Machine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions.

The burgeoning comprehension of protein phase separation (PS) has ushered in a wealth of bioinformatics tools for the prediction of phase-separating proteins (PSPs). These tools often skew towards PSPs with a high content of intrinsically disordered regions (IDRs), thus frequently undervaluing potential PSPs without IDRs. Nonetheless, PS is not only steered by IDRs but also by the structured modular domains and interactions that aren't necessarily reflected in amino acid sequences. In this work, we introduce PSPire, a machine learning predictor that incorporates both residue-level and structure-level features for the precise prediction of PSPs. Compared to current PSP predictors, PSPire shows a notable improvement in identifying PSPs without IDRs, which underscores the crucial role of non-IDR, structure-based characteristics in multivalent interactions throughout the PS process. Additionally, our biological validation experiments substantiate the predictive capacity of PSPire, with 9 out of 11 chosen candidate PSPs confirmed to form condensates within cells.

Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on ß-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the ß-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.

Bioactive compounds and biological functions of medicinal plant-derived extracellular vesicles.

Extracellular vesicles (EVs) are tiny lipid bilayer-enclosed membrane particles released from a variety of cell types into the surrounding environment. These EVs have massive participated in cell-to-cell communication and interspecies communication. In recent years, plant-derived extracellular vesicles (PDEVs) and "exosome-like" EVs populations found in distinct plants have attracted widespread attention. Especially, research on medicinal plant-derived extracellular vesicles (MPDEVs) are increasing, which are considered a kind of promising natural compound. This review summarizes current knowledge on MPDEVs in terms of bioactive compounds, including small RNA, protein, lipid, and metabolite, have been found on the surface and/or in the lumen of MPDEVs. Moreover, both in vitro and in vivo experiments have shown that MPDEVs exert broad biomedical functions, such as anti-inflammatory, anticancer, antioxidant, modulate microbiota, etc. MPDEVs may be a better substitute than animal-derived extracellular vesicles (ADEVs) because of safety and biocompatibility in the future.

Lack of causal association between epilepsy and dementia: A Mendelian randomization analysis.

OBJECTIVE: Epidemiological studies have reported an association between epilepsy and dementia. However, the causal relationship between epilepsy and the risk of dementia is not clear. We aimed to inspect the causal effect of epilepsy on memory loss and dementia. METHODS: We analyzed summary data of epilepsy, memory loss, and dementia from the genome-wide association study (GWAS) using the two-sample Mendelian randomization (MR) method. We used the estimated odds ratio of memory loss and dementia associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: all epilepsy, focal epilepsy (including focal epilepsy with hippocampal sclerosis, lesion-negative focal epilepsy, and focal epilepsy with other lesions), and genetic generalized epilepsy (including childhood absence epilepsy, generalized tonic-clonic seizures alone, Juvenile absence epilepsy, and Juvenile myoclonic epilepsy). RESULTS: According to the result of MR using the inverse variance weighted method (IVW), we found that genetically predicted epilepsy did not causally increase the risk of memory loss and dementia (p > 0.05). Results of the MR-Egger and weighted median method were consistent with the IVW method. CONCLUSIONS: No evidence has been found to support the notion that epilepsy can result in memory loss and dementia. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants.

The validity and IRT psychometric analysis of Chinese version of Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10).

