Miracle-dz/UniFAR-FTUs huggingface dataset:
The role of neuroimaging in Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha‐synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single‐photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD‐related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha‐synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha‐synuclein imaging in humans.
A systematic review of Sec24 cargo interactome

Endoplasmic reticulum (ER)‐to‐Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex‐II (COPII) arm of the trafficking machinery incorporates a wide array of cargo proteins into vesicles through direct or indirect interactions with Sec24, the principal subunit of the COPII coat. Approximately one‐third of all mammalian proteins rely on the COPII‐mediated secretory pathway for membrane insertion or secretion. There are four mammalian Sec24 paralogs and three yeast Sec24 paralogs with emerging evidence of paralog‐specific cargo interaction motifs. Furthermore, individual paralogs also differ in their affinity for a subset of sorting motifs present on cargo proteins. As with many aspects of protein trafficking, we lack a systematic and thorough understanding of the interaction of Sec24 with cargoes. This systematic review focuses on the current knowledge of cargo binding to both yeast and mammalian Sec24 paralogs and their ER export motifs. The analyses show that Sec24 paralog specificity of cargo (and cargo receptors) range from exclusive paralog dependence or preference to partial redundancy. We also discuss how the Sec24 secretion system is hijacked by viral (eg, VSV‐G, Hepatitis B envelope protein) and bacterial (eg, the enteropathogenic Escherichia coli type III secretion system effector NleA/EspI) pathogens.
A narrative review of tumor heterogeneity and challenges to tumor drug therapy

Objective To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors. Background Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients. Methods The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy. Conclusions Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.
Edward Carmeliet: his contributions and scientific legacy

The death of Edward Carmeliet has robbed us of one of the founders of modern cardiac electrophysiology. Here we summarize his contributions and, equally importantly, consider the current situation of the fields which he helped to develop. It would, however, be remiss not to point out that from 1980 to 1987, he was a member of the Editorial Board of The Journal of Physiology, one of the many roles in which he contributed to helping others develop their science. The Journal has also been an important forum for his work and was his publication of choice for the full reports of his mechanistic studies of cardiac electrophysiology. The dazzling variety of topics which he contributed to is also noteworthy and ranges from the basic properties of Ca2+ and K+ currents, the control of action potential duration, excitation–contraction coupling, to translational aspects such as the effects of ischaemia, and antiarrhythmic therapy. Such breadth was perhaps more common in days gone by than today.
Cognitive and Neural State Dynamics of Narrative Comprehension

Narrative comprehension involves a constant interplay of the accumulation of incoming events and their integration into a coherent structure. This study characterizes cognitive states during narrative comprehension and the network-level reconfiguration occurring dynamically in the functional brain. We presented movie clips of temporally scrambled sequences to human participants (male and female), eliciting fluctuations in the subjective feeling of comprehension. Comprehension occurred when processing events that were highly causally related to the previous events, suggesting that comprehension entails the integration of narratives into a causally coherent structure. The functional neuroimaging results demonstrated that the integrated and efficient brain state emerged during the moments of narrative integration with the increased level of activation and across-modular connections in the default mode network. Underlying brain states were synchronized across individuals when comprehending novel narratives, with increased occurrences of the default mode network state, integrated with sensory processing network, during narrative integration. A model based on time-resolved functional brain connectivity predicted changing cognitive states related to comprehension that are general across narratives. Together, these results support adaptive reconfiguration and interaction of the functional brain networks on causal integration of the narratives. SIGNIFICANCE STATEMENT The human brain can integrate temporally disconnected pieces of information into coherent narratives. However, the underlying cognitive and neural mechanisms of how the brain builds a narrative representation remain largely unknown. We showed that comprehension occurs as the causally related events are integrated to form a coherent situational model. Using fMRI, we revealed that the large-scale brain states and interaction between brain regions dynamically reconfigure as comprehension evolves, with the default mode network playing a central role during moments of narrative integration. Overall, the study demonstrates that narrative comprehension occurs through a dynamic process of information accumulation and causal integration, supported by the time-varying reconfiguration and brain network interaction.
Genetically determined low income modifies Alzheimer’s disease risk

Background Socioeconomic status (SES) is considered to be associated with the prevalence of Alzheimer’s disease (AD). However, the causal association remain unclear. Here, we determining whether income has a causal protective effect on the risk of developing AD using Mendelian randomization (MR). Methods Single-nucleotide polymorphisms (SNPs) that are strongly associated with household income levels (P<5×10−8) from the UK Biobank (UKB) (n=286,301) were selected as instrumental variables for this study. Confounding instruments were removed through data set browsing. Selected SNPs were then harmonized with results from an AD genome-wide meta-analysis (71,880 cases, 383,378 controls) including both case-control and proxy cases. The analysis was conducted using MR methods, and multiple sensitivity analyses were applied for testing of potential bias. Results After confounding instrument removal and clumping, 9 SNPs associated with household income level identified by the UKB were left for the MR analysis. Our results demonstrated that higher household income level was causally related with a lower risk of AD (odds ratio 0.78, 95% confidence interval: 0.69–0.89; P<0.001). Multiple sensitivity analyses suggested no obvious evidence for heterogeneity or pleiotropy of the results. Conclusions Under MR assumptions, our results suggest robust evidence of a causal association between household income and AD risk, which may provide potential prevention strategies for this devastating disease.
Multi-functional antibody profiling for malaria vaccine development and evaluation

ABSTRACT Introduction A vaccine would greatly accelerate current global efforts toward malaria elimination. While a partially efficacious vaccine has been achieved for Plasmodium falciparum, a major bottleneck in developing highly efficacious vaccines is a lack of reliable correlates of protection, and the limited application of assays that quantify functional immune responses to evaluate and down-select vaccine candidates in pre-clinical studies and clinical trials. Areas covered In this review, we describe the important role of antibodies in immunity against malaria and detail the nature and functional activities of antibodies against the malaria-causing parasite. We highlight the growing understanding of antibody effector functions against malaria and in vitro assays to measure these functional antibody responses. We discuss the application of these assays to quantify antibody functions in vaccine development and evaluation. Expert opinion It is becoming increasingly clear that multiple antibody effector functions are involved in immunity to malaria. Therefore, we propose that evaluating vaccine candidates needs to move beyond individual assays or measuring IgG magnitude alone. Instead, vaccine evaluation should incorporate the full breadth of antibody response types and harness a wider range of assays measuring functional antibody responses. We propose a 3-tier approach to implementing assays to inform vaccine evaluation.
Biomechanical Properties and Biocompatibility of Implant-Supported Full Arch Fixed Prosthesis Substructural Materials

Objectives: The purpose of this study was to investigate the fracture resistance, biocompatibility, hardness, and transverse strength of non-precious metal alloy (chromium-cobalt; Cr-Co), titanium (Ti), zirconia (Zr), polymethylmethacrylate (PMMA), and polyetheretherketone (PEEK) when employed as substructure materials according to the implant supported full arch fixed prosthesis treatment concept. Materials and Methods: In total, 150 Cr-Co, Ti, Zr, PMMA, and PEEK samples (n = 30 per material) measuring 25 × 2 × 2 mm in size were produced. Of the samples, 50 (n = 10 for each material, all having dimensions of 6 × 3 mm) were subjected to biocompatibility tests. The Vickers hardness test and three-point bending test were performed; fracture resistance measurements were taken and the biocompatibility of the samples was evaluated by the XTT assay. Results: Vickers hardness was highest for Zr (p < 0.05). PEEK and PMMA had the lowest (and similar) fracture resistance values (p < 0.05). Cell proliferation on the surfaces of the materials was similar between PEEK and Zr (p > 0.05), which were the most biocompatible materials. Conclusions: Within the limitations of this study, the most favorable materials in terms of biocompatibility were found as PEEK and Zr. When biomechanical properties are evaluated, the most durable materials can be specified as Cr-Co and Zr. Also, further studies are needed to improve material stability.
Lessons Learned about the Need for Early Screening for Depression during the First Months of the COVID-19 Pandemic in the United States

Abstract A nationwide survey assessed the prevalence and pandemic-related risk factors of major depressive disorder (MDD) at the initial onset of the COVID-19 pandemic. Findings showed a significant increase in the prevalence of MDD (22.7%) compared to the pre-pandemic 12-month estimate (10.4%). Specific pandemic-related concerns, along with significant increases in stress, loneliness, fatigue, and substance use behaviors are noted for those with the provisional diagnosis of MDD. Early screening and detection for potential MDD cases can reduce the severity and duration of maladaptive symptoms, decreasing the risk for future depression episodes and the potential loss of quality of life and productivity.
Effect of parental education and household poverty on recovery after traumatic brain injury in school-aged children

