Thermosensitive Liposomes for Gemcitabine Delivery to Pancreatic Ductal Adenocarcinoma.

Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes to the clinic has been hindered by the low loading efficiency of gemcitabine and by the difficulty of inducing hyperthermia in vivo. This study was designed to investigate the effect of phospholipid content on the stability of liposomes at 37 °C and their release under hyperthermia conditions; this was accomplished by employing a two-stage heating approach. First the liposomes were heated at a fast rate, then they were transferred to a holding bath. Thermosensitive liposomes formulated with DPPC: DSPC: PEG2k (80:15:5, mole%) exhibited minimal release of carboxyfluorescein at 37 °C over 30 min, indicating stability under physiological conditions. However, upon exposure to hyperthermic conditions (43 °C and 45 °C), these liposomes demonstrated a rapid and significant release of their encapsulated content. The encapsulation efficiency for gemcitabine was calculated at 16.9%. Additionally, fluorescent analysis during the removal of unencapsulated gemcitabine revealed an increase in pH. In vitro tests with BxPC3 and KPC cell models showed that these thermosensitive liposomes induced a heat-dependent cytotoxic effect comparable to free gemcitabine at temperatures above 41 °C. This study highlights the effectiveness of the heating mechanism and cell models in understanding the current challenges in developing gemcitabine-loaded heat-sensitive liposomes.

Insertion and Anchoring of HIV-1 Fusion Peptide into Complex Membrane Mimicking Human T-cell.

A fundamental understanding of how HIV-1 envelope (Env) protein facilitates fusion is still lacking. The HIV-1 fusion peptide, consisting of 15 to 22 residues, is the N-terminus of the gp41 subunit of the Env protein. Further, this peptide, a promising vaccine candidate, initiates viral entry into target cells by inserting and anchoring into human immune cells. The influence of membrane lipid reorganization and the conformational changes of the fusion peptide during the membrane insertion and anchoring processes, which can significantly affect HIV-1 cell entry, remains largely unexplored due to the limitations of experimental measurements. In this work, we investigate the insertion of the fusion peptide into an immune cell membrane mimic through multiscale molecular dynamics simulations. We mimic the native T-cell by constructing a 9-lipid asymmetric membrane, along with geometrical restraints accounting for insertion in the context of gp41. To account for the slow timescale of lipid mixing while enabling conformational changes, we implement a protocol to go back and forth between atomistic and coarse-grained simulations. Our study provides a molecular understanding of the interactions between the HIV-1 fusion peptide and the T-cell membrane, highlighting the importance of conformational flexibility of fusion peptides and local lipid reorganization in stabilizing the anchoring of gp41 into the targeted host membrane during the early events of HIV-1 cell entry. Importantly, we identify a motif within the fusion peptide critical for fusion that can be further manipulated in future immunological studies.

The impact of settleable atmospheric particulate on the energy metabolism, biochemical processes, and behavior of a sentinel mangrove crab.

We use the sentinel mangrove crab, Minuca rapax, as a model to investigate the effects of metallic settleable particulate matter (SePM) on wetland. Multiple levels of energetic responses, including (i) metabolic rate and energy budget, (ii) oxidative stress, and (iii) behavioral response by righting time, were assessed as well as the metal and metalloid content in crabs exposed to 0, 0.1 and 1 g.L-1 of SePM, under emerged and submerged conditions over five days, simulating the rigors of the intertidal habitat. Al, Fe, Mn, Cr, and Y exhibited a concentration-dependent increase. Metal concentrations were higher in submerged crabs due to the continuous ingestion of SePM and direct exposure through gills. Exposure concentration up to 1 g.L-1 decreased metabolic rate and enzymatic activities, reduced assimilation efficiency and energy for maintenance, and induces a slower response to righting time, probably by metal effects on nervous system and energy deficits. In conclusion, SePM exposure affects the redox status and physiology of M. rapax depending on he submersion regime and SePM concentration. The disruption to the energy budget and the lethargic behavior in M. rapax exposed to SePM implies potential ecological alterations in the mangrove ecosystem with unknown consequences for the local population.

Influence of membrane on the antigen presentation of the HIV-1 envelope membrane proximal external region (MPER).