OBJECTIVE: The doctor-patient relationship (DPR) plays a crucial role in the Chinese healthcare system, functioning to improve medical quality and reduce medical costs. This study examined the psychometric properties of the Chinese version of the Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10) among general hospital inpatients in China. METHODS: The research recruited 38 resident doctors responsible for 120 participants, and factor analyses were used to assess the construct validity of the scale. Convergent validity was evaluated by examining the correlation between DDPRQ-10 and depressive symptoms, burnout, and self-efficacy, using the Patient Health Questionnaire Depression Scale-9 item (PHQ-9), and the Maslach Burnout Inventory (MBI). Both multidimensional item response theory (MIRT) and unidimensional item response theory (IRT) frameworks were used to estimate the parameters of each item. RESULTS: The Chinese version of DDPRQ-10 showed satisfactory internal consistency (Cronbach's alpha = 0.931), and fitted in a modified two-factor model of positive feelings and negative feelings (χ2/df = 1.494, GFI = 0.925, RMSEA = 0.071, SRMR = 0.008, CFI = 0.985, NFI = 0.958, NNFI = 0.980, TLI = 0.980, IFI = 0.986). Significant correlations with PHQ-9 with DDPRQ-10 and both subscales were revealed (r = 0.293 ~ 0.333, p < .001), while DDPRQ-10 score also significantly correlated with doctors' MBI score (r = -0.467, p < .001). The MIRT model of full scale and IRT models of both subscales showed high discrimination of all items (a = 2.30 ~ 10.18), and the test information within the range of low-quality relationship was relatively high. CONCLUSION: The Chinese version of DDPRQ-10 displayed satisfactory reliability and validity and thus was appropriate for measuring the DPR in Chinese medical settings.

Superhard bulk high-entropy carbides with enhanced toughness via metastable in-situ particles.

Despite the extremely high hardness of recently proposed high-entropy carbides (HECs), the low fracture toughness limits their applications in harsh mechanical environment. Here, we introduce a metastability engineering strategy to achieve superhard HECs with enhanced toughness via in-situ metastable particles. This is realized by developing a (WTaNbZrTi)C HEC showing a solid solution matrix with uniformly dispersed in-situ tetragonal and monoclinic ZrO2 particles. Apart from a high hardness of 21.0 GPa, the HEC can obtain an enhanced fracture toughness of 5.89 MPa·m1/2, significantly exceeding the value predicted by rule of mixture and that of other reported HECs. The toughening effect is primarily attributed to the transformation of the metastable tetragonal ZrO2 particles under mechanical loading, which promotes crack tip shielding mechanisms including crack deflection, crack bridging and crack branching. The work demonstrates the concept of using in-situ metastable particles for toughening bulk high-entropy ceramics by taking advantage of their compositional flexibility.

ß2-Microglobulin coaggregates with Aß and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice.

Extensive studies indicate that ß-amyloid (Aß) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aß itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of ß2-microglobulin (ß2M) and Aß that trigger neurodegeneration in AD. ß2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of ß2M aggravates amyloid pathology independent of MHC class I, and coaggregation with ß2M is essential for Aß neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated ß2M depletion mitigates AD-associated neuropathology, and inhibition of ß2M-Aß coaggregation with a ß2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify ß2M as an essential factor for Aß neurotoxicity and a potential target for treating AD.

The causal relationship between circulating biomarkersand the risk of bipolar disorder: A two-sample Mendelian randomization study.

OBJECTIVE: To identify susceptible biomarkers for the development of bipolar disorder (BD), we conducted a Mendelian Randomization (MR) design to screen circulating proteins for the potential risk of bipolar disorder systematically. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of 4782 human circulating proteins on the risk of bipolar disorder. 376 circulating biomarkers were selected in MR estimation (4406 circulating proteins with less than 3 SNPs were excluded) with 5368 European descents. GWAS meta-analysis of the potential role of all-cause bipolar disorder arose from the Psychiatric Genomics Consortium (41,917 cases, 371,549 controls). RESULTS: After IVW and sensitivity analysis, 4 circulating proteins having causal effects on bipolar disorder were identified. ISG15, as a key player in the innate immune response, decreased the risk of bipolar disorder causally (OR = 0.92, 95% CI = 0.89-0.94, P = 1.46e-09). Furthermore, MLN decreased the risk of bipolar disorder causally (OR = 0.94, 95% CI = 0.91-0.97, P = 1.04e-04). In addition, SFTPC (OR = 0.91, 95% CI = 0.86-0.96, P = 4.47e-04) and VCY (OR = 0.86, 95% CI = 0.77-0.96, P = 8.55e-03) presented a suggestive association with bipolar disorder. CONCLUSIONS: Our findings indicated that ISG15 and MLN showed evidence of causality in bipolar disorder and provided a promising target for the diagnosis and treatment of diseases.

