Affinity for self antigen selects Treg cells with distinct functional properties.

The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper> T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities.

Ultrafast Optically Induced Perturbation of Oxygen Octahedral Rotations in Multiferroic BiFeO3 Thin Films.

The functional properties of complex oxides, including magnetism and ferroelectricity, are closely linked to subtle structural distortions. Ultrafast optical excitations provide the means to manipulate structural features and ultimately to affect the functional properties of complex oxides with picosecond-scale precision. We report that the lattice expansion of multiferroic BiFeO3 following above-bandgap optical excitation leads to distortion of the oxygen octahedral rotation (OOR) pattern. The continuous coupling between OOR and strain was probed using time-resolved X-ray free-electron laser diffraction with femtosecond time resolution. Density functional theory calculations predict a relationship between the OOR and the elastic strain consistent with the experiment, demonstrating a route to employing this approach in a wider range of systems. Ultrafast control of the functional properties of BiFeO3 thin films is enabled by this approach because the OOR phenomena are related to ferroelectricity, and via the Fe-O-Fe bond angles, the superexchange interaction between Fe atoms.

Discovery of new acetamide derivatives of 5-indole-1,3,4-oxadiazol-2-thiol as inhibitors of HIV-1 Tat-mediated viral transcription.

Human immunodeficiency virus-1 (HIV-1) encodes a transcriptional factor called Tat, which is critical for viral transcription. Tat-mediated transcription is highly ordered apart from the cellular manner; therefore, it is considered a target for developing anti-HIV-1 drugs. However, drugs targeting Tat-mediated viral transcription are not yet available. Our high-throughput screen of a compound library employing a dual-reporter assay identified a 1,3,4-oxadiazole scaffold against Tat and HIV-1 infection. Furthermore, a serial structure-activity relation (SAR) study performed with biological assays found 1,3,4-oxadiazole derivatives (9 and 13) containing indole and acetamide that exhibited potent inhibitory effects on HIV-1 infectivity, with half-maximal effective concentrations (EC50) of 0.17 (9) and 0.24 µM (13), respectively. The prominent derivatives specifically interfered with the viral transcriptional step without targeting other infection step(s) and efficiently inhibited the HIV-1 replication cycle in the T cell lines and peripheral blood mononuclear cells infected with HIV-1. Additionally, compared to the wild type, the compounds exhibited similar potency against anti-retroviral drug-resistant HIV-1 strains. In a series of mode-of-action studies, the compounds inhibited the ejection of histone H3 for facilitating viral transcription on the long-terminal repeat (LTR) promoter. Furthermore, SAHA (a histone deacetylase inhibitor) treatment abolished the compound potency, revealing that the compounds can possibly target Tat-regulated epigenetic modulation of LTR to inhibit viral transcription. Overall, our screening identified novel 1,3,4-oxadiazole compounds that inhibited HIV-1 Tat, and subsequent SAR-based optimization led to the derivatives 9 and 13 development that could be a promising scaffold for developing a new class of therapeutic agents for HIV-1 infection.

Metal-Organic Frameworks Marry Sponge: New Opportunities for Advanced Water Treatment.

Metal-organic frameworks (MOFs) have garnered attention across various fields due to their noteworthy features like high specific surface area, substantial porosity, and adjustable performance. In the realm of water treatment, MOFs exhibit great potential for eliminating pollutants such as organics, heavy metals, and oils. Nonetheless, the inherent powder characteristics of MOFs pose challenges in terms of recycling, pipeline blockage, and even secondary pollution in practical applications. Addressing these issues, the incorporation of MOFs into sponges proves to be an effective solution. Strategies like one-pot synthesis, in situ growth, and impregnation are commonly employed for loading MOFs onto sponges. This review comprehensively explores the synthesis strategies of MOFs and sponges, along with their applications in water treatment, aiming to contribute to the ongoing advancement of MOF materials.

