PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease.

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.

Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Trends of antimicrobial susceptibilities and multidrug-resistant colonization rate in patients transferred from long-term care facilities during 2017-2022: a cross-sectional study.

BACKGROUND: With the global increase in the older population, the proportion of those receiving care in long-term care facilities (LTCFs) has also been increasing. We assessed the epidemiology, antibiotic susceptibility, and colonization status of drug-resistant organisms in patients transferred from LTCFs. METHODS: We retrospectively reviewed the medical records of patients transferred from LTCFs between 2017 and 2022. The reasons for admission, antimicrobial susceptibility, and colonization rates of carbapenem-resistant Enterobacterales (CRE), methicillin-resistant Staphylococcus aureus (MRSA), and carbapenem-resistant Acinetobacter baumannii (CRAB) were recorded. We analyzed the susceptibility and colonization rates by year to identify trends. RESULTS: Of the 936 patients transferred from LTCFs, 54.3% were admitted to the intensive care unit and 12.5% died. The most common reason for admission was infection (n = 573, 61.2%), followed by gastrointestinal bleeding (n = 67, 7.2%) and cerebrovascular disorder (n = 65, 6.9%). A total of 452 Enterobacterales strains were isolated, and their susceptibility rates to ciprofloxacin and cefotaxime were 33.3% and 35.6%, respectively. A total of 54.9% were extended-spectrum beta-lactamase-producing strains, and 4.9% of them were carbapenem-resistant, both of which showed an increasing trend (P = 0.024 and P < 0.001, respectively). The prevalence rates of CRE, CRAB, and MRSA colonization were 9.2%, 7.1%, and 23.1%, respectively. CRE colonization showed a significant increase (P < 0.001), with carbapenemase-producing Enterobacterales accounting for 75.9% of cases. CONCLUSIONS: Patients transferred from LTCFs are primarily affected by infections and exhibit high resistance rates. The increasing trend in CRE colonization rates each year highlights the need for the implementation of rigorous infection control measures for effective management.

Dapagliflozin Does Not Protect against Adriamycin-Induced Kidney Injury in Mice.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice. METHODS: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg. RESULTS: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interestingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex. CONCLUSION: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms.

Assessment of oral hypofunction and its association with age among Korean community-dwelling older adults.

BACKGROUND: Due to the increasing proportion of older adults in Korea and growing interest in aging, the concepts of oral aging and oral hypofunction have recently been introduced. Thus, it is necessary to investigate the age-specific oral function levels of Korean older adults and develop expert intervention methods for healthy aging. METHODS: Dysphagia, independence of daily living, and oral hypofunction were assessed in 206 older adults living in Wonju, Gangwon State, South Korea. Subjective dysphagia was assessed through self-report questionnaires using the Dysphagia Handicap Index (DHI), the Korean version of Eating Assessment Tool-10, and the Korean version of the Modified Barthel Index. In addition, the oral hypofunction assessment items included decreased chewing ability, occlusal pressure, tongue pressure, oral dryness, and oral cleanliness. RESULTS: DHI increased significantly with age, with those in their 80 s reporting the most difficulty swallowing. Oral function in terms of chewing ability (maximum occlusal pressure and number of remaining teeth), maximum occlusal pressure, and maximum tongue pressure also declined with increasing age. While there was no significant difference in oral dryness by age, those in their 80 s had dry mouth according to the criteria of the oral moisture checking device. CONCLUSIONS: In an assessment of oral function in community-dwelling, independent Korean older adults, the number of items that were assessed as oral hypofunction increased with age. The findings can be used to standardize the oral hypofunction assessment item and develop age-based individualized intervention plans for the early management of oral health and individual oral myofunctional rehabilitation in Korean community-dwelling older adults.

Bacterial neurotoxic metabolites in multiple sclerosis cerebrospinal fluid and plasma.

The identification of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication, and yet the question regarding the identity of the components responsible for this cross-talk remains open. We previously reported that relapsing remitting multiple sclerosis patients treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and CSF samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identified the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate-treated relapsing remitting multiple sclerosis patients. The levels of the identified metabolites of bacterial origin (p-cresol sulphate, indoxyl sulphate and N-phenylacetylglutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neurofilament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.

Clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea.

BACKGROUND: Invasive fusariosis mainly affects immunocompromised patients including haematopoietic stem cell transplant recipients and those with haematologic malignancy. There are limited studies on invasive fusariosis in the Asia-Pacific region. OBJECTIVE: To describe the clinical characteristics and outcomes of invasive and non-invasive fusariosis in South Korea. PATIENTS/METHODS: From 2005 to 2020, patients with fusariosis who met the revised European Organisation for Research and Treatment of Cancer and the Mycoses Study Group criteria for the definition of proven or probable invasive fusariosis, and those with non-invasive fusariosis were retrospectively reviewed in a tertiary medical centre in Seoul, South Korea. RESULTS: Overall, 26 and 75 patients had invasive and non-invasive fusariosis, respectively. Patients with invasive fusariosis commonly had haematologic malignancy (62%), were solid organ transplant recipients (23%), and had a history of immunosuppressant usage (81%). In non-invasive fusariosis, diabetes mellitus (27%) and solid cancer (20%) were common underlying conditions. Disseminated fusariosis (54%) and invasive pulmonary disease (23%) were the most common clinical manifestations of invasive fusariosis; skin infection (48%) and keratitis (27%) were the most common manifestations of non-invasive fusariosis. Twenty-eight-day and in-hospital mortalities were high in invasive fusariosis (40% and 52%, respectively). In multivariate analysis, invasive fusariosis (adjusted odds ratio, 9.6; 95% confidence interval 1.3-70.8; p = .03) was an independent risk factor for 28-day mortality. CONCLUSIONS: Patients with invasive fusariosis were frequently immunocompromised, and more than half had disseminated fusariosis. Invasive fusariosis was associated with poor prognosis.

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA.

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson's disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5' untranslated region (5' UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5' UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound's selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

Feasibility of facial nerve monitoring using adhesive surface electrodes during parotidectomy: a comparative study with needle electrodes.

PURPOSE: Electrophysiological monitoring of the facial nerve during parotidectomy has been reported as an adjunctive method to prevent facial nerve injury. Classically, a needle electrode is used to obtain electromyographic (EMG) signals from facial muscles during facial nerve monitoring (FNM) of parotid surgery, likewise adhesive surface electrodes. This study aimed to investigate the feasibility of performing FNM with surface electrodes during parotid surgery and to compare EMG values with needle electrodes. METHODS: Thirty patients who underwent parotidectomy under FNM using adhesive surface and needle electrodes were included. Two pairs of adhesive surface electrodes and needle electrodes were used for FNM during parotid surgery. Mean amplitudes were collected after electrical facial nerve stimulation at 1 mA after specimen removal. RESULTS: The mean amplitude of the adhesive surface electrodes was 226.50 ± 118.44 µV (orbicularis oculi muscle) and 469.6 ± 306.06 µV (orbicularis oris muscle), respectively. The mean amplitude of the needle electrodes was 449.85 ± 248.10 µV (orbicularis oculi muscle) and 654.66 ± 395.71 µV (orbicularis oris muscle), respectively. The mean amplitude of the orbicularis oris muscle was significantly greater than that of the orbicularis oculi. The amplitude values measured in the orbicularis oculi muscle showed significant differences between the needle and skin electrodes. CONCLUSIONS: Facial nerve monitoring (FNM) using adhesive surface electrodes is feasible in parotid surgery. Although the mean amplitude value of the surface electrode was relatively lower than that of the needle electrode, the surface electrode is considered a feasible and safe EMG recording device for FNM in parotid surgery.

ssFPN: Scale Sequence (S2) Feature-Based Feature Pyramid Network for Object Detection.

Object detection is a fundamental task in computer vision. Over the past several years, convolutional neural network (CNN)-based object detection models have significantly improved detection accuracyin terms of average precision (AP). Furthermore, feature pyramid networks (FPNs) are essential modules for object detection models to consider various object scales. However, the AP for small objects is lower than the AP for medium and large objects. It is difficult to recognize small objects because they do not have sufficient information, and information is lost in deeper CNN layers. This paper proposes a new FPN model named ssFPN (scale sequence (S2) feature-based feature pyramid network) to detect multi-scale objects, especially small objects. We propose a new scale sequence (S2) feature that is extracted by 3D convolution on the level of the FPN. It is defined and extracted from the FPN to strengthen the information on small objects based on scale-space theory. Motivated by this theory, the FPN is regarded as a scale space and extracts a scale sequence (S2) feature by three-dimensional convolution on the level axis of the FPN. The defined feature is basically scale-invariant and is built on a high-resolution pyramid feature map for small objects. Additionally, the deigned S2 feature can be extended to most object detection models based on FPNs. We also designed a feature-level super-resolution approach to show the efficiency of the scale sequence (S2) feature. We verified that the scale sequence (S2) feature could improve the classification accuracy for low-resolution images by training a feature-level super-resolution model. To demonstrate the effect of the scale sequence (S2) feature, experiments on the scale sequence (S2) feature built-in object detection approach including both one-stage and two-stage models were conducted on the MS COCO dataset. For the two-stage object detection models Faster R-CNN and Mask R-CNN with the S2 feature, AP improvements of up to 1.6% and 1.4%, respectively, were achieved. Additionally, the APS of each model was improved by 1.2% and 1.1%, respectively. Furthermore, the one-stage object detection models in the YOLO series were improved. For YOLOv4-P5, YOLOv4-P6, YOLOR-P6, YOLOR-W6, and YOLOR-D6 with the S2 feature, 0.9%, 0.5%, 0.5%, 0.1%, and 0.1% AP improvements were observed. For small object detection, the APS increased by 1.1%, 1.1%, 0.9%, 0.4%, and 0.1%, respectively. Experiments using the feature-level super-resolution approach with the proposed scale sequence (S2) feature were conducted on the CIFAR-100 dataset. By training the feature-level super-resolution model, we verified that ResNet-101 with the S2 feature trained on LR images achieved a 55.2% classification accuracy, which was 1.6% higher than for ResNet-101 trained on HR images.

Discourse about higher education on Twitter in early phases of COVID-19: A crisis management social network analysis.

The emergence of the COVID-19 pandemic brought changes and efforts for adaption to the new environment in every industry, including higher education. The present study, drawing on crisis management theory as a framework, aimed to understand information and communication sharing behaviors of the higher education community during the pandemic by exploring patterns and discourse on social media. Such analysis provides insight into how information is gained, shared, and used. Tweets including the hashtag #highered were retrieved at five time points in March and August 2020-M1 (retrieved on March 3), M2 (March 17), A1 (August 4), A2 (August 11), and A3 (August 18). Using a social network analysis tool, NodeXL, the collected tweets were analyzed by social network structure, topic, and influencer. Results showed that #highered was used widely in the early stages of the pandemic. The relevant conversation rapidly evolved, as did the prominent influencers. Over time, the conversation centered on the pandemic, the implications of the sudden shift to online learning, and then the subsequent effect on universities, students, faculty, and staff. A crisis preparation phase continued through August 2020, but drivers of information transitioned from well-known news outlets prior to the pandemic to individuals directly experiencing the pandemic. Future research should analyze the validity of information shared by individuals during key decision points of the pandemic and whether higher education is susceptible to the growing spread of disinformation through social media when formulating policy. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-023-11590-2.

Seroprevalence and Risk Factors for Severe Acute Respiratory Syndrome Coronavirus 2 Among Incarcerated Adult Men in Quebec, Canada, 2021.

BACKGROUND: People in prison are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We examined the seroprevalence of SARS-CoV-2 and associated carceral risk factors among incarcerated adult men in Quebec, Canada. METHODS: We conducted a cross-sectional seroprevalence study in 2021 across 3 provincial prisons, representing 45% of Quebec's incarcerated male provincial population. The primary outcome was SARS-CoV-2 antibody seropositivity (Roche Elecsys serology test). Participants completed self-administered questionnaires on sociodemographic, clinical, and carceral characteristics. The association of carceral variables with SARS-CoV-2 seropositivity was examined using Poisson regression models with robust standard errors. Crude and adjusted prevalence ratios (aPR) with 95% confidence intervals (95% CIs) were calculated. RESULTS: Between 19 January 2021 and 15 September 2021, 246 of 1100 (22%) recruited individuals tested positive across 3 prisons (range, 15%-27%). Seropositivity increased with time spent in prison since March 2020 (aPR, 2.17; 95% CI, 1.53-3.07 for "all" vs "little time"), employment during incarceration (aPR, 1.64; 95% CI, 1.28-2.11 vs not), shared meal consumption during incarceration ("with cellmates": aPR, 1.46; 95% CI, 1.08-1.97 vs "alone"; "with sector": aPR, 1.34; 95% CI, 1.03-1.74 vs "alone"), and incarceration post-prison outbreak (aPR, 2.32; 95% CI, 1.69-3.18 vs "pre-outbreak"). CONCLUSIONS: The seroprevalence of SARS-CoV-2 among incarcerated individuals was high and varied among prisons. Several carceral factors were associated with seropositivity, underscoring the importance of decarceration and occupational safety measures, individual meal consumption, and enhanced infection prevention and control measures including vaccination during incarceration.

Assessment of optimal renin-angiotensin-system inhibition strategy in Asian patients with STEMI after primary myocardial revascularization.

BACKGROUND: For the Asian patients with STEMI undergoing PCI, ACEIs are known to have a better outcome than ARBs. However, there is limited evidence to suggest so. METHODS: Among the STEMI registry consist of 1142 Korean patients, we compared the MACE, the composite of myocardial infarction, stoke, death, admission for heart failure, and target vessel revascularization, between the ACEI and ARB groups (Set 1). Further, we defined adequate medication as the administration of a dose equal to or higher than the initiation dose of ACEI according to the heart failure guideline recommendation with a mandatory addition of beta-blockers, and compared the outcomes between the inadequate and adequate medication groups (Set 2). Propensity score matching was used to eliminate difference. RESULTS: In the Set 1 comparison, patients in the ACEI group had a better outcome than those in the ARB group for both whole and matched populations (whole and matched population: Cox regression hazard ratio [HR], 0.645 and 0.535; 95% confidence interval [CI], 0.440-0.944 and 0.296-0.967; p = 0.024 and p = 0.039, respectively). In the Set 2 comparison for the whole population, patients in the inadequate medication group had more MACE than those in the adequate medication group (HR, 0.673; 95% CI, 0.459-0.985; p = 0.042). However, no difference was observed after propensity score matching (HR, 1.023; 95% CI, 0.654-1.602; p = 0.919). CONCLUSION: ACEIs might be a better choice than ARBs after primary revascularization. However, this study's findings suggest that early ACEI dose escalation combined with beta-blocker use may not improve prognosis.

Design, synthesis and evaluation of 15N- and 13C-labeled molecular probes as hyperpolarized nitric oxide sensors.

Nitric oxide (NO) is an important signaling molecule involved in a wide range of biological processes. Development of non-invasive, real-time detection of NO is greatly desired yet remains challenging. Here we report the design and development of novel 15N- and 13C-labeled NO-sensing probes for hyperpolarized nuclear magnetic resonance (HP-NMR) studies. These probes undergo selective and rapid reaction with NO to generate in situ AZO-products that can be monitored with distinguishable NMR signals as a read-out. This study also allows for a direct comparison of the 15N and 13C nuclei performances in hyperpolarized reaction-based probes. The simple and general SABRE-SHEATH hyperpolarization method works on the 15N- and 13C-NO-sensing probes. Measured long spin-lattice relaxation (T1) values, especially for 15N-NO probes, will allow for real-time reaction-based imaging of NO.

Hippocampal Functional Connectivity in Parkinson's Disease.

BACKGROUND: While the hippocampus is not part of the nigrostriatal dopaminergic pathway, influence of Parkinson's disease (PD) on the hippocampus has been consistently implicated. However, it is not clear how the hippocampal changes contribute to the pathology of PD. OBJECTIVES: We aimed to elucidate the physiological changes of the hippocampus in its orchestration with the rest of the brain. METHODS: Using the resting-state fMRI data from Parkinson's Progression Markers Initiative (PPMI), functional connectivity of the hippocampus was analyzed in 93 individuals with PD and 18 individuals without PD. RESULTS: A whole brain voxel-wise analysis showed that the bilateral paracingulate gyri were less connected to the hippocampus in the PD group compared to the control group. The hippocampus-paracingulate dysconnectivity did not show association with cognitive indices. CONCLUSIONS: The hippocampus in PD shows dysconnectivity to the paracingulate gyri.

