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Abstract Background Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. Methods Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. Results MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpβ) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. Conclusions Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.

In this paper we focus on identifying differentially activated brain regions using a light sheet fluorescence microscopy—a recently developed technique for whole-brain imaging. Most existing statistical methods solve this problem by partitioning the brain regions into two classes: significantly and nonsignificantly activated. However, for the brain imaging problem at the center of our study, such binary grouping may provide overly simplistic discoveries by filtering out weak but important signals that are typically adulterated by the noise present in the data. To overcome this limitation, we introduce a new Bayesian approach that allows classifying the brain regions into several tiers with varying degrees of relevance. Our approach is based on a combination of shrinkage priors, widely used in regression and multiple hypothesis testing problems, and mixture models, commonly used in model-based clustering. In contrast to the existing regularizing prior distributions, which use either the spike-and-slab prior or continuous scale mixtures, our class of priors is based on a discrete mixture of continuous scale mixtures and devises a cluster shrinkage version of the horseshoe prior. As a result, our approach provides a more general setting for Bayesian sparse estimation, drastically reduces the number of shrinkage parameters needed, and creates a framework for sharing information across units of interest. We show that this approach leads to more biologically meaningful and interpretable results in our brain imaging problem, since it allows the discrimination between active and inactive regions, while at the same time ranking the discoveries into clusters representing tiers of similar importance.

Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunity and highly expressed in mucosal secretions, shown to target and inhibit neutrophil elastase (NE), cathepsin G and trypsin activity to limit proteolytic activity. In addition to the potent anti-protease activity, SLPI has been demonstrated to exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-κB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mouse model phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis.

Introduction: The response of the brain to space radiation is an important concern for astronauts during space missions. Therefore, we assessed the response of the brain to 28Si ion irradiation (600 MeV/n), a heavy ion present in the space environment, on cognitive performance and whether the response is associated with altered DNA methylation in the hippocampus, a brain area important for cognitive performance. Methods: We determined the effects of 28Si ion irradiation on object recognition, 6-month-old mice irradiated with 28Si ions (600 MeV/n, 0.3, 0.6, and 0.9 Gy) and cognitively tested two weeks later. In addition, we determined if those effects were associated with alterations in hippocampal networks and/or hippocampal DNA methylation. Results: At 0.3 Gy, but not at 0.6 Gy or 0.9 Gy, 28Si ion irradiation impaired cognition that correlated with altered gene expression and 5 hmC profiles that mapped to specific gene ontology pathways. Comparing hippocampal DNA hydroxymethylation following proton, 56Fe ion, and 28Si ion irradiation revealed a general space radiation synaptic signature with 45 genes that are associated with profound phenotypes. The most significant categories were glutamatergic synapse and postsynaptic density. Discussion: The brain's response to space irradiation involves novel excitatory synapse and postsynaptic remodeling.

Abstract A rich and complex temporal structure of variability in postural sway characterizes healthy and adaptable postural control. However, neurodegenerative disorders such as Parkinson’s disease, which often manifest as tremors, rigidity, and bradykinesia, disrupt this healthy variability. This study examined postural sway in young and older adults, including individuals with Parkinson’s disease, under different upright standing conditions to investigate the potential connection between the temporal structure of variability in postural sway and Parkinsonism. A novel and innovative method called oriented fractal scaling component analysis was employed. This method involves decomposing the two-dimensional center of pressure (CoP) planar trajectories to pinpoint the directions associated with minimal and maximal temporal correlations in postural sway. As a result, it facilitates a comprehensive assessment of the directional characteristics within the temporal structure of sway variability. The results demonstrated that healthy young adults control posture along two orthogonal directions closely aligned with the traditional anatomical anteroposterior (AP) and mediolateral (ML) axes. In contrast, older adults and individuals with Parkinson’s disease controlled posture along suborthogonal directions that significantly deviate from the AP and ML axes. These findings suggest that the altered temporal structure of sway variability is evident in individuals with Parkinson’s disease and underlies postural deficits, surpassing what can be explained solely by the natural aging process.

