Investigating the Impact of Social Contact, Coping Strategies, and Social Cognition on Loneliness and Psychological Distress in Older Adults during the COVID-19 Pandemic: An Online Survey

This study investigated factors associated with wellbeing in 114 older adults (aged ≥70) during the COVID-19 pandemic; namely, the effects of social contact, coping strategies, and social cognition. Data was collected through an online survey. The relationships between variables were investigated using multiple linear regression. Qualitative data on wellbeing and coping strategies was also collected and analysed using content analysis. Results showed that participants who lived alone reported higher levels of psychological distress than those who lived with someone else. Higher face-to-face social contact with people from outside of one’s household was associated with lower reported distress; however, virtual social contact and attendance of organised online groups were not associated with distress. Negative coping strategies, including denial, self-blame, and behavioural disengagement were associated with higher distress, whereas Theory-of-Mind ability and cognitive empathy were associated with lower distress. Additionally, the negative relationship between face-to-face social contact and distress was stronger in participants who lived with someone than in participants who lived alone. There was also a suggestion that social cognition, namely cognitive and affective empathy, may moderate the relationship between social contact and distress. This research is important for understanding how older adults can be supported during the COVID-19 pandemic, and implications are discussed. Further research with larger and more representative samples is needed to clarify and confirm these effects. Further research also needs to focus on experiences of carers and cared-for individuals during the COVID-19 pandemic

Complete control of a matter qubit using a single picosecond laser pulse

We demonstrate for the first time that a matter physical two level system, a qubit, can be fully controlled using one ultrafast step. We show that the spin state of an optically excited electron, an exciton, confined in a quantum dot, can be rotated by any desired angle, about any desired axis, during such a step. For this we use a single, resonantly tuned, picosecond long, polarized optical pulse. The polarization of the pulse defines the rotation axis, while the pulse detuning from a non-degenerate absorption resonance, defines the magnitude of the rotation angle. We thereby achieve a high fidelity, universal gate operation, applicable to other spin systems, using only one short optical pulse. The operation duration equals the pulse temporal width, orders of magnitude shorter than the qubit evolution life and coherence times.Comment: main text: 4 pages, 3 figures Supplemental material: 3 pages, 1 figur

Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome

Most transcription factors, including nuclear receptors, are widely modeled as binding regulatory elements as monomers, homodimers, or heterodimers. Recent findings in live cells show that the glucocorticoid receptor NR3C1 (also known as GR) forms tetramers on enhancers, owing to an allosteric alteration induced by DNA binding, and suggest that higher oligomerization states are important for the gene regulatory responses of GR. By using a variant (GRtetra) that mimics this allosteric transition, we performed genome-wide studies using a GR knockout cell line with reintroduced wild-type GR or reintroduced GRtetra. GRtetra acts as a super receptor by binding to response elements not accessible to the wild-type receptor and both induces and represses more genes than GRwt. These results argue that DNA binding induces a structural transition to the tetrameric state, forming a transient higher-order structure that drives both the activating and repressive actions of glucocorticoids.Fil: Paakinaho, Ville. National Institutes of Health; Estados Unidos. University Of Eastern Finland; FinlandiaFil: Johnson, Thomas A.. National Institutes of Health; Estados UnidosFil: Presman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Hager, Gordon L.. National Institutes of Health; Estados Unido

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.Fil: Johnson, Thomas A.. National Institutes of Health; Estados UnidosFil: Paakinaho, Ville. University Of Eastern Finland.; FinlandiaFil: Kim, Sohyoung. National Institutes of Health; Estados UnidosFil: Hager, Gordon L.. National Institutes of Health; Estados UnidosFil: Presman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Power-law behaviour of transcription factor dynamics at the single-molecule level implies a continuum affinity model

Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs-one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multi-exponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.Fil: Garcia, David A.. National Institutes of Health; Estados UnidosFil: Fettweis, Gregory. National Institutes of Health; Estados UnidosFil: Presman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Paakinaho, Ville. University Of Eastern Finland.; FinlandiaFil: Jarzynski, Christopher. University of Maryland; Estados UnidosFil: Upadhyaya, Arpita. University of Maryland; Estados UnidosFil: Hager, Gordon L.. National Institutes of Health; Estados Unido

Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor

Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects.Fil: Presman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Ogara, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Stortz, Martin Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Alvarez, Lautaro Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Pooley, John R.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados Unidos. University of Bristol; Reino UnidoFil: Schiltz, R. Louis. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Grøntved, Lars. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Johnson, Thomas A.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Mittelstadt, Paul R.. National Cancer Institute. Laboratory of Immune Cell Biology; Estados UnidosFil: Ashwell, Jonathan D.. National Cancer Institute. Laboratory of Immune Cell Biology; Estados UnidosFil: Ganesan, Sundar. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados Unidos. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Burton, Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Levi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Hager, Gordon L.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Pecci, Adali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

Structural basis for glucocorticoid receptor multimerization

Resumen del trabajo presentado en el 46º Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en A Coruña (España), del 3 al 6 de septiembre de 2024The glucocorticoid receptor (GR) is a ubiquitously expressed ligand-regulated transcription factor essential for life and one of the most targeted proteins in drug discovery due to its powerful anti-inflammatory actions. The functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity in cells, remains disputed. Here we present a new crystal structure of agonist-bound ancient GR-LBD in a large cell, along with a thorough analysis of previous structural work. The building block of the current structure is a homodimer we previously identified in GR-LBD crystals and its biological relevance has been verified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in live cells. Several mutually exclusive multimeric assemblies of this dimer in the crystal highlight the versatility of GR-LBD for self-association and reveal implications for the conformation of the active full-length receptor. Our results underscore the relevance of non-canonical dimerization modes for GR-LBD, especially of contacts made by key residues such as Tyr545, Pro637 and Asp641. Of note, a non-conservative mutation of the latter, p.Asp641Val, causes Chrousos syndrome in humans. Understanding relevant quaternary assemblies of the GR is pivotal not only to understand and predict the therapeutic outcome of major blockbuster drugs but also to lessen their deleterious side effects and open new avenues for drug desig

The mineralocorticoid receptor forms higher order oligomers upon DNA binding.

The mineralocorticoid and glucocorticoid receptors (MR and GR) are evolutionary related nuclear receptors with highly conserved DNA- and ligand-binding domains (DBD and LBD), which determine promiscuous activation by corticosteroid hormones (aldosterone and glucocorticoids) and binding to a shared DNA consensus sequence, the hormone response element (HRE). In addition, MR and GR functionally interact, likely through direct formation of heteromeric complexes, potentially contributing to cell-specific corticosteroid signaling. It has recently been proposed that agonist and DNA binding promote GR self-association in tetramers. Here we investigated MR quaternary arrangement after receptor activation. To that end we used a fluorescence imaging technique, Number & Brightness (N&B) analysis, in a cell system where receptor-DNA interaction can be studied in live cells in real time. Our results show that agonist-bound MR is a tetramer in the nucleoplasm, forming higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that the formation of large oligomeric complexes is essential for function. We also show that divergence between MR and GR quaternary arrangements are driven by different functionality of multimerization interfaces in the DBD and LBD and their interplay with the N-terminal domain. In spite of contrasting quaternary structures, MR and GR are able to form heteromers. Given the importance of both receptors as pharmacological targets and the differential oligomerization induced by antagonists, our findings suggest that influencing quaternary structure may be important to provide selective modulation of corticosteroid signaling

Average flow constraints and stabilizability in uncertain production-distribution systems

We consider a multi-inventory system with controlled flows and uncertain demands (disturbances) bounded within assigned compact sets. The system is modelled as a first-order one integrating the discrepancy between controlled flows and demands at different sites/nodes. Thus, the buffer levels at the nodes represent the system state. Given a long-term average demand, we are interested in a control strategy that satisfies just one of two requirements: (i) meeting any possible demand at each time (worst case stability) or (ii) achieving a predefined flow in the average (average flow constraints). Necessary and sufficient conditions for the achievement of both goals have been proposed by the authors. In this paper, we face the case in which these conditions are not satisfied. We show that, if we ignore the requirement on worst case stability, we can find a control strategy driving the expected value of the state to zero. On the contrary, if we ignore the average flow constraints, we can find a control strategy that satisfies worst case stability while optimizing any linear cost on the average control. In the latter case, we provide a tight bound for the cost