Cerebellar gray matter and white matter damage among older adults with prediabetes.

AIMS: To investigate alterations in cerebrum and cerebellum in prediabetes. Cerebellar injury in diabetes is traceable, but it has not been systematically studied, and whether cerebellar injury occurs and the degree of damage in prediabetes are not known. METHODS: The current study investigated cerebral and cerebellar gray matter volume, white matter volume, white matter microstructure, and white matter hyperintensity on T1-weighted, T2-weighted fluid-attenuated inversion recovery and diffusion tensor imaging scans in 78 individuals with normal glucose metabolism, 92 with prediabetes, and 108 with type 2 diabetes. RESULTS: Participants with prediabetes showed significant gray matter and white matter atrophy, microstructural damage in the cerebellar and cerebral regions. Additionally, widespread structural alterations were observed in the diabetic stage. The function of the damaged brain area was further decoded in Neurosynth, and the damaged cerebellar area with prediabetic lesions was closely related to motor function, while the area affected by diabetes was related to complex cognitive function in addition to motor function. CONCLUSIONS: Cerebellar injury had already appeared in the prediabetic stage, and cerebellar injury was aggravated in the diabetic stage; therefore, the cerebellum is a key area that is damaged early in the development of diabetes.

Age-related enhancement of the association between episodic memory and gray matter volume in medial temporal and frontal lobes.

BACKGROUND: Episodic memory (EM) deteriorates as a result of normal aging as well as Alzheimer's disease. The neural underpinnings of such age-related memory impairments in older individuals are not well-understood. Although previous research has unveiled the association between gray matter volume (GMV) and EM in the elderly population, such findings exhibit variances across distinct age cohorts. Consequently, an investigation into the dynamic evolution of this relationship with advancing age is imperative. RESULT: The present study utilized a sliding window approach to examine how the correlation between EM and GMV varied with age in a cross-sectional sample of 926 Chinese older adults. We found that both verbal EM (VEM) and spatial EM (SEM) exhibited positive correlations with GMV in extensive areas primarily in the temporal and frontal lobes and that these correlations typically became stronger with older age. Moreover, there were variations in the strength of the correlation between EM and GMV with age, which differed based on sex and the specific type of EM. Specifically, the association between VEM and GMVs in the insula and parietal regions became stronger with age for females but not for males, whereas the association between SEM and GMVs in the parietal and occipital regions became stronger for males but not for females. At the brain system level, there is a significant age-related increase in the correlations between both types of EM and the GMV of both the anterior temporal (AT) system and the posterior medial (PM) system in male group. In females, both types of EM show stronger age-related correlations with the GMV of the AT system compared to males. CONCLUSIONS: Our study revealed a significant positive correlation between GMV in most regions associated with EM and age, particularly in the frontal and temporal lobes. This discovery offers new insights into the connection between brain structure and the diminishing episodic memory function among older individuals.

Vascular Risk Factors and Brain Health in Aging: Insights from a Community-Based Cohort Study.

Background: The aging population and high rates of Alzheimer's disease (AD) create significant medical burdens, prompting a need for early prevention. Targeting modifiable risk factors like vascular risk factors (VRFs), closely linked to AD, may provide a promising strategy for intervention. Objective: This study investigates how VRFs influence cognitive performance and brain structures in a community-based cohort. Methods: In this cross-sectional study, 4,667 participants over 50 years old, drawn from the Beijing Ageing Brain Rejuvenation Initiative project, were meticulously examined. Cognitive function and VRFs (diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking), were comprehensively assessed through one-to-one interviews. Additionally, a subset of participants (n = 719) underwent MRI, encompassing T1-weighted and diffusion-weighted scans, to elucidate gray matter volume and white matter structural network organization. Results: The findings unveil diabetes as a potent detriment to memory, manifesting in atrophy within the right supramarginal gyrus and diminished nodal efficiency and degree centrality in the right inferior parietal lobe. Hypertension solely impaired memory without significant structural changes. Intriguingly, individuals with comorbid diabetes and hypertension exhibited the most pronounced deficits in both brain structure and cognitive performance. Remarkably, hyperlipidemia emerged as a factor associated with enhanced cognition, and preservation of brain structure. Conclusions: This study illuminates the intricate associations between VRFs and the varied patterns of cognitive and brain structural damage. Notably, the synergistic effect of diabetes and hypertension emerges as particularly deleterious. These findings underscore the imperative to tailor interventions for patients with distinct VRF comorbidities, especially when addressing cognitive decline and structural brain changes.

