Subtle Alterations Research Articles

Deep learning-based segmentation in MRI-(immuno)histological examination of myelin and axonal damage in normal-appearing white matter and white matter hyperintensities.

The major vascular cause of dementia is cerebral small vessel disease (SVD). Its diagnosis relies on imaging hallmarks, such as white matter hyperintensities (WMH). WMH present a heterogenous pathology, including myelin and axonal loss. Yet, these might be only the "tip of the iceberg." Imaging modalities imply that microstructural alterations underlie still normal-appearing white matter (NAWM), preceding the conversion to WMH. Unfortunately, direct pathological characterization of these microstructural alterations affecting myelinated axonal fibers in WMH, and especially NAWM, is still missing. Given that there are no treatments to significantly reduce WMH progression, it is important to extend our knowledge on pathological processes that might already be occurring within NAWM. Staining of myelin with Luxol Fast Blue, while valuable, fails to assess subtle alterations in white matter microstructure. Therefore, we aimed to quantify myelin surrounding axonal fibers and axonal- and microstructural damage in detail by combining (immuno)histochemistry with polarized light imaging (PLI). To study the extent (of early) microstructural damage from periventricular NAWM to the center of WMH, we refined current analysis techniques by using deep learning to define smaller segments of white matter, capturing increasing fluid-attenuated inversion recovery signal. Integration of (immuno)histochemistry and PLI with post-mortem imaging of the brains of individuals with hypertension and normotensive controls enables voxel-wise assessment of the pathology throughout periventricular WMH and NAWM. Myelin loss, axonal integrity, and white matter microstructural damage are not limited to WMH but already occur within NAWM. Notably, we found that axonal damage is higher in individuals with hypertension, particularly in NAWM. These findings highlight the added value of advanced segmentation techniques to visualize subtle changes occurring already in NAWM preceding WMH. By using quantitative MRI and advanced diffusion MRI, future studies may elucidate these very early mechanisms leading to neurodegeneration, which ultimately contribute to the conversion of NAWM to WMH.

Machine learning approaches to detect hepatocyte chromatin alterations from iron oxide nanoparticle exposure

This study focuses on developing machine learning models to detect subtle alterations in hepatocyte chromatin organization due to Iron (II, III) oxide nanoparticle exposure, hypothesizing that exposure will significantly alter chromatin texture. A total of 2000 hepatocyte nuclear regions of interest (ROIs) from mouse liver tissue were analyzed, and for each ROI, 5 different parameters were calculated: Long Run Emphasis, Short Run Emphasis, Run Length Nonuniformity, and 2 wavelet coefficient energies obtained after the discrete wavelet transform. These parameters served as input for supervised machine learning models, specifically random forest and gradient boosting classifiers. The models demonstrated relatively robust performance in distinguishing hepatocyte chromatin structures belonging to the group exposed to IONPs from the controls. The study's findings suggest that iron oxide nanoparticles induce substantial changes in hepatocyte chromatin distribution and underscore the potential of AI techniques in advancing hepatocyte evaluation in physiological and pathological conditions.

Automated Speech Analysis in Bipolar Disorder: The CALIBER Study Protocol and Preliminary Results.

Background: Bipolar disorder (BD) involves significant mood and energy shifts reflected in speech patterns. Detecting these patterns is crucial for diagnosis and monitoring, currently assessed subjectively. Advances in natural language processing offer opportunities to objectively analyze them. Aims: To (i) correlate speech features with manic-depressive symptom severity in BD, (ii) develop predictive models for diagnostic and treatment outcomes, and (iii) determine the most relevant speech features and tasks for these analyses. Methods: This naturalistic, observational study involved longitudinal audio recordings of BD patients at euthymia, during acute manic/depressive phases, and after-response. Patients participated in clinical evaluations, cognitive tasks, standard text readings, and storytelling. After automatic diarization and transcription, speech features, including acoustics, content, formal aspects, and emotionality, will be extracted. Statistical analyses will (i) correlate speech features with clinical scales, (ii) use lasso logistic regression to develop predictive models, and (iii) identify relevant speech features. Results: Audio recordings from 76 patients (24 manic, 21 depressed, 31 euthymic) were collected. The mean age was 46.0 ± 14.4 years, with 63.2% female. The mean YMRS score for manic patients was 22.9 ± 7.1, reducing to 5.3 ± 5.3 post-response. Depressed patients had a mean HDRS-17 score of 17.1 ± 4.4, decreasing to 3.3 ± 2.8 post-response. Euthymic patients had mean YMRS and HDRS-17 scores of 0.97 ± 1.4 and 3.9 ± 2.9, respectively. Following data pre-processing, including noise reduction and feature extraction, comprehensive statistical analyses will be conducted to explore correlations and develop predictive models. Conclusions: Automated speech analysis in BD could provide objective markers for psychopathological alterations, improving diagnosis, monitoring, and response prediction. This technology could identify subtle alterations, signaling early signs of relapse. Establishing standardized protocols is crucial for creating a global speech cohort, fostering collaboration, and advancing BD understanding.

