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Reporting of physical activity levels in intensive care unit survivors
Abstract The primary aim of this study was to report the physical activity profiles and the functional status of critically ill patients at one-month post-discharge using the ‘Physical Activity Scale for the Elderly (PASE)’ questionnaire. Study participants included were between 45 and 75 years of age, admitted to ICUs for a minimum of 24 h. Altogether, 110 study participants were included by consecutive sampling, from which six were lost to follow up. This prospective observational study was carried out in the ICU settings of Kasturba Hospital, Manipal. All the participants were assessed for ICU-acquired weakness at ICU discharge and were later followed up after one month for their physical activity level via telephonic follow-up. Participants’ mean age was 57.5 ± 9.82 years, out of which 71% were female. The prevalence of ICU-acquired weakness was found to be 80% in these participants. The median PASE score was 5 (2–27) at one-month follow-up among the participants. Medical Research Council (MRC) sum score showed a statistically significant positive moderate association with PASE score (‘r = 0.70, p < 0.05). The study showed that about 97.1% of ICU survivors lead a sedentary lifestyle and showed alarmingly high levels of physical inactivity at one month post-hospital discharge.
Cost-effectiveness of HIV pre-exposure prophylaxis among female sex workers in Iran
Study on spatial pattern and coupling of county traffic superiority degree and new-type urbanization level in Guizhou Province, China
Structural analysis and core promoter prediction of STAR gene and its regulatory mechanism of progesterone synthesis in bovine luteal cells
Modulatory Neurotransmitter Genotypes Shape Dynamic Functional Connectome Reconfigurations
Dynamic reconfigurations of the functional connectome across different connectivity states are highly heritable, predictive of cognitive abilities, and linked to mental health. Despite their established heritability, the specific polymorphisms that shape connectome dynamics are largely unknown. Given the widespread regulatory impact of modulatory neurotransmitters on functional connectivity, we comprehensively investigated a large set of single nucleotide polymorphisms (SNPs) of their receptors, metabolic enzymes, and transporters in 674 healthy adult subjects (347 females) from the Human Connectome Project. Preregistered modulatory neurotransmitter SNPs and dynamic connectome features entered a Stability Selection procedure with resampling. We found that specific subsets of these SNPs explain individual differences in temporal phenotypes of fMRI-derived connectome dynamics for which we previously established heritability. Specifically, noradrenergic polymorphisms explained Fractional Occupancy, i.e., the proportion of time spent in each connectome state, and cholinergic polymorphisms explained Transition Probability, i.e., the probability to transition between state pairs, respectively. This work identifies specific genetic effects on connectome dynamics via the regulatory impact of modulatory neurotransmitter systems. Our observations highlight the potential of dynamic connectome features as endophenotypes for neurotransmitter-focused precision psychiatry.
Corrosion resistance and pore distribution of hydrophobic modified mortar containing coral sand
Amyloid-Beta Deposition in Basal Frontotemporal Cortex Is Associated with Selective Disruption of Temporal Mnemonic Discrimination
Cerebral amyloid-beta (Aβ) accumulation, a hallmark pathology of Alzheimer's disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aβ contributes to subtle memory deficits observed during the preclinical stage. The heterogeneous emergence of Aβ deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aβ deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aβ-PET) and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aβ pathology would be selectively associated with temporal discrimination performance due to Aβ's propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aβ-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Furthermore, we found that higher Aβ-PET levels in the medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aβ accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and future work is needed to determine whether assessing temporal mnemonic discrimination can aid in predicting emerging AD progression.
A multidimensional approach reveals the function of lactylation related genes in osteoarthritis
Improvement of the optical cavity-based biosensor’s limit of detection using optimal 3-aminopropyltriethoxysilane process
Conspecific presence facilitates 22-kHz ultrasonic calls in male rats exposed to cat odor
Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease
Accumulation of astrocytes around β-amyloid (Aβ) plaques is one of the earliest neuropathological changes in Alzheimer's disease (AD), but the underlying mechanisms and significance remain unclear. Cell adhesion molecule protocadherin-γC5 (Pcdh-γC5) has been reported to implicate in AD. Here, we find elevated expression levels of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes and further reveal that Pcdh-γC5 deficiency leads to exacerbated Aβ deposition in 5×FAD mice. Deletion of Pcdh-γC5 impairs astrocyte migration, astrocytic response to Aβ signaling, and Aβ phagocytosis in both cultured astrocytes in vitro and 5×FAD mice in vivo. Both male and female mice were used in this study. Our findings support a model in which increased expression level of Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and engulfment and phagocytosis of neurotoxic Aβ plaques, therefore exerting a critical neuroprotective function in AD.