Cortical thickness reveals sex differences in verbal and visuospatial memory.

Although previous studies have reported the sex differences in behavior/cognition and the brain, the sex difference in the relationship between memory abilities and the underlying neural basis in the aging process remains unclear. In this study, we used a machine learning model to estimate the association between cortical thickness and verbal/visuospatial memory in females and males and then explored the sex difference of these associations based on a community-elderly cohort (n = 1153, age ranged from 50.42 to 86.67 years). We validated that females outperformed males in verbal memory, while males outperformed females in visuospatial memory. The key regions related to verbal memory in females include the medial temporal cortex, orbitofrontal cortex, and some regions around the insula. Further, those regions are more located in limbic, dorsal attention, and default-model networks, and are associated with face recognition and perception. The key regions related to visuospatial memory include the lateral prefrontal cortex, anterior cingulate gyrus, and some occipital regions. They overlapped more with dorsal attention, frontoparietal and visual networks, and were associated with object recognition. These findings imply the memory performance advantage of females and males might be related to the different memory processing tendencies and their associated network.

Mortality Risk Factors Among People Living with HIV Receiving Second--line Antiretroviral Therapy in Rural China.

BACKGROUND: Second-line antiretroviral therapy (ART) was introduced in Henan Province in 2009. The number of people living with human immunodeficiency virus (HIV) starting this therapy is increasing. OBJECTIVE: This study aimed to investigate the survival and factors affecting mortality among this group. METHODS: We conducted a retrospective cohort study of people living with HIV (PLHIV) who switched to second-line ART between May 1, 2010, and May 1, 2016., using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We followed 3,331 PLHIV for 26,988 person-years, of whom 508 (15.3%) died. The mortality rate was 1.88/100 person-years. After adjusting for confounding factors, we found being a woman (hazard ratio [HR], 0.66; 95% confidence interval [CI] 0.55-0.79), > 50 years old (HR, 2.69; 95%CI, 2.03-3.56), single/windowed (HR, 1.26; 95%CI, 1.04-1.52), having > 6 years of education (HR, 0.78; 95%CI, 0.65-0.94), Chinese medicine (HR, 0.75; 95%CI, 0.52-0.96), liver injury (HR, 1.58; 95%CI, 1.19-2.10), and CD4+ T cell count <200 cells/µl (HR, 1.94; 95%CI, 1.47-2.55), or 200-350 cells/µl (HR, 1.37; 95%CI, 1.03-1.82) were associated with mortality risk. CONCLUSIONS: We found lower mortality among PLHIV who switched to second-line ART than most previous studies. The limitations of a retrospective cohort may, therefore, have biased the data, and prospective studies are needed to confirm the results. Moreover, Chinese medicine combined with second-line ART shows potential as a treatment for HIV.

Effect of the duration of hypertension on white matter structure and its link with cognition.

The relation between hypertension (HTN) and cognition has been reported inclusive results, which may be affected by disease duration. Our study aimed to examine the influence of HTN duration on cognition and its underlying white matter (WM) changes including macrostructural WM hyperintensities (WMH) and microstructural WM integrity. A total of 1218 patients aged ≥55 years with neuropsychological assessment and a subgroup of 233 people with imaging data were recruited and divided into 3 groups (short duration: <5 years, medium duration: 5-20 years, long duration: >20 years). We found that greater HTN duration was preferentially related to worse executive function (EF), processing speed (PS), and more severe WMH, which became more significant during long duration stage. The reductions in WM integrity were evident at the early stage especially in long-range association fibers and then scattered through the whole brain. Increasing WMH and decreasing integrity of specific tracts consistently undermined EF. Furthermore, free water imaging method greatly enhanced the sensitivity in detecting HTN-related WM alterations. These findings supported that the neurological damaging effects of HTN is cumulative and neuroimaging markers of WM at macro- and microstructural level underlie the progressive effect of HTN on cognition.