Development and psychometric validation of the hospitalized patients' expectations for treatment scale-patient version.

Objectives: A general expectation measurement of inpatients across wards is needed in the patient safety management systems of general hospitals. This study developed and psychometrically validated a new scale fulfilling the requirements above: the Hospitalized Patients' Expectations for Treatment Scale-Patient version (HOPE-P). Methods: A total of 35 experts and ten inpatients were interviewed during the formulation of the HOPE-P scale, which was initially designed with three dimensions: doctor-patient communication expectations, treatment outcome expectations, and disease management expectancy. We recruited 210 inpatients from a general hospital in China and explored the reliability, validity, and psychometric characteristics of the questionnaire. Item analysis, construct validity, internal consistency and 7-day test-retest reliability analysis were applied. Results: Exploratory and confirmatory analyses supported a 2-dimension (doctor-patient communication expectation and treatment outcome expectation) structure with satisfactory model fit parameters (root mean square residual (RMR) = 0.035, a root-mean-square-error of approximation (RMSEA) = 0.072, comparative fit index (CFI) = 0.984, Tucker-Lewis index (TLI) = 0.970). Item analysis revealed an appropriate item design (r = 0.573-0.820). The scale exhibited good internal consistency, with Cronbach's α of 0.893, 0.761, and 0.919 for the overall scale, the doctor-patient communication expectation subscale, and the treatment outcome expectation subscale, respectively. The 7-day test-retest reliability was 0.782 (p < .001). Conclusion: Our results indicated that the HOPE-P is a reliable and valid assessment tool to measure the expectations of general hospital inpatients, with a strong capacity to recognize patients' expectations regarding doctor-patient communication and treatment outcomes.

The Chinese version of patient-doctor-relationship questionnaire (PDRQ-9): Factor structure, validation, and IRT psychometric analysis.

Objective: The patient-doctor relationship has been considered as a crucial concept in primary healthcare, while the medical reform launched by the Chinese government in 2009 has brought significant changes to the healthcare system, which made it urgent to introduce reliable measurement instruments for assessing today's doctor-patient relationship in China. This study examined the psychometric properties of the Chinese version of the Patient-Doctor-Relationship Questionnaire-9 item (PDRQ-9) scale among general hospital inpatients in China. Materials and methods: A total of 203 participants responded to the survey, of which 39 completed retest after 7 days. Factor analyses were used to test the construct validity of the scale. Convergent validity was evaluated by the correlation between PDRQ-9 and depressive symptoms measured using PHQ-9 (Patient Health Questionnaire Depression Scale-9 item). Both multidimensional item response theory (MIRT) and unidimensional item response theory (IRT) framework were used to estimate the parameters of each item. Results: The two-factor model of relationship quality and treatment quality was supported (χ2/df = 1.494, GFI = 0.925, RMSEA = 0.071, RMR = 0.008, CFI = 0.985, NFI = 0.958, NNFI = 0.980, TLI = 0.980, IFI = 0.986). The PDRQ-9 and both subscales showed significant correlation with PHQ-9 (r = -0.196∼-0.309) and good internal consistency (Cronbach's alpha = 0.865∼0.933). ANCOVA analysis adjusted with age revealed significant difference in PDRQ-9 ratings between patients with or without significant depressive symptoms (P = 0.019). The 7-day test-retest reliability of the scale was 0.730. The MIRT model of full scale and IRT models of both subscales showed high discrimination of all items (a = 2.46∼38.46), and the test information within the range of low-quality relationship was relatively high. Conclusion: The Chinese version of PDRQ-9 is a valid and reliable rating scale, which can measure the doctor-patient relationship among Chinese patients.

Emotional distress and burnout at a fever clinic in China: Comparison between different periods of COVID-19.