ABSTRACT Objective While prior studies have found parental socioeconomic status (SES) affects the outcomes of pediatric traumatic brain injury (TBI), the longitudinal trajectory of this effect is not well understood. Methods This prospective cohort study included children 8–18 years of age admitted to six sites with a complicated mild (n = 123) or moderate-severe TBI (n = 47). We used caregiver education and household poverty level as predictors, and multiple quality of life and health behavior domains as outcomes. Differences at 6, 12, and 24 months from baseline ratings of pre-injury functioning were compared by SES. We examined the association between measures of SES and domains of functioning over the 24 months post-injury in children with a complicated mild or moderate- severe TBI, and determined how this association varied over time. Results Parental education was associated with recovery among children with complicated mild TBI; outcomes at 6, 12, and 24 months were substantially poorer than at baseline for children with the least educated parents. After moderate-severe TBI, children in households with lower incomes had poorer outcomes compared to baseline across time. Implications Parental education and household income were associated with recovery trajectories for children with TBI of varying severity.
Sublamina-Specific Dynamics and Ultrastructural Heterogeneity of Layer 6 Excitatory Synaptic Boutons in the Adult Human Temporal Lobe Neocortex

Abstract Synapses “govern” the computational properties of any given network in the brain. However, their detailed quantitative morphology is still rather unknown, particularly in humans. Quantitative 3D-models of synaptic boutons (SBs) in layer (L)6a and L6b of the temporal lobe neocortex (TLN) were generated from biopsy samples after epilepsy surgery using fine-scale transmission electron microscopy, 3D-volume reconstructions and electron microscopic tomography. Beside the overall geometry of SBs, the size of active zones (AZs) and that of the three pools of synaptic vesicles (SVs) were quantified. SBs in L6 of the TLN were middle-sized (~5 μm2), the majority contained only a single but comparatively large AZ (~0.20 μm2). SBs had a total pool of ~1100 SVs with comparatively large readily releasable (RRP, ~10 SVs L6a), (RRP, ~15 SVs L6b), recycling (RP, ~150 SVs), and resting (~900 SVs) pools. All pools showed a remarkably large variability suggesting a strong modulation of short-term synaptic plasticity. In conclusion, L6 SBs are highly reliable in synaptic transmission within the L6 network in the TLN and may act as “amplifiers,” “integrators” but also as “discriminators” for columnar specific, long-range extracortical and cortico-thalamic signals from the sensory periphery.
Combination therapy for COVID‐19 in hemodialysis patients: Pharmacological treatments and renal replacement therapy based on the severity

Dear Editor, The mortality risk of Coronavirus disease 2019 (COVID-19) is higher in dialysis patients than in nondialysis patients [1]. In dialysis patients, it is difficult to treat COVID-19 due to various comorbidities. We conducted a combination therapy of pharmacological treatments and renal replacement therapy (RRT) for hemodialysis (HD) patients with COVID-19 between December 2020 and April 2021. The severity was defined as follows: mild (nonor mild pneumonia: presence of clinical or radiographic evidence of lower respiratory tract disease, oxygen saturation [SpO2] ≥96% [breathing ambient air]), moderate (93% < SpO2 < 96%), severe (marked tachypnea [respiratory rate ≥ 30 breaths/min] and hypoxemia [SpO2 ≤ 93%]), and critical (respiratory failure, need for invasive mechanical ventilation). Pharmacological treatments were as follows: (1) antiviral agents (mild–moderate, favipiravir [day 1: 3600 mg; 2–10: 1600]; severe–critical, remdesivir [day 1: 200 mg; 2–5, 7, 9, 12, 15: 100]; (2) dexamethasone (mild–moderate, oral [day 1–5: 6 mg; 6–7: 4; 8–9: 2]; severe–critical, intravenous [day 1–7: 6.6 mg; 8–9: 4.95; 10–11: 3.3; 12–15: 1.65]); (3) antibiotics (mild, oral; moderate, intravenous and oral; severe–critical, two intravenous); (4) antithrombotic agents (mild–moderate, oral; severe, oral or heparin sodium [5000 unit/day]; critical, heparin sodium); (5) protease inhibitor (mild–moderate, camostat mesilate [day 1–7: 600 mg]; severe–critical, nafamostat mesilate [day 1–7: 250 mg] and sivelestat sodium hydrate [day 1–7: 4.8 mg/kg]); and (6) intravenous immunoglobulin (IVIG, severe–critical, day 1–3: 5 g). HD was performed for 4 h (polymethyl methacrylate [PMMA] membrane; blood flow rate [BFR], 100–300 ml/ min; dialysate flow rate [DFR], 500 ml/min) in mild (three times/week) and moderate–severe (six times/week) patients. Continuous RRT (CRRT) for 72–96 h (acrylonitrile-co-methallyl sulfonate surface-treated [AN69ST] membrane; BFR, 100 ml/min; DFR, 500–1000 ml/h) and polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) for 3–6 h (BFR, 100 ml/min) were performed in critical patients. We used nafamostat mesilate or heparin sodium for anticoagulation. All seven patients (two mild, one moderate, two severe, and two critical) received the combination therapy (Table 1). The mild–severe patients recovered uneventfully and were discharged on foot. The critical patients received mechanical ventilation and tracheostomy. The overall 90-day survival rate was 100%. Remdesivir [2] was approved as antiviral agents for severe–critical COVID-19, whereas favipiravir was approved for mild–moderate COVID-19 in Japan. Therefore, we used
Comparative Analysis of Non-Full and Full Endoscopic Spine Technique via Interlaminar Approach for the Treatment of Degenerative Lumbar Spinal Stenosis: A Retrospective, Single Institute, Propensity Score-Matched Study

Study Design: Retrospective study. Objective: To compare the clinical efficacy of posterior lumbar laminectomy decompression under full endoscopic technique (Endo-LOVE) and percutaneous endoscopic medial foraminal decompression (PE-MFD) in the treatment of degenerative lumbar spinal stenosis (DLSS). Methods: Between April 2017 and April 2018, 96 patients with DLSS underwent Endo-LOVE or PE-MFD, including 58 with Endo-LOVE and 38 with PE-MFD. After propensity score matching (PSM), patient characteristics, operation time, intraoperative fluoroscopy times, postoperative bedridden time, hospital stay and postoperative complications were recorded and compared. The clinical efficacy was evaluated according to Oswestry disability index (ODI), visual analogue scale (VAS), lumbar disease JOA and modified MacNab criteria. Results: A total of 96 patients with DLSS were included in the study. After PSM, the 2 groups were comparable in patient demographic and baseline characteristics. The operation time and intraoperative fluoroscopy times in PE-MFD group were significantly more than those in Endo-LOVE group (P < .05). The operation time in PE-MFD group was significantly less than that in Endo-LOVE group (P < .05). The intraoperative fluoroscopy times in PE-MFD group were significantly more than that in Endo-LOVE group (P < .05). The ODI, VAS and lumbar disease JOA in the 2 groups were significantly improved comparing with those before operation (P < .05). According to the modified MacNab criteria, the excellent and good rates of the 2 groups were 93.5% in Endo-LOVE group and 87.1% in PE-MFD group (P > .05). Conclusion: Endo-LOVE and PE-MFD technique can both effectively treat DLSS, and the short-term follow-up results are positive. Endo-LOVE technique has the advantages of fast puncture positioning, less radiation exposure and wider indications. However, PE-MFD needs more radiation exposure and has the possibility of incomplete decompression for complex multiplanar spinal stenosis.
Comparison of tissue pharmacokinetics of esflurbiprofen plaster with flurbiprofen tablets in patients with knee osteoarthritis: A multicenter randomized controlled trial

This open‐label, multicenter, prospective, randomized controlled trial aimed to determine the effectiveness of esflurbiprofen plaster (SFPP) and flurbiprofen tablets (FPTs) on knee osteoarthritis in patients scheduled for total knee arthroplasty by comparing the transfer of esflurbiprofen and flurbiprofen to tissues and fluids. Thirty‐eight patients were randomly assigned in a 1:1 ratio to receive SFPP or FPT. Both groups were then divided into four subgroups, according to whether they received the final dose of SFPP or FPT at 2, 7, 12, or 24 h before planned surgery. The primary endpoints were the esflurbiprofen concentrations in synovium, synovial fluid, and plasma. Areas under concentration–time curves (AUC0–24 h) of esflurbiprofen were calculated for each group. Pain was assessed using a numeric rating scale (NRS) 7 days before and immediately before surgery. The AUC0–24 h in the synovium were 4401.24 and 4862.70 ng·h/g in the SFPP and FPT groups, respectively. Maximum esflurbiprofen concentrations were observed in the synovium, synovial fluids, and plasma after SFPP application for 12 h. The NRS results indicated a long‐lasting effect of SFPP. The AUC of the synovial esflurbiprofen concentration of SFPP indicated that the SFPP is transferred to the synovium and synovial fluid in high concentration. The efficient deep‐tissue transfer of esflurbiprofen suggests that its pharmacokinetic characteristics differ from those of conventional topical NSAIDs. This study was prospectively registered in the Japan Registry of Clinical Trials (registration number: jRCTs031180228).