Multi-domain cognition dysfunction accompanies frontoparietal and temporal amyloid accumulation in the elderly.

It is helpful to understand the pathology of Alzheimer's disease by exploring the relationship between amyloid-ß accumulation and cognition. The study explored the relationship between regional amyloid-ß accumulation and multiple cognitions and study their application value in the Alzheimer's disease diagnosis. 135 participants completed 18F-florbetapir Positron Emission Tomography (PET), structural MRI, and a cognitive battery. Partial correlation was used to examine the relationship between global and regional amyloid-ß accumulation and cognitions. Then, a support vector machine was applied to determine whether cognition-related accumulation regions can adequately distinguish the cognitively normal controls (76 participants) and mild cognitive impairment (30 participants) groups or mild cognitive impairment and Alzheimer's disease (29 participants) groups. The result showed that amyloid-ß accumulation regions were mainly located in the frontoparietal cortex, calcarine fissure, and surrounding cortex and temporal pole regions. Episodic memory-related regions included the frontoparietal cortices; executive function-related regions included the frontoparietal, temporal, and occipital cortices; and processing speed-related regions included the frontal and occipital cortices. Support vector machine analysis showed that only episodic memory-related amyloid-ß accumulation regions had better classification performance during the progression of Alzheimer's disease. Assessing regional changes in amyloid, particularly in frontoparietal regions, can aid in the early detection of amyloid-related decline in cognitive function.

Polydopamine functionalized polyurethane shape memory sponge with controllable expansion performance triggered by near-infrared light for incompressible hemorrhage control.

Uncontrolled expansion of shape memory sponges face a significant challenge in the treatment of lethal incompressible hemorrhage, which can lead to blood overflow or damage to the surrounding tissue. Herein, we developed a polydopamine functionalized polyurethane shape memory sponge (PDA-TPI-PU) with a controllable degree of expansion by near-infrared (NIR) light-triggered stimulation for the treatment of incompressible hemorrhage. The sponge has excellent liquid absorption performance and robust mechanical strength as well as good photothermal conversion ability. Under NIR light of 0.32 W/cm2, the maximum recovery rate of the fixed-shape compression sponge was 91% within 25 s in air and 80% within 25 s in blood. In the SD rat liver penetrating injury model, compared with commercial medical gelatin sponge and PVA sponge, the PDA-TPI-PU sponge could effectively control the bleeding under the NIR light irradiation and did not cause excessive compression of the wound. The sponge with these characteristics shows potential application prospects as a hemostatic material.

Wool keratin/zeolitic imidazolate framework-8 composite shape memory sponge with synergistic hemostatic performance for rapid hemorrhage control.

Uncontrollable hemorrhage and subsequent wound infection pose severe threats to life, especially in the case of deep, non-compressible, massive bleeding. Here, a wool keratin/zeolitic imidazolate framework-8 (WK/ZIF-8) composite shape memory sponge is prepared by incorporating ZIF-8 nanoparticles into wool keratin. The combination of keratin and ZIF-8 particles not only reduces the effect of ZIF-8 particles on cell viability but also bolsters the mechanical properties of the keratin sponge and endows it with antibacterial efficacy. Due to the synergistic effect of the excellent hemostatic performance of keratin and Zn2+ release from ZIF-8 nanoparticles, the porous structure suitable for blood cell adhesion and the shape recovery ability of sponges, the WK/ZIF-8 composite sponge exhibits superior hemostatic performance to commercial medical sponges in SD rat and rabbit hemorrhage models. In addition, in vitro and in vivo antibacterial experiments demonstrate the anti-infection activity of the composite sponge. Overall, the WK/ZIF-8 composite sponge provides a promising approach to rapidly control bleeding and promote wound healing.

