Advancements in dementia research, diagnostics, and care in Latin America: Highlights from the 2023 Alzheimer's Association International conference satellite symposium in Mexico City.

INTRODUCTION: While Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care. METHODS: In 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm. RESULTS: Significant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted. DISCUSSION: The myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Social network interventions to reduce race disparities in living kidney donation: Design and rationale of the friends and family of kidney transplant patients study (FFKTPS).

INTRODUCTION: Racial/ethnic disparities in living donor kidney transplantation (LDKT) are a persistent challenge. Although nearly all directed donations are from members of patients' social networks, little is known about which social network members take steps toward living kidney donation, which do not, and what mechanisms contribute to racial/ethnic LDKT disparities. METHODS: We describe the design and rationale of the Friends and Family of Kidney Transplant Patients Study, a factorial experimental fielding two interventions designed to promote LKD discussions. Participants are kidney transplant candidates at two centers who are interviewed and delivered an intervention by trained center research coordinators. The search intervention advises patients on which social network members are most likely to be LKD contraindication-free; the script intervention advises patients on how to initiate effective LKD discussions. Participants are randomized into four conditions: no intervention, search only, script only, or both search and script. Patients also complete a survey and optionally provide social network member contact information so they can be surveyed directly. This study will seek to enroll 200 transplant candidates. The primary outcome is LDKT receipt. Secondary outcomes include live donor screening and medical evaluations and outcomes. Tertiary outcomes include LDKT self-efficacy, concerns, knowledge, and willingness, measured before and after the interventions. CONCLUSION: This study will assess the effectiveness of two interventions to promote LKD and ameliorate Black-White disparities. It will also collect unprecedented information on transplant candidates' social network members, enabling future work to address network member structural barriers to LKD.

High prevalence of potential psychotropic drugs interactions among Brazilian dental patients.

OBJECTIVE: To determine the prevalence of potential drug-drug interactions involving psychotropics prescribed by dentists, and dispensed by the public healthcare system, as well as to describe the severity and level of evidence of those interactions in the state of Minas Gerais, Brazil. MATERIALS AND METHODS: We conducted data analysis from pharmaceutical claims in which dental patients received systemic psychotropics in 2017. Data from the Pharmaceutical Management System provided the drug dispensing history of the patients, allowing the identification of those on concomitant medication use. The outcome was the occurrence of potential drug-drug interactions, which were detected according to IBM Micromedex®. Independent variables were the patient's sex, age, and the number of drugs used. Descriptive statistics was performed using SPSS v. 26. RESULTS: Overall, 1480 individuals were prescribed psychotropic drugs. The prevalence of potential drug-drug interactions was 24.8% (n = 366). The total of 648 interactions was observed and, most of which were of major severity (n = 438, 67.6%). Most interactions occurred in female individuals (n = 235; 64.2%), with 46.0 (±17.3) years-old, concurrently taking 3.7 (±1.9) drugs. CONCLUSION: A substantial proportion of dental patients presented potential drug-drug interactions, mostly of major severity, which might be life-threatening.

[The 5-5-2 criteria for biliary cannulation and post endoscopic retrograde cholangiopancreatography complications: Experience in a reference hospital, Peru]. / Criterios 5-5-2 de canulación biliar y complicaciones post colangiopancreatografía retrógrada endoscópica: Experiencia en un hospital de referencia, Perú.

The European Society for Gastrointestinal Endoscopy (ESGE) defines "difficult biliary cannulation" by the presence of one or more of the following: more than 5 contacts with the papilla, more than 5 minutes attempting to cannulate, or inadvertent cannulation of the pancreatic duct in 2 or more times (5-5-2 criteria), recommending these cut-off points to perform advanced cannulation techniques in order to reduce the rate of post-ERCP adverse events. Our objective was to evaluate the performance of the 5-5-2 criteria and their association with post-ERCP complications in a reference hospital in Peru. We performed a prospective analytical case-control study and 120 patients who underwent ERCP were enrolled. The case group included 30 patients who met at least one of the 5-5-2 criteria and the control group included 90 patients without any of these criteria. The ERCP- related complications in both groups and their association with each of the 5-5-2 criteria were compared. The ERCP-related complications that occurred were post-ERCP pancreatitis (6.6% in the case group vs. 3.3% in the control group), bleeding (3.3% controls vs. 0% cases) and perforation (1.1% controls vs. 0% cases); no statistically significant differences were observed. The criterion of 2 or more unintended cannulations to the pancreatic duct showed a significant association (OR= 10.29, CI: 1.47-71.98; p= 0.005) with the incidence of post-ERCP pancreatitis. The criteria 5 minutes and 5 attempts were not associated with post-ERCP complications. In conclusion, among 5-5-2 criteria only the unintended cannulation of 2 or more times into the pancreatic duct was associated with an increased risk of post-ERC pancreatitis. The time and number of attempts criteria could be cautiously expanded without increasing the rate of post-ERCP complications.