Chronic anthropogenic disturbance causes prolific resprouting and dwarfing – A case study of a widely distributed subtropical tree

Chronic anthropogenic disturbance (CAD) comprises the additive effect of multiple anthropogenic stressors that lead to subtle but continuous alterations to the structure, composition and functioning of natural ecosystems. However, this effect has been little studied at the tree species level. Here, we examined CAD effects on Chinese beech (Fagus engleriana), a common species in northern subtropical forests that utilizes both vegetative resprouting and seeding as regenerative modes. We computed an index of CAD for each plot based on livestock grazing intensity, wood extraction and miscellaneous resource use. Over 60 20 × 20 m plots, we measured the height and DBH of a total of 1261 Chinese beech individuals (21.02 ± 13.06 per plot, [mean ± SD]), including 593 adults (9.88 ± 4.89), 576 saplings (9.60 ± 8.91) and 92 seedlings (1.53 ± 3.91), and assessed the proportions of each that exhibited resprouting (0.91 ± 0.11, 0.69 ± 0.29, and 0.09 ± 0.25, respectively). CAD was associated with a greater number of individual trees and a proliferation of stems, and with a greater proportion of resprouting seedlings, but had no effect on adult-sized stem DBH. Chinese beech thus appears generally tolerant of CAD, which may ultimately result in its increasing contribution to the maintenance of forest biomass. CAD was also associated with shorter adult and sapling stems, but taller resprouting seedling stems, implying that CAD induced dwarfism as Chinese beech matures. Further analysis showed that the proportion of resprouting was related to small scale wood extraction and miscellaneous resource use, but not to grazing. In the context of better understanding cryptic effects of CAD, our findings show that CAD can alter tree morphology and regenerative processes. These coppicing-type effects of CAD on tree morphology structure are typically associated with higher community biodiversity in managed forest coppice, and future work should investigate the biodiversity consequences of CAD at our study site. Our study shows that CAD has important implications for forest resource utilization, planning, and management, with effects on forest biomass and carbon storage in human-modified landscapes.

Efficient Phosphate Adsorption from Groundwater by Mn-FeOOHs

Manganese co-precipitated with goethite (Mn-FeOOH) is ubiquitous within (sub-)surface environments, which are considered one of the most important sinks for phosphorus pollution management. Accordingly, various mole ratios of Mn-FeOOHs are synthesized and characterized by XRD, FE-SEM, FTIR, BET, XPS, hysteresis loop, acid–base titration and zero potential. According to XRD and FESEM images, the substitution of Mn causes subtle alterations in the microstructure and crystal structure of goethite, and the morphology of Mn-FeOOHs is transformed from needle-shaped goethite to a short-rod-shaped rough surface with increasing Mn substitution. Based on the analysis of BET and acid–base titration, the substitution of Mn into goethite significantly improved the surface area, pore volume, surface properties and active sites of goethite, thereby establishing a theoretical basis for effective subsequent adsorption. Batch experiment results show that the removal rate of phosphate decreases with the increasing solution pH, indicating that acidic groundwater conditions are more conducive to the removal of phosphate. In addition, the adsorption of phosphate on Mn-FeOOHs is independent of ionic strength, indicating that the inner-sphere surface complexation predominated their adsorption behaviors. The isotherm experiment results showed that Mn-G15 exhibits the strongest adsorption capacity for phosphate at pH 5.5 and T = 318 K, with a maximum adsorption capacity of 87.18 mg/g. These findings highlighted the effect of Mn content on the fixation of phosphate onto Mn-FeOOHs from (sub-)surface environments in pollution management.