Isolation and biological activity of natural chalcones based on antibacterial mechanism classification.

Bacterial infection, which is still one of the leading causes of death in humans, poses an enormous threat to the worldwide public health system. Antibiotics are the primary medications used to treat bacterial diseases. Currently, the discovery of antibiotics has reached an impasse, and due to the abuse of antibiotics resulting in bacterial antibiotic resistance, researchers have a critical desire to develop new antibacterial agents in order to combat the deteriorating antibacterial situation. Natural chalcones, the flavonoids consisting of two phenolic rings and a three-carbon α, ß-unsaturated carbonyl system, possess a variety of biological and pharmacological properties, including anti-cancer, anti-inflammatory, antibacterial, and so on. Due to their potent antibacterial properties, natural chalcones possess the potential to become a new treatment for infectious diseases that circumvents existing antibiotic resistance. Currently, the majority of research on natural chalcones focuses on their synthesis, biological and pharmacological activities, etc. A few studies have been conducted on their antibacterial activity and mechanism. Therefore, this review focuses on the antibacterial activity and mechanisms of seventeen natural chalcones. Firstly, seventeen natural chalcones have been classified based on differences in antibacterial mechanisms. Secondly, a summary of the isolation and biological activity of seventeen natural chalcones was provided, with a focus on their antibacterial activity. Thirdly, the antibacterial mechanisms of natural chalcones were summarized, including those that act on bacterial cell membranes, biological macromolecules, biofilms, and quorum sensing systems. This review aims to lay the groundwork for the discovery of novel antibacterial agents based on chalcones.

Brain Network Organization and Aging.

Despite recent substantial progress in neuroscience, the mechanisms and principles of the complex structure, functions, and the relationship between the brain and cognitive functions have not been fully understood. The modeling method of brain network can provide a new perspective for neuroscience research, and it is possible to provide new solutions to the related research problems. On this basis, the researchers define the concept of human brain connectome to highlight and emphasize the importance of network modeling methods in neuroscience. For example, using diffusion-weighted magnetic resonance imaging (dMRI) technology and fiber tractography methods, a white matter connection network of the whole brain can be constructed. From the perspective of brain function, functional magnetic resonance imaging (fMRI) data can build the brain functional connection network. A structural covariation modeling method is used to obtain a brain structure covariation network, and it appears to reflect developmental coordination or synchronized maturation between areas of the brain. In addition, network modeling and analysis methods can also be applied to other types of image data, such as positron emission tomography (PET), electroencephalogram (EEG), and magnetoencephalography (MEG). This chapter mainly reviews the research progress of researchers on brain structure, function, and other aspects at the network level in recent years.

The Aging Patterns of Brain Structure, Function, and Energy Metabolism.

The normal aging process brings changes in brain structure, function, and energy metabolism, which are presumed to contribute to the age-related decline in brain function and cognitive ability. This chapter aims to summarize the aging patterns of brain structure, function, and energy metabolism to distinguish them from the pathological changes associated with neurodegenerative diseases and explore protective factors in aging. We first described the normal atrophy pattern of cortical gray matter with age, which is negatively affected by some neurodegenerative diseases and is protected by a healthy lifestyle, such as physical exercise. Next, we summarized the main types of age-related white matter lesions, including white matter atrophy and hyperintensity. Age-related white matter changes mainly occurred in the frontal lobe, and white matter lesions in posterior regions may be an early sign of Alzheimer's disease. In addition, the relationship between brain activity and various cognitive functions during aging was discussed based on electroencephalography, magnetoencephalogram, and functional magnetic resonance imaging. An age-related reduction in occipital activity is coupled with increased frontal activity, which supports the posterior-anterior shift in aging (PASA) theory. Finally, we discussed the relationship between amyloid-ß deposition and tau accumulation in the brain, as pathological manifestations of neurodegenerative disease and aging.