Dexterous postural control subtly complements movement variability with sensory correlations at many scales. The expressive poise of gymnasts exemplifies this lyrical punctuation of release with constraint, from coarse grain to fine scales. Dexterous postural control upon a 2D support surface might collapse the variation of center of pressure (CoP) to a relatively 1D orientation—a direction often oriented towards the focal point of a visual task. Sensory corrections in dexterous postural control might manifest in temporal correlations, specifically as fractional Brownian motions whose differences are more and less correlated with fractional Gaussian noises (fGns) with progressively larger and smaller Hurst exponent H. Traditional empirical work examines this arrangement of lower-dimensional compression of CoP along two orthogonal axes, anteroposterior (AP) and mediolateral (ML). Eyes-open and face-forward orientations cultivate greater variability along AP than ML axes, and the orthogonal distribution of spatial variability has so far gone hand in hand with an orthogonal distribution of H, for example, larger in AP and lower in ML. However, perturbing the orientation of task focus might destabilize the postural synergy away from its 1D distribution and homogenize the temporal correlations across the 2D support surface, resulting in narrower angles between the directions of the largest and smallest H. We used oriented fractal scaling component analysis (OFSCA) to investigate whether sensory corrections in postural control might thus become suborthogonal. OFSCA models raw 2D CoP trajectory by decomposing it in all directions along the 2D support surface and fits the directions with the largest and smallest H. We studied a sample of gymnasts in eyes-open and face-forward quiet posture, and results from OFSCA confirm that such posture exhibits the classic orthogonal distribution of temporal correlations. Head-turning resulted in a simultaneous decrease in this angle Δθ, which promptly reversed once gymnasts reoriented their heads forward. However, when vision was absent, there was only a discernible negative trend in Δθ, indicating a shift in the angle’s direction but not a statistically significant one. Thus, the narrowing of Δθ may signify an adaptive strategy in postural control. The swift recovery of Δθ upon returning to a forward-facing posture suggests that the temporary reduction is specific to head-turning and does not impose a lasting burden on postural control. Turning the head reduced the angle between these two orientations, facilitating the release of postural degrees of freedom towards a more uniform spread of the CoP across both dimensions of the support surface. The innovative aspect of this work is that it shows how fractality might serve as a control parameter of adaptive mechanisms of dexterous postural control.

Abstract Any reliable biomarker has to be specific, generalizable, and reproducible across individuals and contexts. The exact values of such a biomarker must represent similar health states in different individuals and at different times within the same individual to result in the minimum possible false-positive and false-negative rates. The application of standard cut-off points and risk scores across populations hinges upon the assumption of such generalizability. Such generalizability, in turn, hinges upon this condition that the phenomenon investigated by current statistical methods is ergodic, i.e., its statistical measures converge over individuals and time within the finite limit of observations. However, emerging evidence indicates that biological processes abound with nonergodicity, threatening this generalizability. Here, we present a solution for how to make generalizable inferences by deriving ergodic descriptions of nonergodic phenomena. For this aim, we proposed capturing the origin of ergodicity-breaking in many biological processes: cascade dynamics. To assess our hypotheses, we embraced the challenge of identifying reliable biomarkers for heart disease and stroke, which, despite being the leading cause of death worldwide and decades of research, lacks reliable biomarkers and risk stratification tools. We showed that raw R-R interval data and its common descriptors based on mean and variance are nonergodic and non-specific. On the other hand, the cascade-dynamical descriptors, the Hurst exponent encoding linear temporal correlations, and multifractal nonlinearity encoding nonlinear interactions across scales described the nonergodic heart rate variability more ergodically and were specific. This study inaugurates applying the critical concept of ergodicity in discovering and applying digital biomarkers of health and disease.