Measuring interfacial thermal resistance across carbon nanotubes with in-situ electron microscopy: Unexpected reduction upon detachment and two orders of magnitude variations across diverse morphologies

The dynamic mechanical processes can notably impact the van der Waals (vdW) interaction at nanoscale contact interface and further interfacial thermal transport, but the experimental study is challenging. Here, by integrating a movable nanoprobe within an electron microscope, we dynamically adjusted the contact and detachment processes of vdW contact between two carbon nanotubes (CNTs), while measuring the thermal contact resistance (TCR) in situ with a nanofabricated thermal sensor. The TCR was found to span approximately two orders of magnitude at the moments when two CNTs just came into contact or detached. Surprisingly, during the initial stage of detachment, we observed that TCR unexpectedly further decreased by 65% instead of increasing. This decrease is attributed to the subtle alteration of exact contact interface in the circumferential direction, induced by the real-time observed rotation during the detachment process. A two-order magnitude difference in TCR for the diverse morphologies in static equilibrium between the same pair of CNTs due to the non-uniformity of the CNT surface structures can also support it. Our work provides valuable insights for dynamically modulating nanoscale interfacial thermal transport in various applications.

Cortical structure and subcortical volumes in conduct disorder: a coordinated analysis of 15 international cohorts from the ENIGMA-Antisocial Behavior Working Group

Conduct disorder is associated with the highest burden of any mental disorder in childhood, yet its neurobiology remains unclear. Inconsistent findings limit our understanding of the role of brain structure alterations in conduct disorder. This study aims to identify the most robust and replicable brain structural correlates of conduct disorder. The ENIGMA-Antisocial Behavior Working Group performed a coordinated analysis of structural MRI data from 15 international cohorts. Eligibility criteria were a mean sample age of 18 years or less, with data available on sex, age, and diagnosis of conduct disorder, and at least ten participants with conduct disorder and ten typically developing participants. 3D T1-weighted MRI brain scans of all participants were pre-processed using ENIGMA-standardised protocols. We assessed group differences in cortical thickness, surface area, and subcortical volumes using general linear models, adjusting for age, sex, and total intracranial volume. Group-by-sex and group-by-age interactions, and DSM-subtype comparisons (childhood-onset vs adolescent-onset, and low vs high levels of callous-unemotional traits) were investigated. People with lived experience of conduct disorder were not involved in this study. We collated individual participant data from 1185 young people with conduct disorder (339 [28·6%] female and 846 [71·4%] male) and 1253 typically developing young people (446 [35·6%] female and 807 [64·4%] male), with a mean age of 13·5 years (SD 3·0; range 7-21). Information on race and ethnicity was not available. Relative to typically developing young people, the conduct disorder group had lower surface area in 26 cortical regions and lower total surface area (Cohen's d 0·09-0·26). Cortical thickness differed in the caudal anterior cingulate cortex (d 0·16) and the banks of the superior temporal sulcus (d -0·13). The conduct disorder group also had smaller amygdala (d 0·13), nucleus accumbens (d 0·11), thalamus (d 0·14), and hippocampus (d 0·12) volumes. Most differences remained significant after adjusting for ADHD comorbidity or intelligence quotient. No group-by-sex or group-by-age interactions were detected. Few differences were found between DSM-defined conduct disorder subtypes. However, individuals with high callous-unemotional traits showed more widespread differences compared with controls than those with low callous-unemotional traits. Our findings provide robust evidence of subtle yet widespread brain structural alterations in conduct disorder across subtypes and sexes, mostly in surface area. These findings provide further evidence that brain alterations might contribute to conduct disorder. Greater consideration of this under-recognised disorder is needed in research and clinical practice. Academy of Medical Sciences and Economic and Social Research Council.

Identify Potential Causal Relationships Between Cortical Thickness, Mismatch Negativity, Neurocognition, and Psychosocial Functioning in Drug-Naïve First-Episode Psychosis Patients.