The membrane proximal external region (MPER) of the HIV envelope glycoproteins has generated renewed interest after a recent phase I vaccine trial that presented MPER lipid-peptide epitopes demonstrated promise to elicit a broad neutralization response. The antigenicity of MPER is intimately associated with the membrane, and its presentation relies significantly on the lipid composition. This review brings together recent findings on the influence of membranes on the conformation of MPER and its recognition by broadly neutralizing antibodies. Specifically, the review highlights the importance of properly accounting for the balance between protein-protein and membrane-protein interactions in vaccine design.

Morphology of the scaphotrapeziotrapezoid joint: A multi-domain statistical shape modeling approach.

The scaphotrapeziotrapezoid (STT) joint is involved in load transmission between the wrist and thumb. A quantitative description of baseline STT joint morphometrics is needed to capture the variation of normal anatomy as well as to guide staging of osteoarthritis. Statistical shape modeling (SSM) techniques quantify variations in three-dimensional shapes and relative positions. The objectives of this study are to describe the morphology of the STT joint using a multi-domain SSM. We asked: (1) What are the dominant modes of variation that impact bone and articulation morphology at the STT joint, and (2) what are the morphometrics of SSM-generated STT joints? Thirty adult participants were recruited to a computed tomography study of normal wrist imaging and biomechanics. Segmentations of the carpus were converted to three-dimensional triangular surface meshes. A multi-domain, particle-based entropy system SSM was used to quantify variation in carpal bone shape and position as well as articulation morphology. Articular surface areas and interosseous proximity distributions were calculated between mesh vertex pairs on adjacent bones within distance (2.0 mm) and surface-normal angular (35°) thresholds. In the SSM, the first five modes of variation captured 76.2% of shape variation and contributed to factors such as bone scale, articular geometries, and carpal tilt. Median interosseous proximities-a proxy for joint space-were 1.39 mm (scaphotrapezium), 1.42 mm (scaphotrapezoid), and 0.61 mm (trapeziotrapezoid). This study quantifies morphological and articular variations at the STT joint, presenting a range of normative anatomy. The range of estimated interosseous proximities may guide interpretation of imaging-derived STT joint space.

Multiple sclerosis in Central America and Caribbean countries: frequency and clinical characterization of an emergent disease.

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3-3.5 × 100,000 inhabitants, and the lowest, 0.07-0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.

Altered Plasma Membrane Lipid Composition in Hypertensive Neutrophils Impacts Epithelial Sodium Channel (ENaC) Endocytosis.

Biological membranes are composed of a lipid bilayer with embedded proteins, including ion channels like the epithelial sodium channel (ENaC), which are critical for sodium homeostasis and implicated in arterial hypertension (HTN). Changes in the lipid composition of the plasma membrane can significantly impact cellular processes related to physiological functions. We hypothesized that the observed overexpression of ENaC in neutrophils from HTN patients might result from alterations in the structuring domains within the plasma membrane, disrupting the endocytic processes responsible for ENaC retrieval. This study assessed the structural lipid composition of neutrophil plasma membranes from HTN patients along with the expression patterns of key elements regulating ENaC at the plasma membrane. Our findings suggest alterations in microdomain structure and SGK1 kinase activity, which could prolong ENaC presence on the plasma membrane. Additionally, we propose that the proteasomal and lysosomal degradation pathways are insufficient to diminish ENaC presence at the plasma membrane in HTN. These results highlight the importance of understanding ENaC retrieval mechanisms and suggest that targeting these mechanisms could provide insights for developing drugs to prevent and treat HTN.

Detection of scapholunate interosseous ligament injury using dynamic computed tomography-derived arthrokinematics: A prospective clinical trial.