Background: Frontline healthcare workers (FHWs) experienced psychological stress and heavy workload during COVID-19 pandemic. This study examined the psychological symptoms and occupational burnout of FHWs in a fever clinic during different periods of the pandemic. Methods: A cross-sectional survey of FHWs in the fever clinic of a tertiary hospital was carried out during both the outbreak period and regular period of COVID-19. Psychological measurement instruments including Generalized Anxiety Disorder 7-item, the 9-Question Patient Health Questionnaire, the Maslach Burnout Inventory-Human Service Survey, and the General Self-Efficacy Scale were used to evaluate anxiety, depression, burnout, and self-efficacy, respectively. The correlation between clinical variables was explored. Results: A total of 162 participants were involved in this study, including 118 FHWs during the outbreak period (Group 1) and 44 FHWs during the regular period (Group 2). Anxiety symptoms were more prevalent in Group 2 (x 2 = 27.477) while depressive symptoms were significantly more prevalent in Group 1 (x 2 = 69.538). Burnout rate was higher in Group 2 (x 2 = 29.526). Self-efficacy was higher in Group 1 (t = 3.194). Burnout was positively correlated with anxiety symptoms (r 2 = 0.424) and negatively correlated with self-efficacy (r 2 = -0.312). Conclusion: Anxiety, depressive symptoms and burnout were prevalent in FHWs during different periods of the COVID-19 pandemic. There is a tendency to be less depressed, but more anxious and burned out over time, although the severity of the pandemic is decreasing. Self-efficacy may be an important factor in protecting FHWs from occupational burnout. Support and intervention plans for FHWs should be made at the institutional level.

HPV 16 E6 promotes growth and metastasis of esophageal squamous cell carcinoma cells in vitro.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies worldwide. Increasing evidence suggests that human papillomavirus (HPV) infection may be associated with the etiology of ESCC. However, the precise role of HPV in ESCC remains unclear. METHODS AND RESULTS: Proliferation and apoptosis of ESCC cells upon infection with HPV16 E6 were detected using CCK-8 assays and Western blot analyses. The migration rate was measured with a wound healing assay, and a Transwell Matrigel invasion assay was used to detect the invasive ability. RT-qPCR was performed to detect the expression of E6AP, p53, and miR-34a. The proliferation rates were significantly higher in HPV16E6-transfected cell groups compared with the negative control groups. Bax protein expression was downregulated in HPV16E6-treated groups compared to the controls. The wound healing and Transwell Matrigel invasion assays indicated that HPV16 E6 infection could increase ESCC cell migration and invasion. Furthermore, E6AP, p53 and miR-34a expression were decreased in HPV16 E6-transfected cell lines. CONCLUSION: Our results not only provide evidence that HPV16 E6 promotes cell proliferation, migration, and invasion in ESCC, but also suggests a correlation between HPV infection and E6AP, p53 and miR-34a expression. Consequently, HPV16 E6 may play an important role in ESCC development.

Development and psychometric validation of the hospitalized patients' expectations for treatment scale-clinician version.

Objective: Patient safety management systems in general hospitals require a comprehensive tool for assessing the expectations of inpatients across different wards. This study aimed to develop and psychometrically validate a new scale, the hospitalized patients' expectations for treatment scale-clinician version (HOPE-C), to meet this requirement. Methods: We interviewed 35 experts and 10 inpatients while developing the HOPE-C scale. The scale was initially designed with three dimensions: clinicians' expectations regarding doctor-patient communication, clinicians' expectations regarding treatment outcome, and clinicians' expectations regarding disease management. We recruited 200 inpatients from a general hospital in China. At the same time, 51 clinicians were assigned to the enrolled patients who completed the HOPE-C to examine the reliability, validity, and psychometric characteristics of the questionnaire. We applied item analysis, assessed construct validity, evaluated internal consistency, and conducted a test-retest reliability analysis over 7 days. Results: Both exploratory and confirmatory analyses supported a 2-dimensional structure, comprising doctor-patient communication expectations and treatment outcome expectations, with favorable model fit parameters (root mean square residual [RMR] = 0.042, root mean square error of approximation [RMSEA] = 0.049, comparative fit index [CFI] = 0.989, Tucker-Lewis index [TLI] = 0.984). Item analysis demonstrated appropriate item design (r = 0.744-0.961). The scale exhibited strong internal consistency, with Cronbach's α values of 0.884, 0.816, and 0.840 for the overall scale, the doctor-patient communication expectation subscale, and the treatment outcome expectation subscale, respectively. The 7-day test-retest reliability was 0.996 (p < 0.001). Conclusion: Our findings suggest that the HOPE-C is a reliable and valid assessment tool for measuring the expectations of inpatients in general hospitals. It effectively identifies patients' expectations concerning doctor-patient communication and treatment outcomes.

