New Insights into the Cooperativity and Dynamics of Dimeric Enzymes.

A survey of protein databases indicates that the majority of enzymes exist in oligomeric forms, with about half of those found in the UniProt database being homodimeric. Understanding why many enzymes are in their dimeric form is imperative. Recent developments in experimental and computational techniques have allowed for a deeper comprehension of the cooperative interactions between the subunits of dimeric enzymes. This review aims to succinctly summarize these recent advancements by providing an overview of experimental and theoretical methods, as well as an understanding of cooperativity in substrate binding and the molecular mechanisms of cooperative catalysis within homodimeric enzymes. Focus is set upon the beneficial effects of dimerization and cooperative catalysis. These advancements not only provide essential case studies and theoretical support for comprehending dimeric enzyme catalysis but also serve as a foundation for designing highly efficient catalysts, such as dimeric organic catalysts. Moreover, these developments have significant implications for drug design, as exemplified by Paxlovid, which was designed for the homodimeric main protease of SARS-CoV-2.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

In Situ Formed Microalgae-Integrated Living Hydrogel for Enhanced Tumor Starvation Therapy and Immunotherapy through Photosynthetic Oxygenation.

The effectiveness of various cancer therapies for solid tumors is substantially limited by the highly hypoxic tumor microenvironment (TME). Here, a microalgae-integrated living hydrogel (ACG gel) is developed to concurrently enhance hypoxia-constrained tumor starvation therapy and immunotherapy. The ACG gel is formed in situ following intratumoral injection of a biohybrid fluid composed of alginate, Chlorella sorokiniana, and glucose oxidase, facilitated by the crossing-linking between divalent ions within tumors and alginate. The microalgae Chlorella sorokiniana embedded in ACG gel generate abundant oxygen through photosynthesis, enhancing glucose oxidase-catalyzed glucose consumption and shifting the TME from immunosuppressive to immunopermissive status, thus reducing the tumor cell energy supply and boosting antitumor immunity. In murine 4T1 tumor models, the ACG gel significantly suppresses tumor growth and effectively prevents postoperative tumor recurrence. This study, leveraging microalgae as natural oxygenerators, provides a versatile and universal strategy for the development of oxygen-dependent tumor therapies.

Ddx5 Targeted Epigenetic Modification of Pericytes in Pulmonary Hypertension After Intrauterine Growth Restriction.

Newborns with intrauterine growth restriction (IUGR) have a higher likelihood of developing pulmonary arterial hypertension (PAH) in adulthood. Although there is increasing evidence suggesting that pericytes play a role in regulating myofibroblast transdifferentiation and angiogenesis in malignant and cardiovascular diseases, their involvement in the pathogenesis of IUGR-related pulmonary hypertension and the underlying mechanisms remain incompletely understood. To address this issue, a study was conducted using a Sprague-Dawley rat model of IUGR-related pulmonary hypertension. Our investigation revealed increased proliferation and migration of pulmonary microvascular pericytes in IUGR-related pulmonary hypertension, accompanied by weakened endothelial-pericyte interactions. Through whole-transcriptome sequencing, Ddx5 (DEAD-box protein 5) was identified as one of the hub genes in pericytes. DDX5, a member of the RNA helicase family, plays a role in the regulation of ATP-dependent RNA helicase activities and cellular function. MicroRNAs have been implicated in the pathogenesis of PAH, and microRNA-205 (miR-205) regulates cell proliferation, migration, and angiogenesis. The results of dual-luciferase reporter assays confirmed the specific binding of miR-205 to Ddx5. Mechanistically, miR-205 negatively regulates Ddx5, leading to the degradation of ß-catenin by inhibiting the phosphorylation of Gsk3ß at serine 9. In vitro experiments showed the addition of miR-205 effectively ameliorated pericyte dysfunction. Furthermore, in vivo experiments demonstrated that miR-205 agomir could ameliorate pulmonary hypertension. Our findings indicated that the downregulation of miR-205 expression mediates pericyte dysfunction through the activation of Ddx5. Therefore, targeting the miR-205/Ddx5/p-Gsk3ß/ß-catenin axis could be a promising therapeutic approach for IUGR-related pulmonary hypertension.

Enantioselective Construction of Quaternary Stereocenters via A Chiral Spiro Phosphoric Acid-Assisted Formal Gold Carbene gem-Dialkylation Reaction.

Enantioselective construction of all-carbon quaternary stereocenters has attracted much attention over the past few decades. A variety of catalytic asymmetric methods have been disclosed based on the use of presynthesized complex reagents that impart congested steric hindrance to the reaction center, which generally produce the chiral molecules through forming one C-C bond. The use of readily available reagents that could build two C-C bonds on the same carbonic center with the concomitant assembly of quaternary stereocenters remains challenging. Herein, we disclose a catalytic asymmetric alkyne multifunctionalization reaction using a gold complex and a chiral spiro phosphoric acid (SPA) for synergistic catalysis. In this method, the readily accessible internal alkynes served as the key gold carbene precursors, followed by carbene gem-dialkylation through Mannich-type addition of enolate species or stepwise formal cycloaddition with methylenimines that are derived from 1,3,5-triazinanes in the presence of SPA. The reaction provides practical access to poly-functionalized chiral linear and cyclic ketones that bear two adjacent quaternary stereocenters in generally good yields and excellent enantioselectivities, leading to an essential complement to the asymmetric construction of quaternary stereocenters using readily available materials with high bond formation efficiency.