Longitudinal Sex-at-Birth and Age Analyses of Cortical Structure in the ABCD Study
While the brain continues to develop during adolescence, such development may depend on sex-at-birth. However, the elucidation of such differences may be hindered by analytical decisions (e.g., covariate selection to address brain-size differences) and the typical reporting of cross-sectional data. To further evaluate adolescent cortical development, we analyzed data from the Adolescent Brain Cognitive Development Study, whose cohort of 11,000+ youth participants with biannual neuroimaging data collection can facilitate understanding neuroanatomical change during a critical developmental window. Doubly considering individual differences within the context of group-level effects, we analyzed regional changes in cortical thickness, sulcal depth, surface area, and volume between two timepoints (∼2 years apart) in 9- to 12-year-olds assigned male or female sex-at-birth. First, we conducted linear mixed-effect models to gauge how controlling for intracranial volume, whole-brain volume (WBV), or a summary metric (e.g., mean cortical thickness) influenced interpretations of age-dependent cortical change. Next, we evaluated the relative changes in thickness and surface area as a function of sex-at-birth and age. Here, we showed that WBV (thickness, sulcal depth, volume) and total cortical surface area were more optimal covariates; controlling for different covariates would have substantially altered our interpretations of overall and sex-at-birth-specific neuroanatomical development. Furthermore, we provided evidence to suggest that aggregate change in how cortical thickness is changing relative to surface area is generally comparable across those assigned male or female sex-at-birth, with corresponding change happening at slightly older ages in those assigned male sex-at-birth. Overall, these results help elucidate neuroanatomical developmental trajectories in early adolescence.
Network Mechanisms Underlying the Regional Diversity of Variance and Time Scales of the Brain's Spontaneous Activity Fluctuations
The brain's activity fluctuations have different temporal scales across the brain regions, with associative regions displaying slower timescales than sensory areas. This hierarchy of timescales has been shown to correlate with both structural brain connectivity and intrinsic regional properties. Here, using publicly available human resting-state fMRI and dMRI data, it was found that, while more structurally connected brain regions presented activity fluctuations with longer timescales, their activity fluctuations presented lower variance. The opposite relationships between the structural connectivity and the variance and temporal scales of resting-state fluctuations, respectively, were not trivially explained by simple network propagation principles. To understand these structure–function relationships, two commonly used whole-brain models were studied, namely, the Hopf and Wilson–Cowan models. These models use the brain's connectome to couple local nodes (representing brain regions) displaying noise-driven oscillations. The models show that the variance and temporal scales of activity fluctuations can oppositely relate to connectivity within specific parameter regions, even when all nodes have the same intrinsic dynamics—but also when intrinsic dynamics are constrained by the myelinization-related macroscopic gradient. These results show that, setting aside intrinsic regional differences, connectivity and network state are sufficient to explain the regional differences in fluctuations’ scales. State dependence supports the vision that structure–function relationships can serve as biomarkers of altered brain states. Finally, the results indicate that the hierarchies of timescales and variances reflect a balance between stability and responsivity, with greater and faster responsiveness at the network periphery, while the network core ensures overall system robustness.
Reduced Neural Responses to Natural Foreground versus Background Sounds in the Auditory Cortex
In everyday hearing, listeners face the challenge of understanding behaviorally relevant foreground stimuli (speech, vocalizations) in complex backgrounds (environmental, mechanical noise). Prior studies have shown that high-order areas of human auditory cortex (AC) preattentively form an enhanced representation of foreground stimuli in the presence of background noise. This enhancement requires identifying and grouping the features that comprise the background so they can be removed from the foreground representation. To study the cortical computations supporting this process, we recorded single-unit activity in AC of male and female ferrets during the presentation of concurrent natural sounds from these two categories. In contrast to expectations from studies in high-order AC, single-unit responses to foreground sounds were strongly reduced relative to the paired background in primary and secondary AC. The degree of reduction could not be explained by a neuron's preference for the foreground or background stimulus in isolation but could be partially explained by spectrotemporal statistics that distinguish foreground and background categories. Responses to synthesized sounds with statistics either matched or randomized relative to natural sounds showed progressively decreased reduction of foreground responses as natural sound statistics were removed. These results challenge the expectation that cortical foreground representations emerge directly from a mixed representation in the auditory periphery. Instead, they suggest the early AC maintains a robust representation of background noise. Strong background representations may produce a distributed code, facilitating selection of foreground signals from a relatively small subpopulation of AC neurons at later processing stages.