A redox switch regulates the assembly and anti-CRISPR activity of AcrIIC1.

Anti-CRISPRs (Acrs) are natural inhibitors of bacteria's CRISPR-Cas systems, and have been developed as a safeguard to reduce the off-target effects of CRISPR gene-editing technology. Acrs can directly bind to CRISPR-Cas complexes and inhibit their activities. However, whether this process is under regulation in diverse eukaryotic cellular environments is poorly understood. In this work, we report the discovery of a redox switch for NmeAcrIIC1, which regulates NmeAcrIIC1's monomer-dimer interconversion and inhibitory activity on Cas9. Further structural studies reveal that a pair of conserved cysteines mediates the formation of inactive NmeAcrIIC1 dimer and directs the redox cycle. The redox switch also applies to the other two AcrIIC1 orthologs. Moreover, by replacing the redox-sensitive cysteines, we generated a robust AcrIIC1 variant that maintains potent inhibitory activity under various redox conditions. Our results reveal a redox-dependent regulation mechanism of Acr, and shed light on the design of superior Acr for CRISPR-Cas systems.

Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition.

While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43's RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

Bloom Syndrome Helicase Compresses Single-Stranded DNA into Phase-Separated Condensates.

Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as a genome "caretaker" that processes structured DNA. In contrast, our knowledge of how BLM behaves on single-stranded (ss) DNA is still limited. Here, we demonstrate that BLM possesses the intrinsic ability for phase separation and can co-phase separate with ssDNA to form dynamically arrested protein/ssDNA co-condensates. The introduction of ATP potentiates the capability of BLM to condense on ssDNA, which further promotes the compression of ssDNA against a resistive force of up to 60 piconewtons. Moreover, BLM is also capable of condensing replication protein A (RPA)- or RAD51-coated ssDNA, before which it generates naked ssDNA by dismantling these ssDNA-binding proteins. Overall, our findings identify an unexpected characteristic of a DNA helicase and provide a new angle of protein/ssDNA co-condensation for understanding the genomic instability caused by BLM overexpression under diseased conditions.

Hsp70 exhibits a liquid-liquid phase separation ability and chaperones condensed FUS against amyloid aggregation.

Hsp70 is a key molecular chaperone in the protein quality control system to safeguard protein homeostasis in cells. Previous studies have shown that Hsp70 chaperones TDP-43, a pathogenic protein associated with amyotrophic lateral sclerosis (ALS), in nuclear bodies and prevents it from the pathological aggregation. In this work, we report that Hsp70 undergoes liquid-liquid phase separation, chaperones FUS, another ALS-linked pathogenic protein, in stress granules (SGs), and prevents condensed FUS from amyloid aggregation. Knock-down of Hsp70 does not influence SG assembly but results in the liquid-to-solid transition in SGs. NMR experiments further reveal Hsp70 predominantly uses its C-terminal substrate-binding domain to interact with the low complexity domain of FUS, which represents a mechanism distinct from that interacting with TDP-43. These findings suggest that Hsp70 is widely involved in chaperoning the physiological dynamics of various membrane-less organelles and adopts different mechanisms to prevent the pathological aggregation of different proteins.

Molecular structure of an amyloid fibril formed by FUS low-complexity domain.