Role of ERK in gender difference of fibromyalgia pain.

This study investigated the ERK pathway of the peripheral nervous system and discovered a gender-specific pattern of ERK activation in the dorsal root ganglion of an acid-induced chronic widespread muscular pain model. We employed a twice acid-induced chronic musculoskeletal pain model in rats to evaluate mechanical pain behavior in both male and female groups. We further conducted protein analysis of dissected dorsal root ganglions from both genders. Both male and female rats exhibited a similar pain behavior trend, with females demonstrating a lower pain threshold. Protein analysis of the dorsal root ganglion (DRG) showed a significant increase in phosphorylated ERK after the second acid injection in all groups. However, phosphorylation of ERK was observed in the dorsal root ganglion, with higher levels in the male ipsilateral group compared to the female group. Moreover, there was a no difference between the left and right sides in males, whereas the significant difference was observed in females. In conclusions, the administration of acid injections induced painful behavior in rats, and concurrent with this, a significant upregulation of pERK was observed in the dorsal root ganglia, with a greater magnitude of increase in males than females, and in the contralateral side compared to the ipsilateral side. Our findings shed light on the peripheral mechanisms underlying chronic pain disorders and offer potential avenues for therapeutic intervention.

Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia.

OBJECTIVES: Glymphatic function has not yet been explored in behavioral variant frontotemporal dementia (bvFTD). The spatial correlation between regional glymphatic function and bvFTD remains unknown. METHOD: A total of 74 patients with bvFTD and 67 age- and sex-matched healthy controls (HCs) were selected from discovery dataset and replication dataset. All participants underwent neuropsychological assessment. Glymphatic measures including choroid plexus (CP) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling between blood-oxygen-level-dependent signals and cerebrospinal fluid signals (BOLD-CSF coupling), were compared between the two groups. Regional glymphatic function was evaluated by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, and posterior regions. The bvFTD-related metabolic pattern was identified using spatial covariance analysis based on l8 F-FDG-PET. RESULTS: Patients with bvFTD showed higher CP volume (p < 0.001); anterior and middle DTI-ALPS (p < 0.001); and weaker anterior BOLD-CSF coupling (p < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI-ALPS was negatively associated with the expression of the bvFTD-related metabolic pattern (r = -0.52, p = 0.034) and positively related with regional standardized uptake value ratios of l8 F-FDG-PET in bvFTD-related brain regions (r range: 0.49 to 0.62, p range: 0.017 to 0.047). Anterior and middle glymphatic functions were related to global cognition and disease severity. INTERPRETATION: Our findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD. ANN NEUROL 2023;94:442-456.

Gold-Catalyzed Alkyne Oxidative Cyclization/Mannich-Type Addition Cascade Reaction of Ynamides with 1,3,5-Triazinanes.

Herein, a gold-catalyzed alkyne oxidative cyclization/Mannich-type addition cascade reaction of ynamides with 1,3,5-triazinanes in the presence of a Brønsted acid has been presented. A class of functionalized fluorenes bearing a quaternary carbon center was synthesized directly with moderate to excellent yields via in situ formed α-oxo carbenes using quinoline N-oxide as the oxidant under mild reaction conditions.

Joint contributions from brain activity and activity-independent functional connectivity to working memory aging.

Working memory (WM) impairment has been well characterized in normal aging. Various studies have explored changes in either the regional activity or the interregional connectivity underlying the aging process of WM. We proposed that brain activity and connectivity would independently alter with aging and affect WM performance. WM was assessed with a classical N-back task during functional magnetic resonance imaging in a community-based sample comprising 168 elderly subjects (aged 55-86 years old). Following the rationale of background functional connectivity, we assessed age-related alterations in brain activity and seed-based interregional connectivity independently. Analyses revealed age-related decrease in positive activity of the inferior parietal lobule (IPL) and an increase in the negative activity of the ventral anterior cingulate cortex (ACC), and the local functional dysfunctions were accompanied by alterations in their connectivity to other cortical regions. Importantly, regional activity impairments in the IPL and ACC could mediate age-related effects on accuracy rate and reaction time, respectively, and those effects were further counterbalanced by enhancement of their background functional connectivity. We thus claimed that age-induced alterations in regional activity and interregional connectivity occurred independently and contributed to WM changes in aging. Our findings presented the way brain activity and functional connectivity interact in the late adulthood, thus providing a new perspective for understanding WM and cognitive aging.

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.