[Clinical significance of the presence of granulomas in Crohn's disease]. / Significancia clínica de la presencia de granulomas en enfermedad de Crohn.

Epithelioid granuloma is a characteristic histological feature of Crohn's disease (CD), but their significance with respect to the severity and progression of the disease is still uncertain. OBJECTIVE: To evaluate the clinical characteristics of CD patients in relation to the presence or not of granulomas in histological findings. MATERIALS AND METHODS: An observational, descriptive, retrospective study in patients diagnosed with CD from January 2004 to December 2019 in the gastroenterology department of the Guillermo Almenara Irigoyen National Hospital, Lima-Peru. RESULTS: 55 patients were included. Average age of 56 ± 8.2 years. The median time of disease was 16 months. Have two or more relapses per year (p<0.001; OR=9.75), age less than 30 years (p<0.001; OR=3.57) and a moderate to severe CDAI (≥220 points, OR=11.4, p <0.008) was significantly associated with the presence of granulomas. Severe endoscopic activity (p <0.003; OR=9.91) and the stenosing-penetrating phenotype (p<0.001; OR=22.1) also showed association with the presence of granulomas. The group of granulomas had a higher probability of corticosteroid use (p <0.024; OR=3.92) and immunomodulator (p <0.001; OR=7.10), besides the need for intestinal resection surgery (p<0.027; OR=5.07). CONCLUSIONS: The presence of granulomas in CD may be associated with increased clinical severity, endoscopic severity, immunosuppressive therapy requirement and undergo for intestinal resection.

The effect of chiral N-substituents with methyl or trifluoromethyl groups on the catalytic performance of mono- and bifunctional thioureas.

We evaluated thiourea organocatalysts that incorporate a chiral group which includes a trifluoromethyl moiety and contrasted their performance with non-fluorinated analogs. The comparison between such systems allows the direct study of the NH acidity of a thiourea bonded to an aliphatic substituent. In principle, -CF3 systems feature an enhanced hydrogen bond (HB) donor capacity that is undoubtedly beneficial for HB-catalysis applied to the Baylis-Hillman reaction. We found that the thiourea substituted on both nitrogens with this group accelerates this reaction like Schreiner's thiourea. On the other hand, we observed a different behavior in reactions promoted by bifunctional catalysts (thiourea-primary amine). In the Michael addition of isobutyraldehyde to methyl benzylidenepyruvate, the -CF3 containing catalysts were better than the -CH3 systems, whereas the conjugate addition to N-phenylmaleimide showed the opposite behavior. Theoretical calculations of the transition states indicated that the phenylethyl group in fluorinated and non-fluorinated compounds have different kinds of interactions with the electrophile. These interactions are responsible for a different arrangement of the electrophile and thereby the selectivity of the catalyst. Therefore, it cannot be generalized that in all cases NH acidity correlates with the performance of the catalyst, particularly, with aliphatic substituents that unlike the aromatic ones possess groups that are outside the plane of the thiourea.

Proteome-wide analysis of human motif-domain interactions mapped on influenza a virus.

BACKGROUND: The influenza A virus (IAV) is a constant threat for humans worldwide. The understanding of motif-domain protein participation is essential to combat the pathogen. RESULTS: In this study, a data mining approach was employed to extract influenza-human Protein-Protein interactions (PPI) from VirusMentha,Virus MINT, IntAct, and Pfam databases, to mine motif-domain interactions (MDIs) stored as Regular Expressions (RegExp) in 3DID database. A total of 107 RegExp related to human MDIs were searched on 51,242 protein fragments from H1N1, H1N2, H2N2, H3N2 and H5N1 strains obtained from Virus Variation database. A total 46 MDIs were frequently mapped on the IAV proteins and shared between the different strains. IAV kept host-like MDIs that were associated with the virus survival, which could be related to essential biological process such as microtubule-based processes, regulation of cell cycle check point, regulation of replication and transcription of DNA, etc. in human cells. The amino acid motifs were searched for matches in the immune epitope database and it was found that some motifs are part of experimentally determined epitopes on IAV, implying that such interactions exist. CONCLUSION: The directed data-mining method employed could be used to identify functional motifs in other viruses for envisioning new therapies.

