Thermodynamics of resonating-valence-bond states toward the understanding of quantum spin liquid phenomena.

A quantum spin liquid (QSL) is a state of matter in which spins do not exhibit magnetic order. In contrast to paramagnets, the spins in a QSL interact strongly, similar to conventional ordered magnets; however the thermodynamic stability of QSLs is rarely studied. Here, the thermodynamic properties of centered hexagon nanoclusters were investigated using the Hubbard model, which was solved using exact numerical diagonalization. The total spin, spin-spin correlation functions, local magnetic moments, charge and spin gaps, and magnetocaloric effect were analyzed for a half-filled band as a function of the ratio between the on-site Coulomb repulsion and electronic hopping (U/t). The centered hexagon nanocluster exhibited an antiferromagnetic (AFM) behavior with exotic magnetic ordering. Resonating-valence-bond (RVB) states were observed for intermediate values of U/t, in which short-range spin-spin correlation functions were suppressed to minimize spin frustration. The AFM order was examined in terms of the Néel-like temperature derived from the temperature dependence of the magnetic susceptibility. An interesting result is that the systems under external magnetic fields exhibited an inverse magnetocaloric effect, which was remarkable for intermediate values of U/t, where the RVB state was observed. Owing to the novel discovery of exotic magnetic ordering in triangular moiré patterns in twisted bilayer graphene (TBLG) systems, these results provide insights into the onset of magnetism and the possible spin liquid states in these graphene moiré materials.

Improvement in Quality of Life With the Use of a Technological System Among Patients With Chronic Disease Followed Up in Primary Care (TeNDER Project): Protocol for a Randomized Controlled Trial.

BACKGROUND: Among chronic diseases, cognitive, neurological, and cardiovascular impairments are becoming increasingly prevalent, generating a shift in health and social needs. Technology can create an ecosystem of care integrated with microtools based on biosensors for motion, location, voice, and expression detection that can help people with chronic diseases. A technological system capable of identifying symptoms, signs, or behavioral patterns could provide notification of the development of complications of disease. This would help the self-care of patients with chronic disease and save health care costs, promoting the autonomy and empowerment of patients and their caregivers, improving their quality of life (QoL), and providing health professionals with monitoring tools. OBJECTIVE: The main objective of this study is to evaluate the effectiveness of a technological system (the TeNDER system) to improve quality of life in patients with chronic diseases: Alzheimer disease, Parkinson disease, and cardiovascular disease. METHODS: A multicenter, randomized, parallel-group clinical trial will be conducted with a follow-up of 2 months. The scope of the study will be the primary care health centers of the Community of Madrid belonging to the Spanish public health system. The study population will be patients diagnosed with Parkinson disease, Alzheimer disease, and cardiovascular disease; their caregivers; and health professionals. The sample size will be 534 patients (380 in the intervention group). The intervention will consist of the use of the TeNDER system. The system will monitor the patients by means of biosensors, and their data will be integrated into the TeNDER app. With the information provided, the TeNDER system will generate health reports that can be consulted by patients, caregivers, and health professionals. Sociodemographic variables and technological affinity will be measured, as will views on the usability of and satisfaction with the TeNDER system. The dependent variable will be the mean difference in QoL score between the intervention and control groups at 2 months. To study the effectiveness of the TeNDER system in improving QoL in patients, an explanatory linear regression model will be constructed. All analyses will be performed with the 95% CI and robust estimators. RESULTS: Ethics approval for this project was received on September 11, 2019. The trial was registered on August 14, 2020. Recruitment commenced in April 2021, and the expected results will be available during 2023 or 2024. CONCLUSIONS: This clinical trial among patients with highly prevalent chronic illnesses and the people most involved in their care will provide a more realistic view of the situation experienced by people with long-term illness and their support networks. The TeNDER system is in continuous development based on a study of the needs of the target population and on feedback during its use from the users: patients, caregivers, and primary care health professionals. TRIAL REGISTRATION: ClinicalTrials.gov NCT05681065; https://clinicaltrials.gov/ct2/show/NCT05681065. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47331.

