.72). However, spinetoram significantly reduced natural enemies and phytophagous insect populations compared with the fungus and the control. In conclusion, M. rileyi T9-21 isolate could be a promising alternative for the control of S. frugiperda larvae.

Platelets play a fundamental role in pathological events underlying acute coronary syndrome (ACS). Because platelets do not have a nucleus, proteomics constitutes an optimal approach to follow platelet molecular events associated with the onset of the acute episode. We performed the first high-resolution two-dimensional gel electrophoresis-based proteome analysis of circulating platelets from patients with non-ST segment elevation ACS (NSTE-ACS). Proteins were identified by mass spectrometry and validations were by western blotting. Forty protein features (corresponding to 22 unique genes) were found to be differentially regulated between NSTE-ACS patients and matched controls with chronic ischemic cardiopathy. The number of differences decreased at day 5 (28) and 6 months after the acute event (5). Interestingly, a systems biology approach demonstrated that 16 of the 22 differentially regulated proteins identified are interconnected as part of a common network related to cell assembly and organization and cell morphology, processes very related to platelet activation. Indeed, 14 of those proteins are either signaling or cytoskeletal, and nine of them are known to participate in platelet activation by αIIbβ3 and/or GPVI receptors. Several of the proteins identified participate in platelet activation through post-translational modifications, as shown here for ILK, Src and Talin. Interestingly, the platelet-secreted glycoprotein SPARC was down-regulated in NSTE-ACS patients compared to stable controls, which is consistent with a secretion process from activated platelets. The present study provides novel information on platelet proteome changes associated with platelet activation in NSTE-ACS, highlighting the presence of proteins involved in platelet signaling. This investigation paves the way for future studies in the search for novel platelet-related biomarkers and drug targets in ACS.

Very solid evidence suggests that the core of full length PrPSc is a 4-rung β-solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the β-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133-134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of β-strands, helping us to predict the threading of the β-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc.

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.

Here we report an infant with clinical findings suggestive of Jervell and Lange-Nielsen syndrome (JLNS), including a prolonged QT interval (LQTS) and chronic bilateral sensorineural deafness. NGS analysis revealed one known heterozygous pathogenic missense variant, KCNQ1 p.R259L, previously associated with LQTS but insufficient to explain the cardioauditory disorder. In a screening of proximal intronic regions, we found a heterozygous variant, KCNQ1 c.1686−9 T > C, absent from controls and previously undescribed. Several splicing prediction tools returned low scores for this intronic variant. Driven by the proband’s phenotype rather than the neutral predictions, we have characterized this rare intronic variant. Family analysis has shown that the proband inherited the missense and the intronic variants from his mother and father, respectively. A minigene splicing assay revealed that the intronic variant induced an additional transcript, arising from skipping of exon 14, which was translated into a truncated protein in transfected cells. The splice-out of exon 14 creates a frameshift in exon 15 and a stop codon in exon 16, which is the last exon of KCNQ1. This mis-spliced transcript is expected to escape nonsense-mediated decay and predicted to encode a truncated loss-of-function protein, KCNQ1 p.L563Kfs*73. The analysis of endogenous KCNQ1 expression in the blood of the proband’s parents detected the aberrant transcript only in the patient’s father. Taken together, these analyses confirmed the proband’s diagnosis of JLNS1 and indicated that c.1686−9 T > C is a cryptic splice-altering variant, expanding the known genetic spectrum of biallelic KCNQ1 variant combinations leading to JLNS1.

This study assessed several bioecological aspects of the black fig fly, Silba adipata McAlpine (Diptera: Lonchaeidae), the main pest of fig (Ficus carica L.). Figs were collected from eight sites in the Mexican states of Michoacán (Plan de Ayala, Los Tejones, Antúnez, Tangancícuaro, Indaparapeo, El Carrizal, and Charapendo) and Morelos (Telixtac). No infestation was recorded in figs collected in Charapendo, but, in the remaining sites, it was variable (2–33%). Figs from Plan de Ayala and El Carrizal were longer and contained more larvae than those from Telixtac and Los Tejones. Some figs (≤12) collected in Telixtac and Los Tejones contained few pupae or adults. The survival of larval and pupal stages (≤86%) and the proportion of females (40–53%) were determined at the sites where the infestation of figs was >6% (Telixtac, El Carrizal, Plan de Ayala, and Los Tejones). In the second part of this study, the development of individuals collected in Los Tejones was analyzed under constant conditions. The estimated larval duration time was between 13 and 15 d, whereas pupae lasted 11 d. The survival rate and longevity of females and males were very similar. Our results could help design a program for integrated pest management against S. adipata.