Is the simplest chemical reaction really so simple?

Modern computational methods have become so powerful for predicting the outcome for the H + H2 → H2 + H bimolecular exchange reaction that it might seem further experiments are not needed. Nevertheless, experiments have led the way to cause theorists to look more deeply into this simplest of all chemical reactions. The findings are less simple.

Red blood cell flickering activity locally controlled by holographic optical tweezers.

Red blood cells possess a singular mechanobiology, enabling efficient navigation through capillaries smaller than their own size. Their plasma membrane exhibits non-equilibrium shape fluctuation, often reported as enhanced flickering activity. Such active membrane motion is propelled by motor proteins that mediate interactions between the spectrin skeleton and the lipid bilayer. However, modulating the flickering in living red blood cells without permanently altering their mechanical properties represents a significant challenge. In this study, we developed holographic optical tweezers to generate a force field distributed along the equatorial membrane contour of individual red blood cells. In free-standing red blood cells, we observed heterogeneous flickering activity, attributed to localized membrane kickers. By employing holographic optical forces, these active kickers can be selectively halted under minimal invasion. Our findings shed light on the dynamics of membrane flickering and established a manipulation tool that could open new avenues for investigating mechanotransduction processes in living cells.

Electronic quenching of OH A 2Σ+ induced by collisions with Kr atoms.

Electronic quenching of OH A (2)Σ(+) by Kr was investigated through experimental studies of the collision cross sections and the OH X (2)Π product state distribution. The quenching cross sections decrease with increasing rotational excitation in the excited OH A (2)Σ(+) electronic state. The OH X (2)Π products of quenching exhibit a significant degree of rotational excitation but minimal vibrational excitation. Complementary theoretical studies of the OH (A (2)Σ(+), X (2)Π) + Kr potential energy surfaces (PESs), nonadiabatic coupling, and quasiclassical trajectory calculations were carried out to elucidate the quenching dynamics. Accurate PESs for the two lowest diabatic states of A' symmetry were computed along with the angularly dependent coupling between them. Coupling in nearly linear HO-Kr configurations provides the mechanism for the observed electronic quenching. A deep attractive well on the OH A (2)Σ(+) + Kr PES facilitates access to this region of strong coupling. Surface-hopping quasiclassical trajectory calculations yielded quenching cross sections and a OH X (2)Π product rotational distribution in good accord with experimental observations.

Stereoselective synthesis of highly substituted 1-isomorphans (1-azabicyclo[3.3.1]nonanes).

We describe the first enantioselective synthesis of highly functionalized 1-azabicyclo[3.3.1]nonanes (1-IM). The 1-IM scaffold is present in natural products and drugs and is an isomer of the morphan moiety. The proposed methodology is based on an organocatalytic Michael addition of N-protected piperidine ketoesters to nitroalkenes and an intramolecular nitro-Mannich reaction as key transformations. The 1-IMs feature 6 contiguous stereocenters, substituents at positions 2 and 4, and nitro, ester, and hydroxyl functional groups at positions 3, 5, and 6 respectively. The synthesis is straightforward, highly stereoselective (up to 98% ee, >99 : 1 d.r.), with overall yields of up to 83% and requires only two purification steps.

Comparing the transcriptome of developing native and iPSC-derived mouse retinae by single cell RNA sequencing.

We report the generation and analysis of single-cell RNA-Seq data (> 38,000 cells) from mouse native retinae and induced pluripotent stem cell (iPSC)-derived retinal organoids at four matched stages of development spanning the emergence of the major retinal cell types. We combine information from temporal sampling, visualization of 3D UMAP manifolds, pseudo-time and RNA velocity analyses, to show that iPSC-derived 3D retinal organoids broadly recapitulate the native developmental trajectories. However, we observe relaxation of spatial and temporal transcriptome control, premature emergence and dominance of photoreceptor precursor cells, and susceptibility of dynamically regulated pathways and transcription factors to culture conditions in retinal organoids. We demonstrate that genes causing human retinopathies are enriched in cell-type specifying genes and identify a subset of disease-causing genes with expression profiles that are highly conserved between human retinae and murine retinal organoids. This study provides a resource to the community that will be useful to assess and further improve protocols for ex vivo recapitulation and study of retinal development.

Erythroid SLC7A5/SLC3A2 amino acid carrier controls red blood cell size and maturation.

Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.

A state-to-state dynamical study of the Br + H2 reaction: comparison of quantum and classical trajectory results.