FUS is a multifunctional nuclear protein which undergoes liquid-liquid phase separation in response to stress and DNA damage. Dysregulation of FUS dynamic phase separation leads to formation of pathological fibril closely associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we determined the cryo-EM structure of a cytotoxic fibril formed by the low-complexity (LC) domain of FUS at 2.9 Å resolution. The fibril structure exhibits a new and extensive serpentine fold consisting of three motifs incorporating together via a Tyr triad. FUS LC employs 91 residues to form an enlarged and stable fibril core via hydrophilic interaction and hydrogen bonds, which is distinct from most of previously determined fibrils commonly stabilized by hydrophobic interaction. Our work reveals the structural basis underlying formation of a cytotoxic and thermostable fibril of FUS LC and sheds light on understanding the liquid-to-solid phase transition of FUS in disease.

Temporal dynamic changes of intrinsic brain activity in Alzheimer's disease and mild cognitive impairment patients: a resting-state functional magnetic resonance imaging study.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory impairment. Previous studies have largely focused on alterations of static brain activity occurring in patients with AD. Few studies to date have explored the characteristics of dynamic brain activity in cognitive impairment, and their predictive ability in AD patients. METHODS: One hundred and eleven AD patients, 29 MCI patients, and 73 healthy controls (HC) were recruited. The dynamic amplitude of low-frequency fluctuation (dALFF) and the dynamic fraction amplitude of low-frequency fluctuation (dfALFF) were used to assess the temporal variability of local brain activity in patients with AD or mild cognitive impairment (MCI). Pearson's correlation coefficients were calculated between the metrics and subjects' behavioral scores. RESULTS: The results of analysis of variance indicated that the AD, MCI, and HC groups showed significant variability of dALFF in the cerebellar posterior and middle temporal lobes. In AD patients, these brain regions had high dALFF variability. Significant dfALFF variability was found between the three groups in the left calcarine cortex and white matter. The AD group showed lower dfALFF than the MCI group in the left calcarine cortex. CONCLUSIONS: Compared to HC, AD patients were found to have increased dALFF variability in the cerebellar posterior and temporal lobes. This abnormal pattern may diminish the capacity of the cerebellum and temporal lobes to participate in the cerebrocerebellar circuits and default mode network (DMN), which regulate cognition and emotion in AD. The findings above indicate that the analysis of dALFF and dfALFF based on functional magnetic resonance imaging data may give a new insight into the neurophysiological mechanisms of AD.

EEG power spectral analysis reveals tandospirone improves anxiety symptoms in patients with Alzheimer's disease: a prospective cohort study.

BACKGROUND: To study the efficacy of tandospirone citrate in treating Alzheimer's disease (AD) patients with anxiety. METHODS: Thirty mild-to-moderate AD patients with anxiety symptoms were randomly divided into a monotherapy group (donepezil) and a combination therapy group (donepezil and tandospirone). The treatment lasted for 12 weeks. Drug efficacy was regularly assessed using psychological assessment scales and quantitative pharmaco-electroencephalogram (QPEEG) power spectral analysis. RESULTS: After 12 weeks of treatment, the mean Hamilton Anxiety Scale (HAMA) score and mean Neuropsychiatric Inventory (NPI) score of the combination therapy group were 5.13±4.18 and 4.2±5.0, respectively, which was significantly lower compared to baseline and the monotherapy group (all P<0.05). The mean attention score on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) was 0.07±0.26 for the combination group, which was significantly lower than that of the monotherapy group (P<0.05). QPEEG revealed that the power values of the δ wave in the right prefrontal lobe, left middle temporal lobe and right posterior temporal lobe decreased in the combination therapy group but not in the monotherapy group. Similarly, the power values of the α2 wave in the right parietal, right posterior temporal and left middle temporal lobes, and the ß1 wave power values of left middle temporal and left posterior temporal lobes were also significantly decreased in the combination therapy group, but not in the monotherapy group. CONCLUSIONS: Tandospirone citrate can significantly improve anxiety symptoms and attention in patients with mild to moderate AD. QPEEG examination might provide a objective way for the efficacy of the tandospirone in anxiety symptoms of the patients with Alzheimer's disease.