Neuroanatomical and neurocognitive correlates of delusion in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Neuropsychiatric symptoms and delusions are highly prevalent among people with dementia. However, multiple roots of neurobiological bases and shared neural basis of delusion and cognitive function remain to be characterized. By utilizing a fine-grained multivariable approach, we investigated distinct neuroanatomical correlates of delusion symptoms across a large population of dementing illnesses. METHODS: In this study, 750 older adults with mild cognitive impairment and Alzheimer's disease completed brain structural imaging and neuropsychological assessment. We utilized principal component analysis followed by varimax rotation to identify the distinct multivariate correlates of cortical thinning patterns. Five of the cognitive domains were assessed whether the general cognitive abilities mediate the association between cortical thickness and delusion. RESULTS: The result showed that distributed thickness patterns of temporal and ventral insular cortex (component 2), inferior and lateral prefrontal cortex (component 1), and somatosensory-visual cortex (component 5) showed negative correlations with delusions. Subsequent mediation analysis showed that component 1 and 2, which comprises inferior frontal, anterior insula, and superior temporal regional thickness accounted for delusion largely through lower cognitive functions. Specifically, executive control function assessed with the Trail Making Test mediated the relationship between two cortical thickness patterns and delusions. DISCUSSION: Our findings suggest that multiple distinct subsets of brain regions underlie the delusions among older adults with cognitive impairment. Moreover, a neural loss may affect the occurrence of delusion in dementia largely due to impaired general cognitive abilities.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Exploring transfer effects on memory and its neural mechanisms through a computerized cognitive training in mild cognitive impairment: randomized controlled trial.

BACKGROUND: Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non-memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial. METHODS: Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning-based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non-cognitive scales, and resting-state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within- and between-group comparisons, group × time interactions, and seed-to-voxel analyses in memory-involving brain networks were performed. RESULTS: The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η2 = 0.31), which was related with the increased connectivity in the hippocampal-frontal and fusiform-occipital network. No other cognitive and non-cognitive symptoms differed between groups after adjusting for covariates. CONCLUSION: Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis.

Layer-Controlled Perovskite 2D Nanosheet Interlayer for the Energy Storage Performance of Nanocomposites.

Polymer-based nanocomposites are desirable materials for next-generation dielectric capacitors. 2D dielectric nanosheets have received significant attention as a filler. However, randomly spreading the 2D filler causes residual stresses and agglomerated defect sites in the polymer matrix, which leads to the growth of an electric tree, resulting in a more premature breakdown than expected. Therefore, realizing a well-aligned 2D nanosheet layer with a small amount is a key challenge; it can inhibit the growth of conduction paths without degrading the performance of the material. Here, an ultrathin Sr1.8 Bi0.2 Nb3 O10 (SBNO) nanosheet filler is added as a layer into poly(vinylidene fluoride) (PVDF) films via the Langmuir-Blodgett method. The structural properties, breakdown strength, and energy storage capacity of a PVDF and multilayer PVDF/SBNO/PVDF composites as a function of the thickness-controlled SBNO layer are examined. The seven-layered (only 14 nm) SBNO nanosheets thin film can sufficiently prevent the electrical path in the PVDF/SBNO/PVDF composite and shows a high energy density of 12.8 J cm-3 at 508 MV m-1 , which is significantly higher than that of the bare PVDF film (9.2 J cm-3 at 439 MV m-1 ). At present, this composite has the highest energy density among the polymer-based nanocomposites under the filler of thin thickness.

Novel SARS-CoV-2 entry inhibitors, 2-anilinoquinazolin-4(3H)-one derivatives, show potency as SARS-CoV-2 antivirals in a human ACE2 transgenic mouse model.

The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2-anilinoquinazolin-4(3H)-one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and MERS-CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS-CoV-2. Three candidate drugs, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (1), N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-dichlorophenyl)acetamide (2), and N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID-19. Overall, our data suggest that 2-anilinoquinazolin-4(3H)-one derivatives are promising as potential oral antiviral drug candidates against SARS-CoV-2 infection.