Cortical thickness (CT) alterations, mismatch negativity (MMN) reductions, and cognitive deficits are robust findings in first-episode psychosis (FEP). However, most studies focused on medicated patients, leaving gaps in our understanding of the interrelationships between CT, MMN, neurocognition, and psychosocial functioning in unmedicated FEP. This study aimed to employ multiple mediation analysis to investigate potential pathways among these variables in unmedicated drug-naïve FEP. We enrolled 28 drug-naïve FEP and 34 age and sex-matched healthy controls. Clinical symptoms, neurocognition, psychosocial functioning, auditory duration MMN, and T1 structural magnetic resonance imaging data were collected. We measured CT in the superior temporal gyrus (STG), a primary MMN-generating region. We found a significant negative correlation between MMN amplitude and bilateral CT of STG (CT_STG) in FEP (left: r = -.709, P < .001; right: r = -.612, P = .008). Multiple mediation models revealed that a thinner left STG cortex affected functioning through both direct (24.66%) and indirect effects (75.34%). In contrast, the effects of the right CT_STG on functioning were mainly mediated through MMN and neurocognitive pathways. Bilateral CT_STG showed significant association with MMN, and MMN plays a mediating role between CT and cognition. Both MMN alone and its interaction with cognition mediated the effects of structural alterations on psychosocial function. The decline in overall function in FEP may stem from decreased CT_STG, leading to subsequent MMN deficits and neurocognitive dysfunction. These findings underline the crucial role of MMN in elucidating how subtle structural alterations can impact neurocognition and psychosocial function in FEP.

Thermoluminescence and ATR-FTIR study of UVC-irradiated low-density polyethylene (LDPE) food packaging

This research aims to study the effects of ultraviolet C (UVC) radiation on low-density polyethylene (LDPE) food packaging. Main objectives include evaluating LDPE degradation and detecting UVC radiation using thermoluminescent dosimeters (TLDs) placed under LDPE samples. Results confirm accurate UVC detection after one hour of exposure, providing a useful tool for optimize food treatment procedures.ATR-FTIR spectroscopy analysis revealed subtle alterations (<8 % transmittance relative) in UVC-irradiated LDPE samples, including possible CH breakage (2910 and 2848 cm−1) and potential CC bond vibrations (1470 cm−1), among others. However, observed variations may stem from LDPE properties rather than entirely from UVC radiation. A comparative study of UVC-induced thermoluminescence (TL) emissions provided insights into various TLDs materials. TL kinetic analysis, using computerised glow curve deconvolution (CGCD) method, unveiled trap charge activation due to UVC exposure, including partial ionization, bleaching effect and photo-transfer (PTTL) processes. LDPE samples amplified UVC-TL responses, revealing intensity differences between the TLDs attributed to the PTTL process, accentuated by the lack of an annealing treatment. Additionally, chemical composition of the TL detectors such as, type, concentration, number, oxidation states and ionic radii of their dopants may influence UVC-TL response. Consequently, TL intensity ratios follow as: GR-200 (LiF: Mg, Cu, P) > TLD-100 (LiF: Ti, Mg) > TLD-400 (CaF2: Mn) > TLD-200 (CaF2: Dy). Thus, GR-200 detects ionizing radiation but cannot distinguish between ionizing and non-ionizing UVC radiation, while TLD-100 has limited effectiveness as a UVC radiation detector. In contrast, TLD-400 is suitable for detecting UVC radiation and TLD-200 emerges as the most favorable UVC detector, showing consistent response levels and minimal PTTL effect placed under the LDPE samples without the need of a thermal annealing treatment that makes the TLD-200 to be reusable in a low-cost measurement protocol.

Gait Analysis with Wearable Sensors in Isolated REM Sleep Behavior Disorder Associated with Phenoconversion: An Explorative Study.

Gait disturbance is a vital characteristic of motor manifestation in α- synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α- synucleinopathies (adjusted HR 4.468, 95% CI 1.088- 18.349, p = 0.038). Stride length asymmetry is associated with progression to α- synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD.