We present a detailed theoretical investigation of the dynamics corresponding to the strongly endothermic Br + H(2) (v = 0-1, j = 0) → H + HBr reaction in the 0.85 to 1.9 eV total energy range. State-averaged and state-to-state results obtained through time-independent wave packet (TIWP) and time-independent quantum mechanical (TIQM) calculations and quasiclassical trajectories (QCT) are compared and analyzed. The agreement in the results obtained with both quantum mechanical results is very good overall. However, although QCT calculations reproduce the general features, their agreement with the QM results is sometimes only qualitative. The analysis of the mechanism based on state-averaged results turns out to be deceptive and conveys an oversimplified picture of the reaction consistent with a direct-rebound mechanism. Consideration of state-to-state processes, in contrast, unveils the existence of multiple mechanisms that give rise to a succession of maxima in the differential cross section (DCS). Such mechanisms correlate with different sets of partial waves and display similar collision times when analyzed through the time-dependent DCS.

Lipid nanoparticles for antisense oligonucleotide gene interference into brain border-associated macrophages.

A colloidal synthesis' proof-of-concept based on the Bligh-Dyer emulsion inversion method was designed for integrating into lipid nanoparticles (LNPs) cell-permeating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for mRNA interference. The GR@LNPs were formulated to target brain border-associated macrophages (BAMs) as a central nervous system (CNS) therapy platform for silencing neuroinflammation-related genes. We specifically aim at inhibiting the expression of the gene encoding for lipocalin-type prostaglandin D synthase (L-PGDS), an anti-inflammatory enzyme expressed in BAMs, whose level of expression is altered in neuropsychopathologies such as depression and schizophrenia. The GR@LNPs are expected to demonstrate a bio-orthogonal genetic activity reacting with L-PGDS gene transcripts inside the living system without interfering with other genetic or biochemical circuitries. To facilitate selective BAM phagocytosis and avoid subsidiary absorption by other cells, they were functionalized with a mannosylated lipid as a specific MAN ligand for the mannose receptor presented by the macrophage surface. The GR@LNPs showed a high GR-packing density in a compact multilamellar configuration as structurally characterized by light scattering, zeta potential, and transmission electronic microscopy. As a preliminary biological evaluation of the mannosylated GR@LNP nanovectors into specifically targeted BAMs, we detected in vivo gene interference after brain delivery by intracerebroventricular injection (ICV) in Wistar rats subjected to gene therapy protocol. The results pave the way towards novel gene therapy platforms for advanced treatment of neuroinflammation-related pathologies with ASO@LNP nanovectors.

Biosafety in Dental Health Care During the COVID-19 Pandemic: A Longitudinal Study.

Background: The coronavirus disease 2019 (COVID-19) pandemic had quite an impact on dental health care. Concerns about the risk of SARS-CoV-2 transmission through contaminant fluids and droplet formation during several dental procedures highly impacted dental health care, drastically reducing the number of dental practices worldwide. To monitor SARS-CoV-2 contamination in dental clinics, a longitudinal study was carried out during the return of dental practice at university. Methods: Dental health care professionals [(DHCPs); teachers, undergraduate dental students, and dental assistants] and patients were screened for SARS-CoV-2 RNA in a dental school clinic environment from 11th January to 12th March 2021 (9 weeks). Serological testing was performed on DHCPs in two-time points. Additionally, samples with low Ct values were sequenced to identify the circulating SARS-CoV-2 variant and possible transmission clusters. Results: We found a low number of dental staff (5.8%), patients (0.9%), and environment sites (0.8%) positive for SARS-CoV-2. Most positive cases had asymptomatic to mild symptoms, and two asymptomatic DHCPs presented prolonged infection. In the first week after previous exposure to COVID-19, 16.2% of DHCPs had IgM or IgG antibodies against SARS-CoV-2, and 1/3 of them had undetected antibodies in the last weeks. The variant zeta (P.2) could be detected. No cross-infection was observed between participants. Conclusion: Our study suggests that dental practice can be safely executed when adequate control measures and biosafety protocols are applied. DHCP and patient testing, patient telemonitoring, proper use of personal protection equipment, and sanitization of surfaces are essential to avoid SARS-CoV-2 cross-infection in dental practice.

Association between Stress at Work and Temporomandibular Disorders: A Systematic Review.