Switchable assembly and function of antibody complexes in vivo using a small molecule.

The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.

Atypical Kawasaki Disease after COVID-19 Vaccination: A New Form of Adverse Event Following Immunization.

Kawasaki disease (KD) is a medium-vessel vasculitis that is typically presented during childhood; fewer than 100 cases of KD have been reported worldwide in adult patients who met the criteria according to the American College of Rheumatology. This study presents the case of an 18-year-old patient with no previous history of any disease, who presented atypical KD with liver and kidney dysfunction, with a good response to intravenous immunoglobulin therapy. The symptoms began 22 days after the application of the COVID-19 vaccine (nonreplicating viral vector Vaxzevria), and other conditions were ruled out. The term Adverse Events Following Immunization (AEFI)encompasses all the reactions that follow the application of any vaccine with no necessary causal relationship and can be due to the vaccine product, quality of the vaccine, immunization errors, or anxiety or just happen to be coincident events. These reactions should be reported so that clinicians can identify compatible cases and consider that the presentation of this disease, despite being atypical, can be manifested in adult patients. Likewise, case reports are an important basis for the pharmacovigilance of vaccines.

Guía de práctica clínica para el tamizaje, diagnóstico y tratamiento inicial de cáncer de próstata localizado y localmente avanzado en el Seguro Social del Perú (EsSalud) / Clinical practice guideline for screening, diagnosis and initial treatment of localized and locally advanced prostate cancer in the Peruvian Social Security (EsSalud)

Introducción: El presente artículo resume la guía de práctica clínica (GPC) para el tamizaje, diagnóstico, y tratamiento inicial del cáncer de próstata localizado y localmente avanzado en el Seguro Social del Perú (EsSalud). Objetivo: Proveer recomendaciones clínicas basadas en evidencia para el tamizaje, diagnóstico, y tratamiento inicial de adultos con cáncer de próstata localizado y localmente avanzado en EsSalud. Material y Métodos: Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos, el cual formuló preguntas clínicas. Se realizaron búsquedas sistemáticas de revisiones sistemáticas y ­cuando fue considerado pertinente­ estudios primarios en PubMed durante el 2020 y 2021. Se seleccionó la evidencia para responder cada una de las preguntas clínicas planteadas. Se evaluó la certeza de evidencia usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones. La GPC fue revisada por expertos externos antes de su aprobación. Resultados: La GPC abordó 06 preguntas clínicas, divididas en 03 temas: tamizaje, diagnóstico, y tratamiento inicial. En base a dichas preguntas se formularon 08 recomendaciones (04 fuertes y 04 condicionales), 10 puntos de buena práctica clínica, y 04 flujogramas. Conclusión: Se emitieron recomendaciones basadas en evidencia para el manejo de pacientes con esta patología.

Background:This article summarizes the clinical practice guide (CPG) for the screening, diagnosis, and initial treatment of localized and locally advanced prostate cancer in the Social Security of Peru (EsSalud). To provide evidence-Objective:based clinical recommendations for the screening, diagnosis, and initial treatment of adults with localized and locally advanced prostate cancer in EsSalud. Methods: Aguideline developmentgroup(GDG)wasformed,whichincluded specialist physicians and methodologists, who formulated clinical questions. Systematic searches of systematic reviews were conducted and - when deemed relevant - primary studies in PubMed during 2020 and 2021. Evidence was selected to answer each of the proposed clinical questions. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic working meetings, the GEG used the GRADE methodology to review the evidence and formulate recommendations. The CPG was reviewed by external experts before its approval. The CPG Results: addressed 06 clinical questions, divided into 03 topics: screening, diagnosis, and initial treatment. Based on these questions, 08 recommendations were formulated (04 strong and 04 conditional), 10 points of good clinical practice, and 04 flow charts. Conclusion: Evidence-based recommendations were issued for the management of patients with this pathology

Tissue-targeted R-spondin mimetics for liver regeneration.