Quantitative ultrasound for non-invasive evaluation of subclinical rejection in renal transplantation.

OBJECTIVES: This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction. METHODS: From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups. RESULTS: Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p < 0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen. CONCLUSIONS: Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection. KEY POINTS: • Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection.

Discovery of 2-aminoquinolone acid derivatives as potent inhibitors of SARS-CoV-2.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to threaten human health and create socioeconomic problems worldwide. A library of 200,000 small molecules from the Korea Chemical Bank (KCB) were evaluated for their inhibitory activities against SARS-CoV-2 in a phenotypic-based screening assay to discover new therapeutics to combat COVID-19. A primary hit of this screen was the quinolone structure-containing compound 1. Based on the structure of compound 1 and enoxacin, which is a quinolone-based antibiotic previously reported to have weak activity against SARS-CoV-2, we designed and synthesized 2-aminoquinolone acid derivatives. Among them, compound 9b exhibited potent antiviral activity against SARS-CoV-2 (EC50 = 1.5 µM) without causing toxicity, while having satisfactory in vitro PK profiles. This study shows that 2-aminoquinolone acid 9b provides a promising new template for developing anti-SARS-CoV-2 entry inhibitors.

Survival Benefit of Kidney Transplantation in Patients With End-Stage Kidney Disease and Prior Acute Myocardial Infarction.

Patients with end stage kidney disease (ESKD) and a previous acute myocardial infarction (AMI) have less access to KT. Data on ESKD patients with an AMI history who underwent first KT or dialysis between January 2007 and December 2018 were extracted from the Korean National Health Insurance Service. Patients who underwent KT (n = 423) were chronologically matched in a 1:3 ratio with those maintained on dialysis (n = 1,269) at the corresponding dates, based on time-conditional propensity scores. The 1, 5, and 10 years cumulative incidences for all-cause mortality were 12.6%, 39.1%, and 60.1% in the dialysis group and 3.1%, 7.2%, and 14.5% in the KT group. Adjusted hazard ratios (HRs) of KT versus dialysis were 0.17 (95% confidence interval [CI], 0.12-0.24; p < 0.001) for mortality and 0.38 (95% CI, 0.23-0.51; p < 0.001) for major adverse cardiovascular events (MACE). Of the MACE components, KT was most protective against cardiovascular death (HR, 0.23; 95% CI, 0.12-0.42; p < 0.001). Protective effects of KT for all-cause mortality and MACE were consistent across various subgroups, including patients at higher risk (e.g., age >65 years, recent AMI [<6 months], congestive heart failure). KT is associated with lower all-cause mortality and MACE than maintenance dialysis patients with a prior AMI.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

Polypropylene nanoplastic exposure leads to lung inflammation through p38-mediated NF-κB pathway due to mitochondrial damage.

BACKGROUND: Polypropylene (PP) is used in various products such as disposable containers, spoons, and automobile parts. The disposable masks used for COVID-19 prevention mainly comprise PP, and the disposal of such masks is concerning because of the potential environmental pollution. Recent reports have suggested that weathered PP microparticles can be inhaled, however, the inhalation toxicology of PP microparticles is poorly understood. RESULTS: Inflammatory cell numbers, reactive oxygen species (ROS) production, and the levels of inflammatory cytokines and chemokines in PP-instilled mice (2.5 or 5 mg/kg) increased significantly compared to with those in the control. Histopathological analysis of the lung tissue of PP-stimulated mice revealed lung injuries, including the infiltration of inflammatory cells into the perivascular/parenchymal space, alveolar epithelial hyperplasia, and foamy macrophage aggregates. The in vitro study indicated that PP stimulation causes mitochondrial dysfunction including mitochondrial depolarization and decreased adenosine triphosphate (ATP) levels. PP stimulation led to cytotoxicity, ROS production, increase of inflammatory cytokines, and cell deaths in A549 cells. The results showed that PP stimulation increased the p-p38 and p-NF-κB protein levels both in vivo and in vitro, while p-ERK and p-JNK remained unchanged. Interestingly, the cytotoxicity that was induced by PP exposure was regulated by p38 and ROS inhibition in A549 cells. CONCLUSIONS: These results suggest that PP stimulation may contribute to inflammation pathogenesis via the p38 phosphorylation-mediated NF-κB pathway as a result of mitochondrial damage.