Evidence of multifractal structures has spread to a wider set of physiological time series supporting the intricate interplay of biological and psychological functioning. These dynamics manifest as random multiplicative cascades, embodying nonlinear relationships characterized by recurring division, branching, and aggregation processes implicating noise across successive generations. This investigation focuses on how well the diversity of multifractal properties can be specific to the type of cascade relationship between generation (i.e., multiplicative, additive, or a mixture) as well as to the type of noise (i.e., including additive white Gaussian noise, fractional Gaussian noise, and various amalgamations) among 15 distinct types of binomial cascade processes. Cross-correlation analysis of multifractal spectral features confirms that these features capture nuanced aspects of cascading processes with minimal redundancy. Principal component analysis using 13 distinct multifractal spectral features shows that different cascade processes can manifest multifractal evidence of nonlinearity for distinct reasons. This transparency of multifractal spectral features to underlying cascade dynamics becomes less amenable to machine-learning strategies. Fully connected neural networks struggled to classify the 15 distinct types of cascade processes based on the respective multifractal spectral features (45.5% accuracy) yet demonstrated improved accuracy when addressing single categories of cross-generation relationships, that is, additive (91.6%), multiplicative (75.4%), or additomultiplicative (70.6%). While traditional principal component analysis reveals distinct loadings attributed to individual noise processes, multiplicative relationships between generations effectively make the constituent noise processes less discernible to neural networks. Neural networks may lack sufficient hierarchical depth required to effectively distinguish among nonadditive cascading processes, recommending either elaborating multifractal geometry or using alternate architectures for machine-learning classification of cascades with multiplicative relationships.

Individuals with Parkinson’s disease exhibit tremors, rigidity, and bradykinesia, disrupting normal movement variability and resulting in postural instability. This comprehensive study aimed to investigate the link between the temporal structure of postural sway variability and Parkinsonism by analyzing multiple datasets from young and older adults, including individuals with Parkinson’s disease, across various task conditions. We used the Oriented Fractal Scaling Component Analysis (OFSCA), which identifies minimal and maximal long-range correlations within the center of pressure time series, allowing for detecting directional changes in postural sway variability. The objective was to uncover the primary directions along which individuals exerted control during the posture. The results, as anticipated, revealed that healthy adults predominantly exerted control along two orthogonal directions, closely aligned with the anteroposterior (AP) and mediolateral (ML) axes. In stark contrast, older adults and individuals with Parkinson’s disease exhibited control along suborthogonal directions that notably diverged from the AP and ML axes. While older adults and those with Parkinson’s disease demonstrated a similar reduction in the angle between these two control directions compared to healthy older adults, their reliance on this suborthogonal angle concerning endogenous fractal correlations exhibited significant differences from the healthy aging cohort. Importantly, individuals with Parkinson’s disease did not manifest the sensitivity to destabilizing task settings observed in their healthy counterparts, affirming the distinction between Parkinson’s disease and healthy aging.

Accounts of speech perception disagree on how listeners demonstrate perceptual constancy despite considerable variation in the speech signal due to speakers' coarticulation. According to the spectral contrast account, listeners' compensation for coarticulation (CfC) results from listeners perceiving the target-segment frequencies differently depending on the contrastive effects exerted by the preceding sound's frequencies. In this study, we reexamine a notable finding that listeners apparently demonstrate perceptual adjustments to coarticulation even when the identity of the speaker (i.e., the "source") changes midway between speech segments. We evaluated these apparent across-talker CfC effects on the rationale that such adjustments to coarticulation would likely be maladaptive for perceiving speech in multi-talker settings. In addition, we evaluated whether such cross-talker adaptations, if detected, were modulated by prior experience. We did so by manipulating the exposure phase of three groups of listeners by (a) merely exposing them to our stimuli (b) explicitly alerting them to talker change or (c) implicitly alerting them to this change. All groups then completed identical test blocks in which we assessed their CfC patterns in within- and across-talker conditions. Our results uniformly demonstrated that, while all three groups showed robust CfC shifts in the within-talker conditions, no such shifts were detected in the across-talker condition. Our results call into question a speaker-neutral explanation for CfC. Broadly, this demonstrates the need to carefully examine the perceptual demands placed on listeners in constrained experimental tasks and to evaluate whether the accounts that derive from such settings scale up to the demands of real-world listening.