Temporomandibular disorders (TMD) have been traditionally associated with psychosocial factors; however, occupational stress as a factor related to TMD has not been adequately assessed in the literature. The aim was to investigate the association between stress at work and TMD on adult paid workers. An electronic search included PubMed, Scopus, Web of Science, Embase, and LILACS databases. Manual searches in the included articles' reference and gray literature were performed. There were no restrictions regarding language or publication period. The inclusion criteria comprised observational studies with paid workers of any category, of both sexes, above 18 years old, assessing occupational stress/stress or distress and TMD as diagnosis or isolated signs and symptoms. Methodological quality was evaluated using Joanna Briggs tools. We narratively assessed the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. We collected 12 studies. 50% reported a positive association between stress and TMD diagnostic across various job categories. On the other hand, TMJ sounds (a TMD sign) and work stress were associated only in a musicians' population. However, the shortage of eligible articles and the methodological limitations provided a very low certainty of the evidence; only 4 of the studies used validated tools for both stress and TMD (2 reporting positive association). The association between stress and TMD is inconclusive by the available data. In the future, we expect more robust epidemiologic studies addressing these relevant aspects.

Moulding hydrodynamic 2D-crystals upon parametric Faraday waves in shear-functionalized water surfaces.

Faraday waves, or surface waves oscillating at half of the natural frequency when a liquid is vertically vibrated, are archetypes of ordering transitions on liquid surfaces. Although unbounded Faraday waves patterns sustained upon bulk frictional stresses have been reported in highly viscous fluids, the role of surface rigidity has not been investigated so far. Here, we demonstrate that dynamically frozen Faraday waves-that we call 2D-hydrodynamic crystals-do appear as ordered patterns of nonlinear gravity-capillary modes in water surfaces functionalized with soluble (bio)surfactants endowing in-plane shear stiffness. The phase coherence in conjunction with the increased surface rigidity bears the Faraday waves ordering transition, upon which the hydrodynamic crystals were reversibly molded under parametric control of their degree of order, unit cell size and symmetry. The hydrodynamic crystals here discovered could be exploited in touchless strategies of soft matter and biological scaffolding ameliorated under external control of Faraday waves coherence.

Multiple particle tracking analysis in isolated nuclei reveals the mechanical phenotype of leukemia cells.

The nucleus is fundamentally composed by lamina and nuclear membranes that enclose the chromatin, nucleoskeletal components and suspending nucleoplasm. The functional connections of this network integrate external stimuli into cell signals, including physical forces to mechanical responses of the nucleus. Canonically, the morphological characteristics of the nucleus, as shape and size, have served for pathologists to stratify and diagnose cancer patients; however, novel biophysical techniques must exploit physical parameters to improve cancer diagnosis. By using multiple particle tracking (MPT) technique on chromatin granules, we designed a SURF (Speeded Up Robust Features)-based algorithm to study the mechanical properties of isolated nuclei and in living cells. We have determined the apparent shear stiffness, viscosity and optical density of the nucleus, and how the chromatin structure influences on these biophysical values. Moreover, we used our MPT-SURF analysis to study the apparent mechanical properties of isolated nuclei from patients of acute lymphoblastic leukemia. We found that leukemia cells exhibited mechanical differences compared to normal lymphocytes. Interestingly, isolated nuclei from high-risk leukemia cells showed increased viscosity than their counterparts from normal lymphocytes, whilst nuclei from relapsed-patient's cells presented higher density than those from normal lymphocytes or standard- and high-risk leukemia cells. Taken together, here we presented how MPT-SURF analysis of nuclear chromatin granules defines nuclear mechanical phenotypic features, which might be clinically relevant.

Other Potential CKD Hotspots in the World: The Cases of Mexico and the United States.

Hotspots of chronic kidney disease of unknown etiology (CKDu) have been identified throughout the globe, of which the Mesoamerican nephropathy in Central America is the most conspicuous example. It affects mainly agricultural workers, heat exposure during extenuating shifts leading to sudden dehydration and subsequent acute kidney injury (AKI) episodes is the main hypothesis, with other factors such as environmental and social determinants playing an underlying role. Recent reports have suggested that Mexico and the United States may have newly identified CKDu hotspots. Studies from Tierra Blanca, a rural region in Mexico, have shown that the prevalence of probable CKD is high (25%) among the population, of which almost half of the identified cases had no known risk factor (such as diabetes or hypertension). Studies in Hispanic agricultural workers from California and Florida have shown that heat stress and dehydration is frequent and is correlated with AKI episodes after a work shift (33% of workers in one shift). Because recurrent AKI is an established risk factor for CKD, these studies strengthen the evidence that suggests an association between this occupational exposure and CKD. Whether the etiology responsible for the entities described is the same as in other CKDu hotspots in the world remains unknown. The development of preventative and intervention strategies is the most urgent priority to address this issue.