The Dimensionality of Hydrogen Bond Networks Induces Diverse Physical Properties of Peptide Crystals.

Short peptides are attractive building blocks for the fabrication of self-assembled materials with significant biological, chemical, and physical properties. The microscopic and macroscopic properties of assemblies are usually closely related to the dimensionality of formed hydrogen bond networks. Here, two completely different supramolecular architectures connected by distinct hydrogen bond networks were obtained by simply adding a hydroxyl group to switch from cyclo-tryptophan-alanine (cyclo-WA) to cyclo-tryptophan-serine (cyclo-WS). While hydroxyl-bearing cyclo-WS molecules provided an additional hydrogen bond donor that links to adjacent molecules, forming a rigid three-dimensional network, cyclo-WA arranged into a water-mediated zipper-like structure with a softer two-dimensional layer template. This subtle alteration resulted in a 14-fold enhancement of Young's modulus values in cyclo-WS compared to cyclo-WA. Both cyclo-dipeptides exhibit biocompatibility, high fluorescence, and piezoelectricity. The demonstrated role of dimensionality of hydrogen bond networks opens new avenues for rational design of materials with precise morphologies and customizable properties for bioelectronic applications.

Dynamic evaluation of corneal cross-linking and osmotic diffusion effects using optical coherence elastography

Dynamic deformation events induced by osmosis or photochemical stiffening substantially influence geometrical and mechanical assessments in post-mortem corneas, therefore need to be carefully monitored in experimental settings. In this study, we employed optical coherence elastography (OCE) to quantify dynamic deformation processes at high resolution in freshly enucleated porcine corneas. Osmotic effects were studied by immerging n = 9 eyes in preservation media of three different tonicities. Dynamic processes underlying corneal cross-linking (CXL) were studied by subjecting n = 6 eyes to standard Dresden treatment, while three control groups were used. The entire procedures were performed under an OCE setup during up to 80 min, acquiring a volumetric scan every 20 s. Changes in OCE-derived axial deformations were incrementally calculated between consecutive scans. Preservation conditions had a strong influence on the observed strain patterns, which were consistent with the tonicity of the medium (swelling in hypotonic, deswelling in hypertonic environment). In the CXL group, we observed deswelling of the anterior stroma 10 min after starting the UV irradiation, which was not observed in any control group (p = 0.007). The presented results proved OCE to be a valuable technique to quantify subtle dynamic biomechanical alterations in the cornea resulting from CXL and preservation solutions.

Matrix metalloprotease-7 is associated with post-COVID-19 persistent lung abnormalities.

This study indicates that increased MMP-7 in patients with post-COVID-19 is associated with lung abnormalities in gas exchange and subtle structural alterations in HRCT suggestive of fibrosis. https://bit.ly/4etsvk5.

Characteristics of the Structural Connectivity in Patients with Brain Injury and Chronic Health Symptoms: A Pilot Study.

Diffusion properties from diffusion tensor imaging (DTI) are exquisitely sensitive to white matter abnormalities incurred during traumatic brain injury (TBI), especially for those patients with chronic post-TBI symptoms such as headaches, dizziness, fatigue, etc. The evaluation of structural and functional connectivity using DTI has become a promising method for identifying subtle alterations in brain connectivity associated with TBI that are otherwise not visible with conventional imaging. This study assessed whether TBI patients with (n = 17) or without (n = 16) chronic symptoms (TBIcs/TBIncs) exhibit any changes in structural connectivity (SC) and mean fractional anisotropy (mFA) of intra- and inter-hemispheric connections when compared to a control group (CG) (n = 13). Reductions in SC and mFA were observed for TBIcs compared to CG, but not for TBIncs. More connections were found to have mFA reductions than SC reductions. On the whole, SC is dominated by ipsilateral connections for all the groups after the comparison of contralateral and ipsilateral connections. More contra-ipsi reductions of mFA were found for TBIcs than TBIncs compared to CG. These findings suggest that TBI patients with chronic symptoms not only demonstrate decreased global and regional mFA but also reduced structural network connectivity.