Dose-escalated radiotherapy for clinically localized and locally advanced prostate cancer.

BACKGROUND: Treatments for clinically localized prostate cancer include radical prostatectomy, external beam radiation therapy, brachytherapy, active surveillance, hormonal therapy, and watchful waiting. For external beam radiation therapy, oncological outcomes may be expected to improve as the dose of radiotherapy (RT) increases. However, radiation-mediated side effects on surrounding critical organs may also increase. OBJECTIVES: To assess the effects of dose-escalated RT in comparison with conventional dose RT for curative treatment of clinically localized and locally advanced prostate cancer. SEARCH METHODS: We performed a comprehensive search using multiple databases including trial registries and other sources of grey literature, up until 20 July 2022. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included parallel-arm randomized controlled trials (RCTs) of definitive RT in men with clinically localized and locally advanced prostate adenocarcinoma. RT was dose-escalated RT (equivalent dose in 2 Gy [EQD2] ≥ 74 Gy, lesser than 2.5 Gy per fraction) versus conventional RT (EQD2 < 74 Gy, 1.8 Gy or 2.0 Gy per fraction). Two review authors independently classified studies for inclusion or exclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of the evidence of RCTs. MAIN RESULTS: We included nine studies with 5437 men in an analysis comparing dose-escalated RT versus conventional dose RT for the treatment of prostate cancer. The mean participant age ranged from 67 to 71 years. Almost all men had localized prostate cancer (cT1-3N0M0). Primary outcomes Dose-escalated RT probably results in little to no difference in time to death from prostate cancer (hazard ratio [HR] 0.83, 95% CI 0.66 to 1.04; I2 = 0%; 8 studies; 5231 participants; moderate-certainty evidence). Assuming a risk of death from prostate cancer of 4 per 1000 at 10 years in the conventional dose RT group, this corresponds to 1 fewer men per 1000 (1 fewer to 0 more) dying of prostate cancer in the dose-escalated RT group. Dose-escalated RT probably results in little to no difference in severe RT toxicity of grade 3 or higher late gastrointestinal (GI) toxicity (RR 1.72, 95% CI 1.32 to 2.25; I2 = 0%; 8 studies; 4992 participants; moderate-certainty evidence); 23 more men per 1000 (10 more to 40 more) in the dose-escalated RT group assuming severe late GI toxicity as 32 per 1000 in the conventional dose RT group. Dose-escalated RT probably results in little to no difference in severe late genitourinary (GU) toxicity (RR 1.25, 95% CI 0.95 to 1.63; I2 = 0%; 8 studies; 4962 participants; moderate-certainty evidence); 9 more men per 1000 (2 fewer to 23 more) in the dose-escalated RT group assuming severe late GU toxicity as 37 per 1000 in the conventional dose RT group. Secondary outcomes Dose-escalated RT probably results in little to no difference in time to death from any cause (HR 0.98, 95% CI 0.89 to 1.09; I2 = 0%; 9 studies; 5437 participants; moderate-certainty evidence). Assuming a risk of death from any cause of 101 per 1000 at 10 years in the conventional dose RT group, this corresponds to 2 fewer men per 1000 (11 fewer to 9 more) in the dose-escalated RT group dying of any cause. Dose-escalated RT probably results in little to no difference in time to distant metastasis (HR 0.83, 95% CI 0.57 to 1.22; I2 = 45%; 7 studies; 3499 participants; moderate-certainty evidence). Assuming a risk of distant metastasis of 29 per 1000 in the conventional dose RT group at 10 years, this corresponds to 5 fewer men per 1000 (12 fewer to 6 more) in the dose-escalated RT group developing distant metastases. Dose-escalated RT may increase overall late GI toxicity (RR 1.27, 95% CI 1.04 to 1.55; I2 = 85%; 7 studies; 4328 participants; low-certainty evidence); 92 more men per 1000 (14 more to 188 more) in the dose-escalated RT group assuming overall late GI toxicity as 342 per 1000 in the conventional dose RT group. However, dose-escalated RT may result in little to no difference in overall late GU toxicity (RR 1.12, 95% CI 0.97 to 1.29; I2 = 51%; 7 studies; 4298 participants; low-certainty evidence); 34 more men per 1000 (9 fewer to 82 more) in the dose-escalated RT group assuming overall late GU toxicity as 283 per 1000 in the conventional dose RT group. Based on long-term follow-up (up to 36 months), dose-escalated RT may result or probably results in little to no difference in the quality of life using 36-Item Short Form Survey; physical health (MD -3.9, 95% CI -12.78 to 4.98; 1 study; 300 participants; moderate-certainty evidence) and mental health (MD -3.6, 95% CI -83.85 to 76.65; 1 study; 300 participants; low-certainty evidence), respectively. AUTHORS' CONCLUSIONS: Compared to conventional dose RT, dose-escalated RT probably results in little to no difference in time to death from prostate cancer, time to death from any cause, time to distant metastasis, and RT toxicities (except overall late GI toxicity). While dose-escalated RT may increase overall late GI toxicity, it may result, or probably results, in little to no difference in physical and mental quality of life, respectively.