Calretinin-Expressing Neurons in the Basal Forebrain Specifically Contact Granule Cells in the Olfactory Bulb and Modulate Odor Learning
GABAergic neurons in basal forebrain (BF) nuclei project densely to all layers of the mouse main olfactory bulb (OB), the first relay in odor information processing. However, BF projection neurons are diverse, and the contribution of each subtype to odor information processing is not known. In the present study, we used retrograde and anterograde tracing methods together with whole-brain light–sheet analyses, patch-clamp recordings coupled with optogenetic and chemogenetic approaches during spontaneous odor discrimination, and go/no-go odor discrimination/learning tests to characterize the synaptic targets in the OB of BF calretinin-expressing (CR+) GABAergic cells and to reveal their functional implications. We used mice of either sex to show that OB-projecting CR+ neurons innervate the bulbar granule cell (GC) layer but not the glomerular layer. Optogenetic stimulation of CR+ axonal projections in OB slices elicited monosynaptic GABAergic currents in GCs. Retrograde rabies virus-based transsynaptic tracing experiments confirmed these synaptic connections and further suggested that CR+ neurons provide the principal, if not the unique, BF input onto GCs. Chemogenetic inhibition of CR+ neurons in the BF of male mice did not affect odor discrimination in habituation/dishabituation tasks but led to impairment in odor learning during go/no-go odor–associative tasks. Our results revealed a subtype-specific projection pattern in the OB of a select population of BF neurons and suggested that distinct BF GABAergic projections have distinct effects on odor information processing and learning.
Noninvasive Brain Stimulation over the Frontopolar Cortex Promotes Willingness to Exert Cognitive Effort in a Foraging-Like Sequential Choice Task
Individuals avoid spending cognitive effort unless expected rewards offset the perceived costs. Recent work employing tasks that provide explicit information about demands and incentives suggests causal involvement of the frontopolar cortex (FPC) in effort-based decision-making. Using transcranial direct current stimulation (tDCS), we examined whether the FPC's role in motivating effort generalizes to sequential choice problems in which task demand and reward rates vary indirectly and as a function of experience. In a double-blind, within-subject design, 46 participants (36 female, 8 male, 1 “neither/other”) received anodal (i.e., excitatory) or sham stimulation over the right FPC during an Effort Foraging Task, which required choosing between harvesting patches for successively decreasing resources or traveling to replenished patches by performing a cognitive task with environment-specific difficulty. As expected, participants exited patches later (i.e., exhibited lower exit thresholds) when traveling required greater (versus less) effort, indicating increased travel costs in high-effort environments. Under anodal tDCS, the difference in exit thresholds between environments was significantly smaller relative to sham. Finally, individual differences analyses hint that participants with lower self-reported motivation to exert effort exhibited greater travel cost reductions following tDCS. Together, these findings support the theorized causal role of the FPC in motivating cognitively effortful behavior, expand its role to more ecologically valid serial decisions, and highlight the potential for tDCS as a tool to increase motivation with potential clinical applications.
Absolute Number of Three Populations of Interneurons and All GABAergic Synapses in the Human Hippocampus
The human hippocampus, essential for learning and memory, is implicated in numerous neurological and psychiatric disorders, each linked to specific neuronal subpopulations. Advancing our understanding of hippocampal function requires computational models grounded in precise quantitative neuronal data. While extensive data exist on the neuronal composition and synaptic architecture of the rodent hippocampus, analogous quantitative data for the human hippocampus remain very limited. Given the critical role of local GABAergic interneurons in modulating hippocampal functions, we employed unbiased stereological techniques to estimate the density and total number of three major GABAergic cell types in the male and female human hippocampus: parvalbumin (PV)-expressing, somatostatin (SOM)-positive, and calretinin (CR)-positive interneurons. Our findings reveal an estimated 49,400 PV-positive, 141,500 SOM-positive, and 250,600 CR-positive interneurons per hippocampal hemisphere. Notably, CR-positive interneurons, which are primarily interneuron-selective in rodents, were present in humans at a higher proportion. Additionally, using three-dimensional electron microscopy, we estimated ∼25 billion GABAergic synapses per hippocampal hemisphere, with PV-positive boutons comprising ∼3.5 billion synapses, or 14% of the total GABAergic synapses. These findings contribute crucial quantitative insights for modeling human hippocampal circuits and understanding its complex regulatory dynamics.
Reply to: Validation of blood-based detection of breast cancer highlights importance for cross-population validation
Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer
Abstract ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated with potentially targetable molecular features, notably a high immune response and high FGFR4 expression. Strikingly, molecular features that define the HER2E subtype in luminal disease are also consistent in HER2-positive disease, including an epigenetic mechanism for high FGFR4 expression in breast cancer.