Effects of increased nitrate intake from beetroot juice on blood markers of oxidative stress and inflammation in older adults with hypertension

BackgroundVascular oxidative stress and low-grade inflammation are important in the pathology of cardiovascular disorders, including hypertension. Cell culture and animal studies suggest that inorganic dietary nitrate may attenuate oxidative stress and inflammation through nitric oxide (NO), and there is a need to investigate whether this translates to humans. AimIn this randomised, placebo-controlled crossover study, by measuring a combination of multiple blood biomarkers, we evaluated whether previously reported benefits of dietary nitrate translate to a reduced oxidative stress and an improved inflammation status in 15 men and women (age range: 56–71 years) with treated hypertension. MethodsWe investigated the effects of a single ∼400 mg-dose of nitrate at 3 h post-ingestion (3H POST) and the daily consumption of 2 × ∼400 mg of nitrate over 4 weeks (4WK POST), through nitrate-rich versus nitrate-depleted (placebo) beetroot juice. Measurements included plasma nitrate and nitrite (NOx), oxidised low-density lipoprotein (oxLDL), F2-isoprostanes, protein carbonyls, oxidised (GSSG) and reduced glutathione (GSH); and serum high-sensitive C-reactive protein (hsCRP), chemokines, cytokines, and adhesion molecules. Flow cytometry was used to assess the relative proportion of blood monocyte subsets. ResultsAt 4WK POST nitrate intervention, the oxLDL/NOx ratio decreased (mainly due to increases in plasma nitrate and nitrite) and the GSH/GSSG ratio (a sensitive biomarker for alterations in the redox status) increased, compared with placebo (for both ratios P < 0.01). The relative proportion of classical (CD14+CD16−) monocytes decreased at 4WK POST for placebo compared to nitrate intervention (P < 0.05). Other oxidative stress and inflammatory markers were not altered by increased nitrate intake relative to placebo. ConclusionsThe data from this study point toward a subtle alteration in the redox balance toward a less pro-oxidative profile by a regular intake of inorganic nitrate from plant foods. Clinical trial registry numberNCT04584372 (ClinicialTrials.gov).

Association Between Subclinical Thyroid Dysfunction and Cognitive Decline: Findings From the ELSA-Brasil Study.

Thyroid dysfunction has been associated with cognitive decline and dementia. However, the role of subtle thyroid hormone alterations in cognitive function is still debatable. Participants without overt thyroid dysfunction aged 35-74 years at baseline were evaluated in 3 study waves (2008-2010, 2012-2014, and 2017-2019). We assessed baseline thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Cognitive performance was evaluated every 4 years in each wave using 10-word immediate and late recall, word recognition, semantic (animals category) and phonemic (letter f) verbal fluency, and the trail-making B-version tests. A global composite z-score was derived from these tests. The associations of TSH, FT4, and FT3 levels with cognitive decline over time were evaluated using linear mixed-effect models adjusted for sociodemographic, clinical, and lifestyle variables. In 9524 participants (mean age 51.2 ± 8.9 years old, 51% women, 52% White), there was no association between baseline TSH, FT4, and FT3 levels and cognitive decline during the follow-up. However, increase in FT4 levels over time was associated with faster memory (β = -0.004, 95% CI = -0.007; -0.001, p = .014), verbal fluency (β = -0.003, 95% CI = -0.007; -0.0005, p = .021), executive function (β = -0.004, 95% CI = -0.011; -0.003, p < .001), and global cognition decline (β = -0.003, 95% CI = -0.006; -0.001, p = .001). Decrease in FT4 levels over time was associated with faster verbal fluency (β = -0.003, 95% CI = -0.007; -0.0004, p = .025) and executive function (β = -0.004, 95% CI = -0.007; -0.0003, p = .031) decline. An increase or decrease in FT4 levels over time was associated with faster cognitive decline in middle-aged and older adults without overt thyroid dysfunction during 8 years of follow-up.

Evaluating the Long-Term Effects of Orthodontic Treatment on Facial Esthetics and Aging.