Scapholunate interosseous ligament injuries are a major cause of wrist instability and can be difficult to diagnose radiographically. To improve early diagnosis of scapholunate ligament injuries, we compared injury detection between bilateral routine clinical radiographs, static CT, and dynamic four-dimensional CT (4DCT) during wrist flexion-extension and radioulnar deviation. Participants with unilateral scapholunate ligament injuries were recruited to a prospective clinical trial investigating the diagnostic utility of 4DCT imaging for ligamentous wrist injury. Twenty-one participants underwent arthroscopic surgery to confirm scapholunate ligament injury. Arthrokinematics, defined as distributions of interosseous proximities across radioscaphoid and scapholunate articular surfaces at different positions within the motion cycle, were used as CT-derived biomarkers. Preoperative radiographs, static CT, and extrema of 4DCT were compared between uninjured and injured wrists using Wilcoxon signed rank or Kolmogorov-Smirnov tests. Median interosseous proximities at the scapholunate interval were significantly greater in the injured versus the uninjured wrists at static-neutral and maximum flexion, extension, radial deviation, and ulnar deviation. Mean cumulative distribution functions at the radioscaphoid joint were not significantly different between wrists but were significantly shifted at the scapholunate interval towards increased interosseous proximities in injured versus uninjured wrists in all positions. Median and cumulative distribution scapholunate proximities from static-neutral and 4DCT-derived extrema reflect injury status.

Entamoeba histolytica: In Silico and In Vitro Oligomerization of EhHSTF5 Enhances Its Binding to the HSE of the EhPgp5 Gene Promoter.

Throughout its lifecycle, Entamoeba histolytica encounters a variety of stressful conditions. This parasite possesses Heat Shock Response Elements (HSEs) which are crucial for regulating the expression of various genes, aiding in its adaptation and survival. These HSEs are regulated by Heat Shock Transcription Factors (EhHSTFs). Our research has identified seven such factors in the parasite, designated as EhHSTF1 through to EhHSTF7. Significantly, under heat shock conditions and in the presence of the antiamoebic compound emetine, EhHSTF5, EhHSTF6, and EhHSTF7 show overexpression, highlighting their essential role in gene response to these stressors. Currently, only EhHSTF7 has been confirmed to recognize the HSE as a promoter of the EhPgp5 gene (HSE_EhPgp5), leaving the binding potential of the other EhHSTFs to HSEs yet to be explored. Consequently, our study aimed to examine, both in vitro and in silico, the oligomerization, and binding capabilities of the recombinant EhHSTF5 protein (rEhHSTF5) to HSE_EhPgp5. The in vitro results indicate that the oligomerization of rEhHSTF5 is concentration-dependent, with its dimeric conformation showing a higher affinity for HSE_EhPgp5 than its monomeric state. In silico analysis suggests that the alpha 3 α-helix (α3-helix) of the DNA-binding domain (DBD5) of EhHSTF5 is crucial in binding to the major groove of HSE, primarily through hydrogen bonding and salt-bridge interactions. In summary, our results highlight the importance of oligomerization in enhancing the affinity of rEhHSTF5 for HSE_EhPgp5 and demonstrate its ability to specifically recognize structural motifs within HSE_EhPgp5. These insights significantly contribute to our understanding of one of the potential molecular mechanisms employed by this parasite to efficiently respond to various stressors, thereby enabling successful adaptation and survival within its host environment.

Predicting permeation of compounds across the outer membrane of P. aeruginosa using molecular descriptors.

The ability Gram-negative pathogens have at adapting and protecting themselves against antibiotics has increasingly become a public health threat. Data-driven models identifying molecular properties that correlate with outer membrane (OM) permeation and growth inhibition while avoiding efflux could guide the discovery of novel classes of antibiotics. Here we evaluate 174 molecular descriptors in 1260 antimicrobial compounds and study their correlations with antibacterial activity in Gram-negative Pseudomonas aeruginosa. The descriptors are derived from traditional approaches quantifying the compounds' intrinsic physicochemical properties, together with, bacterium-specific from ensemble docking of compounds targeting specific MexB binding pockets, and all-atom molecular dynamics simulations in different subregions of the OM model. Using these descriptors and the measured inhibitory concentrations, we design a statistical protocol to identify predictors of OM permeation/inhibition. We find consistent rules across most of our data highlighting the role of the interaction between the compounds and the OM. An implementation of the rules uncovered in our study is shown, and it demonstrates the accuracy of our approach in a set of previously unseen compounds. Our analysis sheds new light on the key properties drug candidates need to effectively permeate/inhibit P. aeruginosa, and opens the gate to similar data-driven studies in other Gram-negative pathogens.

Endovascular resolution of post-surgical complications in the portal vein: Report of two cases.