Patulous eustachian tube after balloon eustachian tuboplasty in a post-radiation patient.

BACKGROUND: Balloon eustachian tuboplasty (BET) is a minimally invasive surgical treatment that is effective and safe for obstructive eustachian tube dysfunction. However, BET complications include excessive widening of the eustachian tube, causing a patulous eustachian tube (PET). Herein, we report a case of PET following BET in a patient who underwent radiation therapy and reviewed the literature on considerations for reducing complications after BET. CASE PRESENTATION: A 63-year-old woman complained of bilateral ear fullness after concurrent chemoradiation therapy for nasopharyngeal lymphoma. BET was performed on the left side because the left-sided serous otitis media persisted. A left-sided PET was performed two weeks after the BET, along with eustachian tube silicone plug insertion on the left side. The patient became asymptomatic immediately after the surgery, with no recurrence reported after a 12-month follow-up period. CONCLUSIONS: To our knowledge, there has been no report of PET following BET in a post-radiation patient, and it was successfully treated via ET silicone plug insertion.

Carrying Position-Independent Ensemble Machine Learning Step-Counting Algorithm for Smartphones.

Current step-count estimation techniques use either an accelerometer or gyroscope sensors to calculate the number of steps. However, because of smartphones unfixed placement and direction, their accuracy is insufficient. It is necessary to consider the impact of the carrying position on the accuracy of the pedometer algorithm, because of people carry their smartphones in various positions. Therefore, this study proposes a carrying-position independent ensemble step-counting algorithm suitable for unconstrained smartphones in different carrying positions. The proposed ensemble algorithm comprises a classification algorithm that identifies the carrying position of the smartphone, and a regression algorithm that considers the identified carrying position and calculates the number of steps. Furthermore, a data acquisition system that collects (i) label data in the form of the number of steps estimated from the Force Sensitive Resistor (FSR) sensors, and (ii) input data in the form of the three-axis acceleration data obtained from the smartphones is also proposed. The obtained data were used to allow the machine learning algorithms to fit the signal features of the different carrying positions. The reliability of the proposed ensemble algorithms, comprising a random forest classifier and a regression model, was comparatively evaluated with a commercial pedometer application. The results indicated that the proposed ensemble algorithm provides higher accuracy, ranging from 98.1% to 98.8%, at self-paced walking speed than the commercial pedometer application, and the machine learning-based ensemble algorithms can effectively and accurately predict step counts under different smart phone carrying positions.

Current Uses of Mushrooms in Cancer Treatment and Their Anticancer Mechanisms.

Cancer is the leading cause of mortality worldwide. Various chemotherapeutic drugs have been extensively used for cancer treatment. However, current anticancer drugs cause severe side effects and induce resistance. Therefore, the development of novel and effective anticancer agents with minimal or no side effects is important. Notably, natural compounds have been highlighted as anticancer drugs. Among them, many researchers have focused on mushrooms that have biological activities, including antitumor activity. The aim of this review is to discuss the anticancer potential of different mushrooms and the underlying molecular mechanisms. We provide information regarding the current clinical status and possible modes of molecular actions of various mushrooms and mushroom-derived compounds. This review will help researchers and clinicians in designing evidence-based preclinical and clinical studies to test the anticancer potential of mushrooms and their active compounds in different types of cancers.

Dopamine is an aryl hydrocarbon receptor agonist.

Tryptophan metabolites exhibit aryl hydrocarbon receptor (AhR) agonist activity and recent studies show that the phenylalanine metabolites serotonin and carbidopa, a drug used in treating Parkinson's disease, activated the AhR. In this study, we identified the neuroactive hormone dopamine as an inducer of drug-metabolizing enzymes CYP1A1, CYP1B1, and UGT1A1 in colon and glioblastoma cells and similar results were observed for carbidopa. In contrast, carbidopa but not dopamine exhibited AhR activity in BxPC3 pancreatic cancer cells whereas minimal activity was observed for both compounds in Panc1 pancreatic cancer cells. In contrast with a previous report, the induction responses and cytotoxicity of carbidopa was observed only at high concentrations (100 µM) in BxPC3 cells. Our results show that similar to serotonin and several tryptophan metabolites, dopamine is also an AhR-active compound.

Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB.

Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (SynTg) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in SynTg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.