Textural and Volumetric Changes of the Temporal Lobes in Semantic Variant Primary Progressive Aphasia and Alzheimer's Disease.

BACKGROUND: Texture analysis may capture subtle changes in the gray matter more sensitively than volumetric analysis. We aimed to investigate the patterns of neurodegeneration in semantic variant primary progressive aphasia (svPPA) and Alzheimer's disease (AD) by comparing the temporal gray matter texture and volume between cognitively normal controls and older adults with svPPA and AD. METHODS: We enrolled all participants from three university hospitals in Korea. We obtained T1-weighted magnetic resonance images and compared the gray matter texture and volume of regions of interest (ROIs) between the groups using analysis of variance with Bonferroni posthoc comparisons. We also developed models for classifying svPPA, AD and control groups using logistic regression analyses, and validated the models using receiver operator characteristics analysis. RESULTS: Compared to the AD group, the svPPA group showed lower volumes in five ROIs (bilateral temporal poles, and the left inferior, middle, and superior temporal cortices) and higher texture in these five ROIs and two additional ROIs (right inferior temporal and left entorhinal cortices). The performances of both texture- and volume-based models were good and comparable in classifying svPPA from normal cognition (mean area under the curve [AUC] = 0.914 for texture; mean AUC = 0.894 for volume). However, only the texture-based model achieved a good level of performance in classifying svPPA and AD (mean AUC = 0.775 for texture; mean AUC = 0.658 for volume). CONCLUSION: Texture may be a useful neuroimaging marker for early detection of svPPA in older adults and its differentiation from AD.

Circadian rest-activity rhythm and longitudinal brain changes underlying late-life cognitive decline.