Orthodontic treatment is known to significantly impact facial esthetics, but there is a lack of long-term studies examining its effects, particularly in conjunction with the natural aging process. This study aims to fill this gap by investigating the enduring effects of orthodontic treatment on facial esthetics and aging over a 15-year period. Three hundred orthodontic patients aged 12 to 25 at the start of treatment were included. Dental alignment, soft tissue transformations, skeletal changes, and patient-reported outcomes were measured objectively. Statistical analyses were conducted to compare pretreatment and post-treatment measurements. Significant improvements were observed across various aspects following orthodontic treatment. Dental alignment showed a marked reduction in crowding, with an average decrease of 5.2 mm. Soft tissue transformations revealed notable advancements in lip positioning, averaging 3.8 mm, along with increased lip thickness. Skeletal changes were relatively modest, characterized by subtle alterations in chin positioning and mandibular angles. Patients reported high levels of satisfaction, reflected by an average score of 9.2 on the satisfaction scale. Despite treatment efficacy, the aging process continued to manifest natural changes in skin elasticity and fat distribution over the 15-year follow-up period. These findings underscore the multifaceted nature of orthodontic outcomes and highlight the importance of considering long-term effects on facial esthetics and aging. This longitudinal study provides valuable insights into the long-term effects of orthodontic treatment on facial esthetics and aging. It highlights significant improvements in dental alignment and soft tissue transformations, along with sustained patient satisfaction. However, modest skeletal changes and the ongoing aging process emphasize the need for managing patient expectations. These findings can guide practitioners and patients in making informed decisions regarding orthodontic interventions.

A Metric to Characterize Differentially Methylated Region Sets Detected from Methylation Array Data

Background: Identifying differentially methylated region (DMR) is a basic but important task in epigenomics, which can help investigate the mechanisms of diseases and provide methylation biomarkers for screening diseases. A set of methods have been proposed to identify DMRs from methylation array data. However, it lacks effective metrics to characterize different DMR sets and enable a straight way for comparison. Methods: In this study, we introduce a metric, DMRn, to characterize DMR sets detected by different methods from methylation array data. To calculate DMRn, firstly, the methylation differences of DMRs are recalculated by incorporating the correlations between probes and their represented CpGs. Then, DMRn is calculated based on the number of probes and the dense of CpGs in DMRs with methylation differences falling in each interval. Result &amp; Discussion: By comparing the DMRn of DMR sets predicted by seven methods on four scenario, the results demonstrate that DMRn can make an efficient guidance for selecting DMR sets, and provide new insights in cancer genomics studies by comparing the DMR sets from the related pathological states. For example, there are many regions with subtle methylation alteration in subtypes of prostate cancer are altered oppositely in the benign state, which may indicate a possible revision mechanism in benign prostate cancer. Conclusion: Futhermore, when applied to datasets that underwent different runs of batch effect removal, the DMRn can help to visualize the bias introduced by multi-runs of batch effect removal. The tool for calculating DMRn is available in the GitHub repository(https://github.com/xqpeng/DMRArrayMetric).

Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice.

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness.

Stereochemical inversion at a 1,4-cyclohexyl PROTAC linker fine-tunes conformation and binding affinity

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small-molecule degraders made of a linker connecting a target-binding moiety to a ubiquitin E3 ligase-binding moiety. The linker unit is known to influence the physicochemical and pharmacokinetic properties of PROTACs, as well as the properties of ternary complexes, in turn impacting on their degradation activity in cells and in vivo. Our LRRK2 PROTAC XL01126, bearing a trans-cyclohexyl group in the linker, is a better and more cooperative degrader than its corresponding cis- analogue despite its much weaker binary binding affinities. Here, we investigate how this subtle stereocenter alteration in the linker affects the ligand binding affinity to the E3 ligase VHL. We designed a series of molecular matched pairs, truncating from the full PROTACs down to the VHL ligand, and find that across the series the trans-cyclohexyl compounds showed consistently weaker VHL-binding affinity compared to the cis- counterparts. High-resolution co-crystal structures revealed that the trans linker exhibits a rigid stick-out conformation, while the cis linker collapses into a folded-back conformation featuring a network of intramolecular contacts and long-range interactions with VHL. These observations are noteworthy as they reveal how a single stereochemical inversion within a PROTAC linker impacts conformational rigidity and binding mode, in turn fine-tuning differentiated propensity to binary and ternary complex formation, and ultimately cellular degradation activity.