White matter changes underlie hypertension-related cognitive decline in older adults.

Hypertension has been well recognized as a risk factor for cognitive impairment and dementia. Although the underlying mechanisms of hypertension-affected cognitive deterioration are not fully understood, white matter changes (WMCs) seem to play an important role. WMCs include low microstructural integrity and subsequent white matter macrostructural lesions, which are common on brain imaging in hypertensive patients and are critical for multiple cognitive domains. This article provides an overview of the impact of hypertension on white matter microstructural and macrostructural changes and its link to cognitive dysfunction. Hypertension may induce microstructural changes in white matter, especially for the long-range fibers such as anterior thalamic radiation (ATR) and inferior fronto-occipital fasciculus (IFOF), and then macrostructural abnormalities affecting different lobes, especially the periventricular area. Different regions' WMCs would further exert different effects to specific cognitive domains and accelerate brain aging. As a modifiable risk factor, hypertension might provide a new perspective for alleviating and delaying cognitive impairment.

A new strategy of transforming an ACQ compound into an AIE theranostic system for bacterial imaging and photodynamic antibacterial therapy.

An organic chemical with fluorescence quenching properties [aggregation-caused quenching (ACQ)] may often be transformed by adding functional groups that cause aggregation-induced emission (AIE) to its molecular scaffold. Such structural change techniques, however, sometimes require challenging chemical reactions. SF136 is a type of chalcone, and it is an typical ACQ organic compound. In this study, cationic surfactants like hexadecyltrimethylammonium bromide (CTAB) and polyethyleneimine (PEI) were used to convert the ACQ compound SF136 into an AIE compound without adding any AIE structure units. In comparison to SF136, the SF136-CTAB NPS system not only demonstrated improved bacterial fluorescence imaging capabilities, but also increased photodynamic antibacterial activity, which is connected to its improved targeting and reactive oxygen species (ROS) production abilities. It is a promising theranostic substance against bacteria owing to these enhanced qualities. Other ACQ fluorescent compounds may also benefit from using this approach, broadening the scope of their potential applications.

A sensitive label-free biosensor based on Ag2S-sensitived Bi2WO6/BiOBr heterojunction for photoelectrochemical immunoassay of prostate specific antigen.

Prostate cancer is one of the most common cancers in the world, and its early diagnosis can effectively reduce mortality. A new label-free photoelectrochemical (PEC) immunosensor on the basis of Bi2WO6/BiOBr nanocomposite materials has been successfully prepared for the test of prostate-specific antigen (PSA) in human serum in this work. The Ag2S-sensitized Bi2WO6/BiOBr heterojunction was used as a photosensitive material, which effectively improved the photocurrent response. On Bi2WO6/BiOBr surface, dopamine immobilized PSA antibody by self-polymerizing to form polydopamine membrane. Antigen and antibody are specifically combined to achieve quantitative detection of PSA according to the current changes at different concentrations of antigen. Under the optimal experimental conditions, the PEC immunosensor has an ideal linear relationship between 1 pg/mL - 50 ng/mL, and the detection limit is 0.084 pg/mL. In addition, the prepared immunosensor has good stability, reproducibility and selectivity, providing a new method for the detection of PSA in actual sample analysis.

Flavihumibacter fluminis sp. nov., a novel thermotolerant bacterium isolated from river silt.

