Many-body correlations in a multistep variational approach

We discuss a multistep variational approach for the study of many-body correlations. The approach is developed in a boson formalism (bosons representing particle-hole excitations) and based on an iterative sequence of diagonalizations in subspaces of the full boson space. Purpose of these diagonalizations is that of searching for the best approximation of the ground state of the system. The procedure also leads us to define a set of excited states and, at the same time, of operators which generate these states as a result of their action on the ground state. We examine the cases in which these operators carry one-particle one-hole and up to two-particle two-hole excitations. We also explore the possibility of associating bosons to Tamm-Dancoff excitations and of describing the spectrum in terms of only a selected group of these. Tests within an exactly solvable three-level model are provided.Comment: 24 pages, 6 figures, to appear in Phys. Rev.

Hepatic PPARs: their role in liver physiology, fibrosis and treatment

Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease

Multipair approach to pairing in nuclei

The ground state of a general pairing Hamiltonian for a finite nuclear system is constructed as a product of collective, real, distinct pairs. These are determined sequentially via an iterative variational procedure that resorts to diagonalizations of the Hamiltonian in restricted model spaces. Different applications of the method are provided that include comparisons with exact and projected BCS results. The quantities that are examined are correlation energies, occupation numbers and pair transfer matrix elements. In a first application within the picket-fence model, the method is seen to generate the exact ground state for pairing strengths confined in a given range. Further applications of the method concern pairing in spherically symmetric mean fields and include simple exactly solvable models as well as some realistic calculations for middle-shell Sn isotopes. In the latter applications, two different ways of defining the pairs are examined: either with J=0 or with no well-defined angular momentum. The second choice reveals to be more effective leading, under some circumstances, to solutions that are basically exact.Comment: To appear in Physical Review

Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA

Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance

Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population

Age-related alterations in default mode network: Impact on working memory performance

The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand

Extension of random-phase approximation preserving energy weighted sum rules: an application to a 3-level Lipkin model

A limitation common to all extensions of random-phase approximation including only particle-hole configurations is that they violate to some extent the energy weighted sum rules. Considering one such extension, the improved RPA (IRPA), already used to study the electronic properties of metallic clusters, we show how it can be generalized in order to eliminate this drawback. This is achieved by enlarging the configuration space, including also elementary excitations corresponding to the annihilation of a particle (hole) and the creation of another particle (hole) on the correlated ground state. The approach is tested within a solvable 3-level model.Comment: 2 figure

Age-related alterations in simple declarative memory and the effect of negative stimulus valence

Healthy aging has been shown to modulate the neural circuitry underlying simple declarative memory; however, the functional impact of negative stimulus valence on these changes has not been fully investigated. Using BOLD fMRI, we explored the effects of aging on behavioral performance, neural activity, and functional coupling during the encoding and retrieval of novel aversive and neutral scenes. Behaviorally, there was a main effect of valence with better recognition performance for aversive greater than neutral stimuli in both age groups. There was also a main effect of age with better recognition performance in younger participants compared to older participants. At the imaging level, there was a main effect of valence with increased activity in the medial-temporal lobe (amygdala and hippocampus) during both encoding and retrieval of aversive relative to neutral stimuli. There was also a main effect of age with older participants showing decreased engagement of medial-temporal lobe structures and increased engagement of prefrontal structures during both encoding and retrieval sessions. Interestingly, older participants presented with relatively decreased amygdalar-hippocampal coupling and increased amygdalar-prefrontal coupling when compared to younger participants. Furthermore, older participants showed increased activation in prefrontal cortices and decreased activation in the amygdala when contrasting the retrieval of aversive and neutral scenes. These results suggest that although normal aging is associated with a decline in declarative memory with alterations in the neural activity and connectivity of brain regions underlying simple declarative memory, memory for aversive stimuli is relatively better preserved than for neutral stimuli, possibly through greater compensatory prefrontal cortical activit

Increased C-reactive protein concentration and suicidal behavior in people with psychiatric disorders: A systematic review and meta-analysis

Objective: Suicide is a leading cause of death worldwide. Identifying factors associated with suicidality (suicidal ideation [SI]/suicidal behavior) could increase our understanding of the pathophysiological underpinnings of suicide and improve its prevention. Methods: We conducted a systematic review (PubMed/PsycInfo/Cochrane databases, up to September 2020) and random-effect meta-analysis including observational studies comparing peripheral C-reactive protein (CRP) levels in suicidal versus non-suicidal patients affected by any psychiatric disorder and healthy controls (HC). Primary outcome was the CRP standardized mean difference (SMD) between patients with high suicidality versus those with absent or low suicidality. Secondary outcomes were SMD of CRP levels between those with suicide attempt versus no suicide attempt, as well as between those with (high) versus low or absent SI. Quality of included studies was measured with Newcastle-Ottawa scale. Results: Out of initial 550 references, 21 observational studies involving 7682 subjects (7445 with mood disorders or first-episode psychosis, 237 HC) were included. A significant association of CRP levels with suicidality (SMD 0.688, 95% CI 0.476–0.9, p < 0.001) emerged. CRP levels were higher in individuals with high SI (SMD 1.145, 95% CI 0.273–2.018, p = 0.010) and in those with suicide attempt (SMD 0.549, 95%CI 0.363–0.735, p < 0.001) than non-suicidal individuals (either patients or HC). Main analyses were confirmed in sensitivity analysis (removing HC), and after adjusting for publication bias. The cross-sectional design of included studies, and the high heterogeneity of diagnosis and treatment limit the generalizability of these results. Median quality of included studies was high. Conclusion: CRP is associated with higher suicidality in patients with mental disorders. Large cohort studies longitudinally monitoring CRP levels are needed to explore its longitudinal association with suicidality

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans