Parkinson's disease with anxiety: clinical characteristics and their correlation with oxidative stress, inflammation, and pathological proteins.

OBJECTIVE: This study was performed to explore the differences in the clinical characteristics and oxidative stress indicators, inflammatory factors, and pathological proteins in serum between Parkinson's disease (PD) with anxiety (PD-A) and with no anxiety (PD-NA) patients, and further correlations among clinical characteristics and above variables were analyzed in PD-A and PD-NA groups. METHODS: A total of 121 patients with PD were enrolled in this study and assessed by the Hamilton Anxiety Scale (14 items) (HAMA-14). These patients were divided into PD-A and PD-NA groups according to a cut-off point of 7 of HAMA-14. Demographic variables were collected, and clinical symptoms were assessed by multiple rating scales. The levels of free radicals, inflammatory factors, and pathological proteins in serum were measured by chemical colorimetric method and enzyme-linked immunosorbent assay (ELISA). The differences of above variables were compared between PD-A and PD-NA groups, and the correlations of clinical symptoms with the abovevariables were analyzed in PD-A and PD-NA groups. RESULTS: The frequency of PD-A was 62.81%. PD-A group exhibited significantly impaired motor dysfunction and multiple non-motor symptoms, including fatigue, sleep behavior disorder, restless leg syndrome and autonomic dysfunction, and dramatically compromised activities of daily living compard with PD-NA group. PD-A group displayed prominently increasedlevels of hydroxyl radical (·OH) and tumor necrosis factor (TNF)-α, and a decreased nitric oxide (NO) level in serum compared with PD-NA group (P<0.001, P = 0.001, P= 0.027, respectively). ·OH, NO, and TNF-α were identified as the risk factors of PD-A (OR = 1.005, P = 0.036; OR = 0.956, P = 0.017; OR = 1.039, P = 0.033, respectively). In PD patients, HAMA-14 score was significantly and positively correlated with the levels of ·OH and TNF-α in serum (P<0.001, P = 0.002, respectively). In PD-A group, ·OH level was significantly and negatively correlated with Aß1-42 level, while TNF-α level was significantly and positively correlated with P-tau (S396) level in serum. CONCLUSIONS: The frequency of PD-A is high. PD-A patients present more severe motor dysfunction and multiple non-motor symptoms, and poorer activities of daily living. The increased levels of ·OH and TNF-α levels and the decreased NO level in serum are all associated with more severe anxiety in PD patients.Findings from this study may provide in-depth insights into the clinical characteristics, underlying mechanisms of PD-A, and potential correlations among anxiety, oxidative stress, inflammation, and cognitive decline in PD patients.

Ectopic Expression of PtrLBD39 Retarded Primary and Secondary Growth in Populus trichocarpa.

Primary and secondary growth of trees are needed for increments in plant height and stem diameter, respectively, affecting the production of woody biomass for applications in timber, pulp/paper, and related biomaterials. These two types of growth are believed to be both regulated by distinct transcription factor (TF)-mediated regulatory pathways. Notably, we identified PtrLBD39, a highly stem phloem-specific TF in Populus trichocarpa and found that the ectopic expression of PtrLBD39 in P. trichocarpa markedly retarded both primary and secondary growth. In these overexpressing plants, the RNA-seq, ChIP-seq, and weighted gene co-expression network analysis (WGCNA) revealed that PtrLBD39 directly or indirectly regulates TFs governing vascular tissue development, wood formation, hormonal signaling pathways, and enzymes responsible for wood components. This regulation led to growth inhibition, decreased fibrocyte secondary cell wall thickness, and reduced wood production. Therefore, our study indicates that, following ectopic expression in P. trichocarpa, PtrLBD39 functions as a repressor influencing both primary and secondary growth.

Optimized Traffic Light System with AIC and Application to the 2021 M6.7 Yangbi Earthquake Sequence.

One important question in earthquake prediction is whether a moderate or large earthquake will be followed by an even bigger one. Through temporal b-value evolution analysis, the traffic light system can be used to estimate if an earthquake is a foreshock. However, the traffic light system does not take into account the uncertainty of b-values when they constitute a criterion. In this study, we propose an optimization of the traffic light system with the Akaike Information Criterion (AIC) and bootstrap. The traffic light signals are controlled by the significance level of the difference in b-value between the sample and the background rather than an arbitrary constant. We applied the optimized traffic light system to the 2021 Yangbi earthquake sequence, which could be explicitly recognized as foreshock-mainshock-aftershock using the temporal and spatial variations in b-values. In addition, we used a new statistical parameter related to the distance between earthquakes to track earthquake nucleation features. We also confirmed that the optimized traffic light system works on a high-resolution catalog that includes small-magnitude earthquakes. The comprehensive consideration of b-value, significance probability, and seismic clustering might improve the reliability of earthquake risk judgment.

A pairwise pseudo-likelihood approach for left-truncated and interval-censored data under the Cox model.

Left truncation commonly occurs in many areas, and many methods have been proposed in the literature for the analysis of various types of left-truncated failure time data. For the situation, a common approach is to conduct the analysis conditional on truncation times, and the method is relatively simple but may not be efficient. In this paper, we discuss regression analysis of such data arising from the proportional hazards model that also suffer interval censoring. For the problem, a pairwise pseudo-likelihood approach is proposed that aims to recover some missing information in the conditional methods. The resulting estimator is shown to be consistent and asymptotically normal. A simulation study is conducted to assess the performance of the proposed method and suggests that it works well in practical situations and is indeed more efficient than the existing method. The approach is also applied to a set of real data arising from an AIDS cohort study.

Assessing Earthquake Forecast Performance Based on b Value in Yunnan Province, China.

Many studies have shown that b values tend to decrease prior to large earthquakes. To evaluate the forecast information in b value variations, we conduct a systematic assessment in Yunnan Province, China, where the seismicity is intense and moderate-large earthquakes occur frequently. The catalog in the past two decades is divided into four time periods (January 2000-December 2004, January 2005-December 2009, January 2010-December 2014, and January 2015-December 2019). The spatial b values are calculated for each 5-year span and then are used to forecast moderate-large earthquakes (M ≥ 5.0) in the subsequent period. As the fault systems in Yunnan Province are complex, to avoid possible biases in b value computation caused by different faulting regimes when using the grid search, the hierarchical space-time point-process models (HIST-PPM) proposed by Ogata are utilized to estimate spatial b values in this study. The forecast performance is tested by Molchan error diagram (MED) and the efficiency is quantified by probability gain (PG) and probability difference (PD). It is found that moderate-large earthquakes are more likely to occur in low b regions. The MED analysis shows that there is considerable precursory information in spatial b values and the forecast efficiency increases with magnitude in the Yunnan Province. These results suggest that the b value might be useful in middle- and long-term earthquake forecasts in the study area.

Correlations of apathy with clinical symptoms of Alzheimer's disease and olfactory dysfunctions: a cross-sectional study.

BACKGROUND: Apathy is one of the most common symptoms of Alzheimer's disease (AD), however, correlations of apathy with demographic variables, cognitive functions, neuropsychiatric symptoms, activity of daily living and olfactory functions in AD patients are still lacking comprehensive investigations. METHODS: This is a cross-sectional study. Total 124 typical AD patients were consecutively recruited from April 2014 to April 2017. In 124 AD patients, 47 cases (37.9%) were male and 77 cases were female; patients' age were 43-93 years with an average of 68 years. Patients were divided into AD with apathy (AD-A) and AD with no apathy (AD-NA) groups according to the score of Modified Apathy Evaluation Scale, then were evaluated cognitive functions, neuropsychiatric symptoms and activity of daily living, and tested olfactory functions. Above variables were compared between AD-A and AD-NA groups. Further correlation analyses and linear regression analysis were performed between apathy and above variables. RESULTS: Compared with AD-NA group, global cognitive level, verbal memory, verbal fluency and activity of daily living were significantly compromised in AD-A group (P < 0.002); depression and agitation were severely displayed in AD-A group (P < 0.002). Apathy was negatively correlated with global cognitive function, verbal memory, verbal fluency and activity of daily living (P < 0.05). There was no significant difference of olfactory functions between the two groups (P > 0.002), and correlations between apathy and olfactory threshold, olfactory identification and global olfactory function were significant (P < 0.05) but quite weak (|r| < 0.3). Further linear regression analysis showed that only verbal fluency and instrumental activities of daily living were independently associated with apathy. CONCLUSIONS: Independent correlations among apathy, verbal fluency and instrumental activities of daily living in AD patients might be related to the common brain area involved in their pathogeneses.

Kinetics and toxicological potential of heavy metal leaching from asphalt pavements.

The leaching of heavy metals from asphalt pavement has attracted increasing attention due to its associated environmental risks. Comprehending the leaching process is crucial for ensuring the safe utilization of asphalt pavement. This study investigates heavy metal leaching kinetics from asphalt pavements using tank-leaching tests and dynamic simulations employing both first and second-order kinetic models. Furthermore, this study reveals the toxicological potential of heavy metal leaching from asphalt pavement by assessing its temporal metal accessibility based on the obtained kinetic attributes. Six distinct asphalt mixtures were prepared and tested, each exhibiting two different gradations. The findings demonstrated that both kinetic models effectively elucidated the leaching process. Notably, the relatively stable final leaching stages primarily adhered to first-order kinetics, while the second-order kinetics provided a superior description of the more intricate initial leaching stages. In terms of toxicological potential, the results indicated that recycled waste-incorporated asphalt pavements, specifically bottom ash-incorporated asphalt and asphalt rubber, exhibited excessive heavy metal leaching for varying durations, ranging from several days to months under specific conditions. This study has provided valuable insights into the metal leaching kinetics of asphalt pavements and their associated toxicological impact, significantly advancing the current understanding of the consequences of heavy metal leaching from asphalt pavements.

Robust Covariance Matrix Estimation for High-Dimensional Compositional Data with Application to Sales Data Analysis.

Compositional data arises in a wide variety of research areas when some form of standardization and composition is necessary. Estimating covariance matrices is of fundamental importance for high-dimensional compositional data analysis. However, existing methods require the restrictive Gaussian or sub-Gaussian assumption, which may not hold in practice. We propose a robust composition adjusted thresholding covariance procedure based on Huber-type M-estimation to estimate the sparse covariance structure of high-dimensional compositional data. We introduce a cross-validation procedure to choose the tuning parameters of the proposed method. Theoretically, by assuming a bounded fourth moment condition, we obtain the rates of convergence and signal recovery property for the proposed method and provide the theoretical guarantees for the cross-validation procedure under the high-dimensional setting. Numerically, we demonstrate the effectiveness of the proposed method in simulation studies and also a real application to sales data analysis.

Real-world application of a fast stool DNA test for colorectal cancer screening in primary screening positive population.

BACKGROUND: Stool DNA test has been emerged as an effective noninvasive method for colorectal cancer (CRC) screening, but the real-world performance of stool DNA test in Chinese population has rarely been reported. METHODS: A total of 36,527 subjects were recruited in Haining City from January 2021 to December 2021. Participants underwent primary screening by taking both two-samples fecal immunochemical tests (FITs) and high-risk factor questionnaire (HRFQ), and those who tested either positive by FITs or evaluated to be high risk by HRFQ were recommended to undertake subsequent stool DNA test and colonoscopy. RESULTS: Of 36,527 participants, 34,778 (95%) completed both HRFQ and FITs, 9947 (29%) showed positive results during primary screening, and the colonoscopy compliance rate was 49%. Of primary screening positives, 8733 (88%) completed stool sample collections, and colonoscopy results from 4293 eligible participants were used for analyzing the performance of stool DNA test. The sensitivities for detecting CRC and advanced adenomas (AA) were 100% (95% CI: 60-100%) and 40% (95% CI: 34-46%), and the area under curve (AUC) was 0.961 (95% CI:0.954-0.967) and 0.625 (95% CI: 0.609-0.641), respectively. The specificity of stool DNA test was 84% (95% CI: 82-85%). The false-positive rate for stool DNA test is about 10% less than that of primary screening. CONCLUSION: Stool DNA test is a cost-effective and promising alternative strategy for CRC screening in China.

Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolism.

Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.

Alzheimer's disease with sleep insufficiency: a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier.

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer's disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease.

Improving paediatric flow in an UK Paediatric Assessment Unit.

The 2010 Royal College of Paediatrics and Child Health (RCPCH) guidelines for acute paediatric services set standards for time to senior review for paediatric medical admissions in the UK as tier two doctor (registrar) review within 4 hours and consultant review within 14 hours. Our aim was to implement these standards in our unit through increasing proportions of reviews within these timeframes and measuring the impact on patient flow. Four quality improvement cycles were completed between March 2018 and March 2020 capturing data from 288 patient data sets. Recommendations included the extension of consultant on-site availability out of routine working hours (after cycle 1), highlighting patients awaiting consultant review during team handover (after cycle 2), and improving tier two doctor rostering (after cycle 3). After highlighting patients for consultant priority review, the proportion of patients seen within 14 hours improved from 53.3% (cycle 2) to 95% (cycle 3, p=0.005). Improved tier two doctor cover increased the proportion meeting registrar review within 4 hours from 82.9% (cycle 3) to 96.2% (cycle 4, p=0.028). A large proportion of paediatric patients were managed and discharged at tier two doctor level (65.6% over cycles 1-4). An inverse correlation was seen (R=-0.587) between time to discharge and the number of tier two doctors on shift (cycle 4). The interventions conducted demonstrated significant improvement in proportions of paediatric patients seen within the RCPCH timeframes. Adequate tier two doctor staffing is a priority for prompt review and discharge of acute paediatric patients. Future work aims to consider factors such as nursing rostering, bed management and the impact of COVID-19 on paediatric flow.

Proteomic Analysis of Alfalfa (Medicago sativa L.) Roots in Response to Rhizobium Nodulation and Salt Stress.

(1) Background: Alfalfa is an important legume forage throughout the world. Although alfalfa is considered moderately tolerant to salinity, its production and nitrogen-fixing activity are greatly limited by salt stress. (2) Methods: We examined the physiological changes and proteomic profiles of alfalfa with active nodules (NA) and without nodules (NN) under NaCl treatment. (3) Results: Our data suggested that NA roots showed upregulation of the pathways of abiotic and biotic stress responses (e.g., heat shock proteins and pathogenesis-related proteins), antioxidant enzyme synthesis, protein synthesis and degradation, cell wall degradation and modification, acid phosphatases, and porin transport when compared with NN plants under salt stress conditions. NA roots also upregulated the processes or proteins of lipid metabolism, heat shock proteins, protein degradation and folding, and cell cytoskeleton, downregulated the DNA and protein synthesis process, and vacuolar H+-ATPase proteins under salt stress. Besides, NA roots displayed a net H+ influx and low level of K+ efflux under salt stress, which may enhance the salt tolerance of NA plants. (4) Conclusions: The rhizobium symbiosis conferred the host plant salt tolerance by regulating a series of physiological processes to enhance stress response, improve antioxidant ability and energy use efficiency, and maintain ion homeostasis.

Electromagnetic field controlled domain wall displacement for induced strain tailoring in BaTiO3-epoxy nanocomposite.

Failure in an epoxy polymer composite material is prone to initiate by the coalescence of microcracks in its polymer matrix. As such, matrix toughening via addition of a second phase as rigid or/and rubber nano/micro-particles is one of the most popular approaches to improve the fracture toughness across multiple scales in a polymer composite, which dissipates fracture energy via deformation mechanisms and microcracks arrest. Few studies have focused on tailorable and variable toughening, so-called 'active toughening', mainly suggesting thermally induced strains which offer slow and irreversible toughening due to polymer's poor thermal conductivity. The research presented in the current article has developed an instantaneous, reversible extrinsic strain field via remote electromagnetic radiation. Quantification of the extrinsic strain evolving in the composite with the microwave energy has been conducted using in-situ real-time fibre optic sensing. A theoretical constitutive equation correlating the exposure energy to micro-strains has been developed, with its solution validating the experimental data and describing their underlying physics. The research has utilised functionalised dielectric ferroelectric nanomaterials, barium titanate (BaTiO3), as a second phase dispersed in an epoxy matrix, able to introduce microscopic electro-strains to their surrounding rigid epoxy subjected to an external electric field (microwaves, herein), as result of their domain walls dipole displacements. Epoxy Araldite LY1564, a diglycidyl ether of bisphenol A associated with the curing agent Aradur 3487 were embedded with the BaTiO3 nanoparticles. The silane coupling agent for the nanoparticles' surface functionalisation was 3-glycidoxypropyl trimethoxysilane (3-GPS). Hydrogen peroxide (H2O2, 30%) and acetic acid (C2H4O2, 99.9%) used as functionalisation aids, and the ethanol (C2H6O, 99.9%) used for BaTiO3 dispersion. Firstly, the crystal microstructure of the functionalised nanoparticles and the thermal and dielectric properties of the achieved epoxy composite materials have been characterised. It has been observed that the addition of the dielectric nanoparticles has a slight impact on the curing extent of the epoxy. Secondly, the surface-bonded fibre Bragg grating (FBG) sensors have been employed to investigate the real-time variation of strain and temperature in the epoxy composites exposed to microwaves at 2.45 GHz and at different exposure energy. The strains developed due to the in-situ exposure at composite, adhesive and their holding fixture material were evaluated using the FBG. The domain wall induced extrinsic strains were distinguished from the thermally induced strains, and found that the increasing exposure energy has an instantaneously increasing effect on the development of such strains. Post-exposure Raman spectra showed no residual field in the composite indicating no remnant strain field examined under microwave powers < 1000 W, thus suggesting a reversible strain introduction mechanism, i.e. the composite retaining its nominal properties post exposure. The dielectric composite development and quantifications presented in this article proposes a novel active toughening technology for high-performance composite applications in numerous sectors.

Research advances on circulating long noncoding RNAs as biomarkers of cardiovascular diseases.

Cardiovascular diseases (CVD) such as myocardial ischemia, myocardial infarction, heart failure, atherosclerosis, hypertension, arrhythmia, and their complications diseases are associated with increased morbidity and mortality, it is necessary to develop new diagnostic markers for CVD. LncRNAs have become a new class of biomarkers in CVD with good development prospects. Numerous studies have confirmed lncRNAs feasibility as diagnostic, prognostic and predictive tools for different types of CVD. In this review, we summarized the available knowledge regarding the clinical application value and pathophysiological mechanism of circulating lncRNA as potential biomarkers of cardiovascular disease. We reviewed the scope of application and changes of circulating lncRNAs such as ZFAS1, CDR1AS, CHAST, UCA1, HOTAIR, MIAT, NEAT1, LIPCAR, H19, NRF, NRON, MHRT, PVT1, Heat2, CASC7, GAS5, MALAT1, APPAT, HIF1A-AS1, KCNQ1OT1, NEXN in different kinds of CVD and discussed their clinical application potential as biomarker, which can help us better understand the mechanism of CVD.

A PtrLBD39-mediated transcriptional network regulates tension wood formation in Populus trichocarpa.

Tension wood (TW) is a specialized xylem tissue formed in angiosperm trees under gravitational stimulus or mechanical stresses (e.g., bending). The genetic regulation that underlies this important mechanism remains poorly understood. Here, we used laser capture microdissection of stem xylem cells coupled with full transcriptome RNA-sequencing to analyze TW formation in Populus trichocarpa. After tree bending, PtrLBD39 was the most significantly induced transcription factor gene; it has a phylogenetically paired homolog, PtrLBD22. CRISPR-based knockout of PtrLBD39/22 severely inhibited TW formation, reducing cellulose and increasing lignin content. Transcriptomic analyses of CRISPR-based PtrLBD39/22 double mutants showed that these two genes regulate a set of TW-related genes. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify direct targets of PtrLBD39. We integrated transcriptomic analyses and ChIP-seq assays to construct a transcriptional regulatory network (TRN) mediated by PtrLBD39. In this TRN, PtrLBD39 directly regulates 26 novel TW-responsive transcription factor genes. Our work suggests that PtrLBD39 and PtrLBD22 specifically control TW formation by mediating a TW-specific TRN in Populus.

Clinical Features and Potential Mechanisms Relating Neuropathological Biomarkers and Blood-Brain Barrier in Patients With Alzheimer's Disease and Hearing Loss.

Background: The aim of this study was to explore clinical features and potential mechanisms relating neuropathological biomarkers and blood-brain barrier (BBB) in Alzheimer's disease (AD) and hearing loss (HL). Materials and Methods: A total of 65 patients with AD were recruited and auditory function was assessed by threshold of pure tone audiometry (PTA). Patients were divided into AD with HL (AD-HL) and AD with no HL (AD-nHL) groups based on the standard of World Health Organization. Clinical symptoms were assessed by multiple rating scales. The levels of neuropathological biomarkers of ß amyloid1-42 (Aß1-42) and multiple phosphorylated tau (P-tau), and BBB factors of matrix metalloproteinases (MMPs), receptor of advanced glycation end products, glial fibrillary acidic protein, and low-density lipoprotein receptor related protein 1 were measured. Results: (1) Compared with AD-nHL group, AD-HL group had significantly impaired overall cognitive function and cognitive domains of memory, language, attention, execution, and activities of daily living (ADL) reflected by the scores of rating scales (P < 0.05). PTA threshold was significantly correlated with the impairments of overall cognitive function and cognitive domains of memory and language, and ADL in patients with AD (P < 0.05). (2) P-tau (S199) level was significantly increased in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD. (3) MMP-3 level was significantly elevated in CSF from AD-HL group (P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD (P < 0.05). (4) In AD-HL group, P-tau (S199) level was significantly and positively correlated with the levels of MMP-2 and MMP-3 in CSF (P < 0.05). Conclusion: AD-HL patients have severely compromised overall cognitive function, multiple cognitive domains, and ADL. The potential mechanisms of AD-HL involve elevations of AD neuropathological biomarker of P-tau (S199) and BBB factor of MMP-3, and close correlations between P-tau (S199) and MMP-2/MMP-3 in CSF. Findings from this investigation highly suggest significance of early evaluation of HL for delaying AD progression, and indicate new directions of drug development by inhibiting neuropathological biomarkers of AD and protecting BBB.

Potential roles of oxidative distress on neurodegeneration in Parkinson's disease with neuropsychiatric symptoms.

Background: Neuropsychiatric symptoms (NPSs) belong to a category of non-motor symptoms of Parkinson's disease (PD), which seriously compromise the quality of life and prognosis of PD. This study focused on the correlations between NPSs, free radicals, neuroinflammatory factors, and neuropathological proteins in cerebrospinal fluid (CSF) in patients with PD, aiming to provide insights into the potential mechanisms and therapeutic target for PD with NPSs (PD-NPSs). Methods: In total, 129 patients with PD were enrolled and assessed by the Neuropsychiatric Symptoms Inventory (NPI); they were divided into the PD-NPSs group (75 patients) and PD with no NPSs (PD-nNPSs) group (54 patients). The levels of hydrogen peroxide (H2O2) and nitric oxide (NO), and hydroxyl radical (·OH), anti-oxidative enzyme, neuroinflammatory factors, and neuropathological proteins in CSF from patients with PD were measured. The levels of the above variables were compared between PD-NPSs and PD-nNPSs groups, and correlation analyses among the above variables were conducted. Results: (1) The levels of H2O2 and NO in CSF from the PD-NPSs group were significantly elevated compared with the PD-nNPSs group (p = 0.001), and NPI score positively correlated with the levels of H2O2 and NO (r = 0.283, P = 0.001; r = 0.231, P = 0.008). Reversely, total superoxide dismutase (tSOD) activity in CSF from the PD-NPSs group was significantly reduced compared with the PD-nNPSs group (p = 0.011), and negatively correlated with NPI score (r = -0.185, p = 0.036). (2) The tumor necrosis factor (TNF)-α level in CSF from the PD-NPSs group was significantly decreased compared with the PD-nNPSs group (p = 0.002) and negatively correlated with NPI score (r = -0.211, p = 0.016). (3) The total tau (T-tau) level in CSF from the PD-NPSs group was significantly higher than in the PD-nNPSs group (p = 0.014) and positively correlated with the NPI score (r = 0.167, p = 0.060). (4) The levels of H2O2 and NO positively correlated with the T-tau level in CSF from the PD-NPSs group (r = 0.183, p = 0.039; r = 0.251, P = 0.004), and the levels of TNF-α and T-tau showed a negative correlation (r = -0.163, p = 0.067). Conclusion: Oxidative distress characterized by the elevations of H2O2 and NO levels may closely correlate with the neurodegeneration in brain regions related to PD-NPSs. Thus, therapeutic antioxidants may become an important target for PD-NPSs therapy.

Unveiling the self-association and desolvation in crystal nucleation.

As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to investigate the relationship between the solvent and nucleation kinetics. Induction times at different supersaturation in six solvents were measured. FTIR and NMR spectroscopy were employed to explore the solvent-solute interactions and the self-association properties in solution. Density functional theory (DFT) was adopted to evaluate the strength of solute-solvent interactions and the molecular conformations in different solvents. Based on these spectroscopy data, molecular simulation and nucleation kinetic results, a comprehensive understanding of the relationship between molecular structure, crystal structure, solution chemistry and nucleation dynamics is discussed. Both the solute-solvent interaction strength and the supramolecular structure formed by the self-association of solute molecules affect the nucleation rate. The findings reported here shed new light on the molecular mechanism of nucleation in solution.

Enhancement of lysozyme crystallization under ultrasound field.

With the increasing demand for biopharmaceuticals, a method to crystallize biomolecule products with high quality, high yield and uniform size distribution as well as regular crystal habit is needed. In this work, ultrasound was used as a nucleation accelerator to decrease the energy barrier for lysozyme crystal formation. Crystallization experiments on egg-white lysozyme were carried out with and without ultrasound. The effect of ultrasound on induction time, metastable zone width, crystal size and morphology and process yield was investigated in detail. The nucleation-promoting effect produced by ultrasound is illustrated by the reduction of metastable zone width and induction time. By inducing faster nucleation, ultrasound leads to protein crystals grow at lower supersaturation levels with shorter induction time. It was found that ultrasound could result in uniform size distribution of the product due to the preventing of aggregation. However, long time continuous application of ultrasound could result in smaller particle size. Hence, ultrasonic-stop method was found to be a more appropriate strategy to enhance the crystallization process of proteins such as lysozyme.