R-spondin (RSPO) proteins amplify Wnt signaling and stimulate regeneration in a variety of tissues. To repair tissue in a tissue-specific manner, tissue-targeted RSPO mimetic molecules are desired. Here, we mutated RSPO (RSPO2 F105R/F109A) to eliminate LGR binding while preserving ZNRF3/RNF43 binding and targeted the mutated RSPO to a liver specific receptor, ASGR1. The resulting bi-specific molecule (αASGR1-RSPO2-RA) enhanced Wnt signaling effectively in vitro, and its activity was limited to ASGR1 expressing cells. Systemic administration of αASGR1-RSPO2-RA in mice specifically upregulated Wnt target genes and stimulated cell proliferation in liver but not intestine (which is more responsive to non-targeted RSPO2) in healthy mice, and improved liver function in diseased mice. These results not only suggest that a tissue-specific RSPO mimetic protein can stimulate regeneration in a cell-specific manner, but also provide a blueprint of how a tissue-specific molecule might be constructed for applications in a broader context.

Kv1.3 blockade inhibits proliferation of vascular smooth muscle cells in vitro and intimal hyperplasia in vivo.

The modulation of voltage-gated K+ (Kv) channels, involved in cell proliferation, arises as a potential therapeutic approach for the prevention of intimal hyperplasia present in in-stent restenosis (ISR) and allograft vasculopathy (AV). We studied the effect of PAP-1, a selective blocker of Kv1.3 channels, on development of intimal hyperplasia in vitro and in vivo in 2 porcine models of vascular injury. In vitro phenotypic modulation of VSMCs was associated to an increased functional expression of Kv1.3 channels, and only selective Kv1.3 channel blockers were able to inhibit porcine VSMC proliferation. The therapeutic potential of PAP-1 was then evaluated in vivo in swine models of ISR and AV. At 15-days follow-up, morphometric analysis demonstrated a substantial reduction of luminal stenosis in the allografts treated with PAP-1 (autograft 2.72 ± 1.79 vs allograft 10.32 ± 1.92 vs allograft + polymer 13.54 ± 8.59 vs allograft + polymer + PAP-1 3.06 ± 1.08 % of luminal stenosis; P = 0.006) in the swine model of femoral artery transplant. In the pig model of coronary ISR, using a prototype of PAP-1-eluting stent, no differences were observed regarding % of stenosis compared to control stents (31 ± 13 % vs 37 ± 18%, respectively; P = 0.372) at 28-days follow-up. PAP-1 treatment was safe and did not impair vascular healing in terms of delayed endothelialization, inflammation or thrombosis. However, an incomplete release of PAP-1 from stents was documented. We conclude that the use of selective Kv1.3 blockers represents a promising therapeutic approach for the prevention of intimal hyperplasia in AV, although further studies to improve their delivery method are needed to elucidate its potential in ISR.

CuI-Catalyzed Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides with Cyclobutenones.

The catalytic asymmetric 1,3-dipolar cycloaddition of cyclobutenones with azomethine ylides provides straightforward access to densely substituted 3-azabicyclo[3.2.0]heptanes. In the presence of CuI/(R)-Fesulphos as the catalytic system, high levels of diastereoselectivity and enantioselectivity were achieved (up to 98% enantiomeric excess (ee)).

Stereoselective Ag-Catalyzed 1,3-Dipolar Cycloaddition of Activated Trifluoromethyl-Substituted Azomethine Ylides.

A silver-catalyzed 1,3-dipolar cycloaddition of fluorinated azomethine ylides and activated olefins is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of fluorinated pyrrolidines. Broad scope and high levels of diastereoselectivity have been achieved simply by using AgOAc/PPh3 as the catalyst system. The high efficiency of the cycloaddition relies on the presence of a metal-coordinating group on the imine moiety, such as an ester or heteroaryl group. The asymmetric version of the cycloaddition has been developed by using Taniaphos as a chiral ligand.

Ni-Catalyzed [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters.

A variety of cycloheptapyrane derivatives were prepared via Ni-catalyzed formal [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters. The asymmetric version of the process can be achieved using either an enantiomerically enriched cyclopropane as the starting material or a racemic cyclopropane and a chiral Lewis acid.

Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.

Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.