Stenosis of the portal vein is one of the main complications after hepatobiliar and pancreatic surgery, with a reported incidence of 19.6% after pancreaticoduodenectomy and 3% after liver transplant. It is associated with the intraoperative resection of the portal vein, local recurrence of the primary tumor and radiotherapy. The portal lesion secondary to bile drainage catheter insertion is extremely rare or unusual, with few cases described in the literature. This article describes 2 cases: the first of a male patients 49 years old post-operative to liver transplant with partial portal thrombosis and stenosis of the mesoportal joint, and the second a female patient 50 years old with history of cholecystectomy, exploration of the bile duct and placement of Kehr "T" tube with secondary portal lesion. The 2 cases were successfully treated through minimally invasive procedures by an interventionist radiologist.

A comprehensive evaluation of 80 consecutive robotic low anterior resections: impact of not mobilizing the splenic flexure alongside low-tie vascular ligation as a standardized technique.

Rectal cancer surgery represents challenges due to its location. To overcome them and minimize the risk of anastomosis-related complications, some technical maneuvers or even a diverting ileostomy may be required. One of these technical steps is the mobilization of the splenic flexure (SFM), especially in medium/low rectal cancer. High-tie vascular ligation may be another one. However, the need of these maneuvers may be controversial, as especially SFM may be time-consuming and increase the risk of iatrogenic. The objective is to present the short- and long-term outcomes of a low-tie ligation combined with no SFM in robotic low anterior resection (LAR) for mid- and low rectal cancer as a standardized technique. A retrospective observational single-cohort study was carried out at Reina Sofia University Hospital, Cordoba, Spain. 221 robotic rectal resections between Jul-18th-2018 and Jan-12th-2023 were initially considered. After case selection, 80 consecutive robotic LAR performed by a single surgeon were included. STROBE checklist assessed the methodological quality. Histopathological, morbidity and oncological outcomes were assessed. Anastomotic stricture occurrence and distance to anal verge were evaluated after LAR by rectosigmoidoscopy. Variables related to the ileostomy closure such as time to closure, post-operative complications or hospital stay were also considered. The majority of patients (81.2%) presented a mid-rectal cancer and the rest, lower location (18.8%). All patients had adequate perfusion of the anastomotic stump assessed by indocyanine green. Complete total mesorectal excision was performed in 98.8% of the patients with a lymph node ratio < 0.2 in 91.3%. The anastomotic leakage rate was 5%. One patient (1.5%) presented local recurrence. Anastomosis stricture occurred in 7.5% of the patients. The limitations were small cohort and retrospective design. The non-mobilization of the splenic flexure with a low-tie ligation in robotic LAR is a feasible and safe procedure that does not affect oncological outcomes.

Bluetooth Device Identification Using RF Fingerprinting and Jensen-Shannon Divergence.

The proliferation of radio frequency (RF) devices in contemporary society, especially in the fields of smart homes, Internet of Things (IoT) gadgets, and smartphones, underscores the urgent need for robust identification methods to strengthen cybersecurity. This paper delves into the realms of RF fingerprint (RFF) based on applying the Jensen-Shannon divergence (JSD) to the statistical distribution of noise in RF signals to identify Bluetooth devices. Thus, through a detailed case study, Bluetooth RF noise taken at 5 Gsps from different devices is explored. A noise model is considered to extract a unique, universal, permanent, permanent, collectable, and robust statistical RFF that identifies each Bluetooth device. Then, the different JSD noise signals provided by Bluetooth devices are contrasted with the statistical RFF of all devices and a membership resolution is declared. The study shows that this way of identifying Bluetooth devices based on RFF allows one to discern between devices of the same make and model, achieving 99.5% identification effectiveness. By leveraging statistical RFFs extracted from noise in RF signals emitted by devices, this research not only contributes to the advancement of the field of implicit device authentication systems based on wireless communication but also provides valuable insights into the practical implementation of RF identification techniques, which could be useful in forensic processes.

Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane.

The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through ß-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.

Is there an association between family members' season of birth that could influence birth seasonality? Evidence from Spain and France.