IntroductionThe availability of quality primary health care (PHC) services in Nigeria is limited. The PHC system faces significant challenges and the improvement and expansion of PHC services is constrained by low government spending on health, especially on PHC. Out-of-pocket (OOP) expenditures dominate health spending in Nigeria and the reliance on OOP payments leads to financial burdens on the poorest and most vulnerable populations. To address these challenges, the Nigerian government has implemented several legislative and policy reforms, including the National Health Insurance Authority (NHIA) Act enacted in 2022 to make health insurance mandatory for all Nigerian citizens and residents. Our study aimed to determine the costs of providing PHC services at public health facilities in Kaduna and Kano, Nigeria. We compared the actual PHC service delivery costs to the normative costs of delivering the Minimum Service Package (MSP) in the two states.MethodsWe collected primary data from 50 health facilities (25 per state), including PHC facilities—health posts, health clinics, health centers—and general hospitals. Data on facility-level recurrent costs were collected retrospectively for 2019 to estimate economic costs from the provider’s perspective. Statewide actual costs were estimated by extrapolating the PHC cost estimates at sampled health facilities, while normative costs were derived using standard treatment protocols (STPs) and the populations requiring PHC services in each state.ResultsWe found that average actual PHC costs per capita at PHC facilities—where most PHC services should be provided according to government guidelines—ranged from US$ 18.9 to US$ 28 in Kaduna and US$ 15.9 to US$ 20.4 in Kano, depending on the estimation methods used. When also considering the costs of PHC services provided at general hospitals—where approximately a third of PHC services are delivered in both states—the actual per capita costs of PHC services ranged from US$ 20 to US$ 30.6 in Kaduna and US$ 17.8 to US$ 22 in Kano. All estimates of actual PHC costs per capita were markedly lower than the normative per capita costs of delivering quality PHC services to all those who need them, projected at US$ 44.9 in Kaduna and US$ 49.5 in Kano.DiscussionBridging this resource gap would require significant increases in expenditures on PHC in both states. These results can provide useful information for ongoing discussions on the implementation of the NHIA Act including the refinement of provider payment strategies to ensure that PHC providers are remunerated fairly and that they are incentivized to provide quality PHC services.

IntroductionThe Government of Ethiopia (GoE) has made significant progress in expanding access to primary health care (PHC) over the past 15 years. However, achieving national PHC targets for universal health coverage will require a significant increase in PHC financing. The purpose of this study was to generate cost evidence and provide recommendations to improve PHC efficiency.MethodsWe used the open access Primary Health Care Costing, Analysis, and Planning (PHC-CAP) Tool to estimate actual and normative recurrent PHC costs in nine Ethiopian regions. The findings on actual costs were based on primary data collected in 2018/19 from a sample of 20 health posts, 25 health centers, and eight primary hospitals. Three different extrapolation methods were used to estimate actual costs in the nine sampled regions. Normative costs were calculated based on standard treatment protocols (STPs), the population in need of the PHC services included in the Essential Health Services Package (EHSP) as per the targets outlined in the Health Sector Transformation Plan II (HSTP II), and the associated costs. PHC resource gaps were estimated by comparing actual cost estimates to normative costs.ResultsOn average, the total cost of PHC in the sampled facilities was US$ 11,532 (range: US$ 934–40,746) in health posts, US$ 254,340 (range: US$ 68,860–832,647) in health centers, and US$ 634,354 (range: US$ 505,208–970,720) in primary hospitals. The average actual PHC cost per capita in the nine sampled regions was US$ 4.7, US$ 15.0, or US$ 20.2 depending on the estimation method used. When compared to the normative cost of US$ 38.5 per capita, all these estimates of actual PHC expenditures were significantly lower, indicating a shortfall in the funding required to deliver an expanded package of high-quality services to a larger population in line with GoE targets.DiscussionThe study findings underscore the need for increased mobilization of PHC resources and identify opportunities to improve the efficiency of PHC services to meet the GoE’s PHC targets. The data from this study can be a critical input for ongoing PHC financing reforms undertaken by the GoE including transitioning woreda-level planning from input-based to program-based budgeting, revising community-based health insurance (CBHI) packages, reviewing exempted services, and implementing strategic purchasing approaches such as capitation and performance-based financing.

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.