A yellow, Gram-stain-positive, strictly aerobic, thermotolerant, non-motile and rod-shaped bacterial strain, designated RY-1T, was isolated from a silt sample of Fuyang River, Wuqiang County, Hengshui City, Hebei Province, PR China. Cells showed oxidase- and catalase-positive activities. Growth occurred at 20-45 °C (optimum, 37 °C) and pH 6.0-8.0 (optimum, pH 7.0), and in the presence of 0-1.5 % (w/v) NaCl (optimum, 0%). A phylogenetic tree based on 16S rRNA gene sequences revealed that strain RY-1T formed a phylogenetic lineage with Flavihumibacter members within the family Chitinophagaceae. A comparison of 16S rRNA gene sequences showed that strain RY-1T was most closely related to Flavihumibacter cheonanensis WS16T (98.6 %), Flavihumibacter sediminis CJ663T (97.7 %) and Flavihumibacter solisilvae 3-3T (97.6 %). The genome size of strain RY-1T was 4.71 Mb, and the DNA G+C content was 44.3  %. The average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity values between strain RY-1T and reference strains were all lower than the threshold values for species delineation. Strain RY-1T contained menaquinone-7 and iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1G as the sole respiratory isoprenoid quinone and major cellular fatty acids (≥5 %), respectively. The major polar lipids consisted of phosphatidylethanolamine, three unidentified aminolipids and four unidentified lipids. According to the results of phenotypic, phylogenetic and chemotaxonomic characteristics, strain RY-1T represents a novel species of the genus Flavihumibacter, for which the name Flavihumibacter fluminis sp. nov. is proposed. The type strain is RY-1T (=GDMCC 1.2775T=JCM 34870T).

Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines.

Proteolysis Targeting Chimeras (PROTACs) based on multi-target inhibitors have been reported several times recently. The advantages of PROTACs technology and the synergistic mechanism of multi-target drugs endow this class of protein degraders with special research significance. Herein, twelve new PROTACs based on Sunitinib and VHL-ligand were synthesized and evaluated for their in vitro anticancer activities. Among them, PROTACs 5 (IC50 = 2.9 ± 1.5 µM) exhibited the most significant antiproliferative activity against HL-60 cells. Western blot results showed that PROTAC 5 reduced the protein levels of FLT-3 and c-KIT in HL-60 cells, and induced the degradation of FLT-3 via the ubiquitin-proteasome system. Moreover, PROTACs 5 and 6 reduced the protein levels of FLT-3 in K562 cells. These results suggest that PROTAC 5 has the potential for further research, especially in combination with small molecule kinase inhibitors to study multidrug resistance of tyrosine kinase inhibitors in cancer treatment.

Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy.

Glycolysis is a complex metabolic process that occurs to convert glucose into pyruvate to produce energy for living cells. Normal cells oxidized pyruvate into adenosine triphosphate and carbon dioxide in the presence of oxygen in mitochondria while cancer cells preferentially metabolize pyruvate to lactate even in the presence of oxygen in order to maintain a slightly acidic micro-environment of PH 6.5 and 6.9, which is beneficial for cancer cell growth and metastasis. Therefore targeting glycolytic signaling pathways provided new strategy for anti-cancer therapy. Natural products are important sources for the treatment of diseases with a variety of pharmacologic activities. Accumulated studies suggested that natural products exhibited remarkable anti-cancer properties both in vitro and in vivo. Plenty of studies suggested natural products like flavonoids, terpenoids and quinones played anti-cancer properties via inhibiting glucose metabolism targets in glycolytic pathways. This study provided an updated overview of natural products controlling glycolytic pathways, which also provide insight into druggable mediators discovery targeting cancer glucose metabolism.

Progress of isolation, chemical synthesis and biological activities of natural chalcones bearing 2-hydroxy-3-methyl-3-butenyl group.

Chalcones have a three-carbon α,ß-unsaturated carbonyl system composed of two phenolic rings. Many chalcones have shown broad spectrum of biological activities with clinical potentials against various diseases. They are usually abundant in seeds, fruit skin, bark and flowers of most edible plants. Among them, chalcones bearing 2-hydroxy-3-methyl-3-butenyl (HMB) group have been reported several times in the past few decades due to their novel scaffolds and numerous interesting biological activities. In this paper, we reviewed the isolation of twelve natural chalcones and a natural chalcone-type compound bearing 2-hydroxy-3-methyl-3-butenyl group discovered so far, and reviewed their synthesis methods and biological activities reported in the literature. We anticipate that this review will inspire further research of natural chalcones.