The number of births varies by season. Research on birth seasonality has shown that women's season of birth somehow influences that of their children, but factors underlying the intergenerational transmission of birth seasonality remain unknown. With data from Spain and France, we analysed the possibility of transmission of birth season between generations, testing whether relatives tended to be born in the same season. Results indicated that there was an association-a similarity-between parents' and children's birth seasons, partially explaining the stability of seasonal patterns over time. This association also existed between parents' birth seasons. While parents' association is directly explained by an excess of marriages with spouses born in the same month, the overall association may be explained by two facts: different socio-demographic groups show differentiated birth patterns, and relatives share socio-demographic features. Birth season seems to be related to family characteristics, which should be controlled for when assessing birth-month effects on subsequent social/health outcomes.

Structural characterization of PaaX, the main repressor of the phenylacetate degradation pathway in Escherichia coli W: A novel fold of transcription regulator proteins.

PaaX is a transcriptional repressor of the phenylacetic acid (PAA) catabolic pathway, a central route for bacterial aerobic degradation of aromatic compounds. Induction of the route is achieved through the release of PaaX from its promoter sequences by the first compound of the pathway, phenylacetyl-coenzyme A (PA-CoA). We report the crystal structure of PaaX from Escherichia coli W. PaaX displays a novel type of fold for transcription regulators, showing a dimeric conformation where the monomers present a three-domain structure: an N-terminal winged helix-turn-helix domain, a dimerization domain similar to the Cas2 protein and a C-terminal domain without structural homologs. The domains are separated by a crevice amenable to harbour a PA-CoA molecule. The biophysical characterization of the protein in solution confirmed several hints predicted from the structure, i.e. its dimeric conformation, a modest importance of cysteines and a high dependence of solubility and thermostability on ionic strength. At a moderately acidic pH, the protein formed a stable folding intermediate with remaining α-helical structure, a disrupted tertiary structure and exposed hydrophobic patches. Our results provide valuable information to understand the stability and mechanism of PaaX and pave the way for further analysis of other regulators with similar structural configurations.

Alucinosis peduncular en esclerosis múltiple, síntoma poco común en la expresión de enfermedad desmielinizante / Peduncular hallucinosis in multiple sclerosis, a rare symptom in demyelinating disease

Introducción: La alucinosis peduncular (AP) hace referencia a alucinaciones autodiscriminadas, cuyo origen son lesiones en el mesencéfalo y en el puente. Presentación del caso: Paciente 27 años, femenina, con alucinaciones visuales, auditivas autodiscriminadas por ella misma, sin antecedentes previos de importancia y con lesiones en resonancia magnética cerebral y cervical en el pedúnculo cerebeloso superior, tegmento pontino, y en columna cervical con bandas oligoclonales patrón 2, que cumplían criterios de Mc Donalds para esclerosis múltiple. Discusión: La alucinosis peduncular hace referencia a la presencia de alucinaciones visuales, criticadas por el paciente, con la consecuencia de lesiones de las vías inhibitorias por deaferentación y desinhibición mesencéfalotalámicas, y retinogenículo calcarina, descritas como manifestación de múltiples patologías neurológicas como trauma, afectación vascular, tumores y pocos casos de enfermedad desmielinizante, entre otras. Conclusión: La alucinosis peduncular es una forma atípica de presentación de lesiones pontomesencefálicas descritas en varias patologías; se debe tener en cuenta en la localización de la lesión neurológica; se han reportado pocos casos como síntoma de la enfermedad desmielinizante.

Introduction: Peduncular hallucinosis (PA) refers to self-discriminating hallucinations, these are caused by lesions in the midbrain and pons. Presentation of the case: 27-year-old right handed female patient with visual and auditory hallucinations self-discriminated by the patient, with no prior history of importance and with lesions in cerebral and cervical Magnetic Resonance in the superior cerebellar peduncle, pontine tegmentum, and in the cervical spine with pattern 2 oligo clonal bands, which met Mc Donald's criteria for multiple sclerosis. Discussion: Peduncular hallucinosis refers to the presence of visual hallucinations criticized by the patient, consequence of lesions in the inhibitory pathways with deafferentation and disinhibition of the midbrain-thalamic and retinogeniculus-calcarine pathways. Described as a manifestation of multiple neurological pathologies such as trauma, vascular, tumor and few cases of demyelinating among others. Conclusion: Peduncular hallucinosis is an atypical form of presentation of pontomesencephalic lesions described in several pathologies, it must be taken into account when locating the neurological lesion, few cases have been reported as symptom of the demyelinating disease.