AIM: The neurobiological substrates underlying the relationship of circadian rest-activity rhythm (RAR) alteration with accelerated late-life cognitive decline are not clearly understood. In the present study, the longitudinal relationship of objectively measured circadian RAR with in vivo Alzheimer disease (AD) pathologies and cerebrovascular injury was investigated in older adults without dementia. METHODS: The present study included 129 participants without dementia who participated in the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease) cohort. All participants underwent actigraphy at baseline and two consecutive [11 C] Pittsburgh compound-B positron emission tomography (PET), [18 F] fluorodeoxyglucose-PET, magnetic resonance imaging, and Mini-Mental State Examination (MMSE) at baseline and at a 2-year follow-up assessment. The associations of circadian RAR with annualized change in neuroimaging measures including global amyloid-beta retention, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensity volume were examined. RESULTS: Delayed acrophase at baseline was significantly associated with greater annualized decline of AD-CM over a 2-year period, but not with that of other neuroimaging measures. In contrast, other circadian RAR parameters at baseline had no association with annualized change of any neuroimaging measures. Annualized decline of AD-CM was also significantly positively associated with the annual change in MMSE scores. Furthermore, a mediation analysis showed that greater reduction in AD-CM mediated the effect of delayed acrophase at baseline on faster decline of MMSE score. CONCLUSION: The findings indicate that delayed acrophase in late life may cause or predict hypometabolism at AD-signature brain regions, which underlies cognitive decline in the near future.

Facial Expressions Track Depressive Symptoms in Old Age.

Facial expressions play a crucial role in the diagnosis of mental illnesses characterized by mood changes. The Facial Action Coding System (FACS) is a comprehensive framework that systematically categorizes and captures even subtle changes in facial appearance, enabling the examination of emotional expressions. In this study, we investigated the association between facial expressions and depressive symptoms in a sample of 59 older adults without cognitive impairment. Utilizing the FACS and the Korean version of the Beck Depression Inventory-II, we analyzed both "posed" and "spontaneous" facial expressions across six basic emotions: happiness, sadness, fear, anger, surprise, and disgust. Through principal component analysis, we summarized 17 action units across these emotion conditions. Subsequently, multiple regression analyses were performed to identify specific facial expression features that explain depressive symptoms. Our findings revealed several distinct features of posed and spontaneous facial expressions. Specifically, among older adults with higher depressive symptoms, a posed face exhibited a downward and inward pull at the corner of the mouth, indicative of sadness. In contrast, a spontaneous face displayed raised and narrowed inner brows, which was associated with more severe depressive symptoms in older adults. These findings suggest that facial expressions can provide valuable insights into assessing depressive symptoms in older adults.

Weight loss and risk of dementia in individuals with versus without obesity.

INTRODUCTION: Using nationwide cohort data, we aimed to elucidate whether baseline obesity altered the relationship between loss in body mass index (BMI) or waist circumference (WC) and risk of dementia. METHODS: Among 9689 participants whose BMIs and WCs were repeatedly measured over 1 year, 1:1 propensity score matching was conducted between participants with and without obesity (n = 2976 per group, mean age 70.9). For each group, we explored the association between loss in BMI, or WC, and incidence of dementia during an approximately 4-year follow-up period. RESULTS: BMI loss was associated with an increased risk of all-cause dementia and Alzheimer's disease in participants without obesity; however, this association was absent in participants with obesity. WC loss was associated with decreased Alzheimer's disease risk only in participants with obesity. DISCUSSION: Only unfavorable loss (loss from non-obese state) in BMI, not WC, can be a metabolic biomarker of prodromal dementia.

Subpicosecond Optical Stress Generation in Multiferroic BiFeO3.

Optical excitation leads to ultrafast stress generation in the prototypical multiferroic BiFeO3. The time scales of stress generation are set by the dynamics of the population of excited electronic states and the coupling of the electronic configuration to the structure. X-ray free-electron laser diffraction reveals high-wavevector subpicosecond-time scale stress generation following ultraviolet excitation of a BiFeO3 thin film. Stress generation includes a fast component with a 1/e rise time with an upper limit of 300 fs and longer-rise time components extending to 1.5 ps. The contributions of the fast and delayed components vary as a function of optical fluence, with a reduced a fast-component contribution at high fluence. The results provide insight into stress-generation mechanisms linked to the population of excited electrons and point to new directions in the application of nanoscale multiferroics and related ferroic complex oxides. The fast component of the stress indicates that structural parameters and properties of ferroelectric thin film materials can be optically modulated with 3 dB bandwidths of at least 0.5 THz.