Photoplethysmography has been routinely used for health monitoring in the past decades. Even though in daily medical practice, photoplethysmograms (PPGs) are recorded at red and near infra-red light ...(rPPGs), during the last decade, PPGs obtained at green light (gPPGs) have been widely used in wearable devices, such as wristbands and smartwatches, thus providing highly usable and accessible daily health monitoring. It is well recognized that PPG signals obtained at NIR light contain sufficient information about a person's health; furthermore, they are well-studied and highly complex. By contrast, green light PPGs have not been sufficiently studied; thus, it is not clear whether the provided information is as valuable as that obtained by rPPGs, as green light photoplethysmography is formed at papillary dermis and higher skin levels. However, the gPPG signal is recognized to be more robust to motion artifacts compared with rPPGs. As rPPG dynamics has been recognized as chaotic, this study is aimed at investigating the properties of gPPGs and compare them with those of rPPGs to determine whether gPPG dynamics is chaotic as well. The motivation for this question was not only to investigate whether gPPGs can be used for the same range of applications as rPPGs but also to obtain insight into whether the complexity of rPPGs is solely due to processes in deeper layers of the tissue or it is influenced by the higher-skin layers processes that create gPPGs. The obtained results demonstrated that gPPGs, as well as rPPGs, are chaotic, which implies that processes in the upper layers create chaos in PPG data, whereas the contribution of arterial blood volume changes is not completely clear.
AADC deficiency causes severe motor and intellectual disability as a result of reduced catecholamine levels. Kojima et al. report beneficial effects of gene therapy in six patients with heterogeneous ...genetic backgrounds. Gene delivery into putamen improved motor function in all patients, plus verbal and cognitive skills in one moderate-phenotype patient.
Abstract
In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-18Ffluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.
10.1093/brain/awy331_video1
awy331media1
5991361892001
LY294002 and wortmannin are chemical compounds that act as potent inhibitors of phosphoinositide 3-kinases (PI3Ks). Both of them are generally used to inhibit cell proliferation as cancer treatment ...by inhibiting the PI3K/protein kinase B (AKT) signaling pathway. In this study, LY294002 (but not wortmannin) showed an abnormal ability to enhance AKT phosphorylation (at Ser472) specifically in gemcitabine (GEM)-resistant pancreatic cancer (PC) cell lines PK59 and KLM1-R. LY294002 was shown to activate AKT and accumulate phospho-AKT at the intracellular membrane in PK59, which was abolished by treatment with AKTi-1/2 or wortmannin. Inhibiting AKT phosphorylation by treatment with AKTi-1/2 or wortmannin further enhanced LY294002-induced cell death in PK59 and KLM1-R cells. In addition, treatment with wortmannin alone failed to inhibit cell proliferation in both PK59 and KLM1-R cells. Thus, our results reveal that LY294002 displays the opposite effect on PI3K-dependent AKT phosphorylation, which maintains cell survival from the cytotoxicity introduced by LY294002 itself in GEM-resistant pancreatic cancer cells. We suggest that targeting the PI3K/AKT signaling pathway with inhibitors may be counterproductive for patients with PC who have acquired GEM-resistance.
Abstract
High-speed atomic force microscopy (HS-AFM) is a scanning probe microscopy that can capture structural dynamics of biomolecules in real time at single molecule level near physiological ...condition. Albeit much improvement, while scanning one frame of HS-AFM movies, biomolecules often change their conformations largely. Thus, the obtained frame images can be hampered by the time-difference, the asynchronicity, in the data acquisition. Here, to resolve this data asynchronicity in the HS-AFM movie, we developed Kalman filter and smoother methods, some of the sequential Bayesian filtering approaches. The Kalman filter/smoother methods use alternative steps of a short time-propagation by a linear dynamical system and a correction by the likelihood of AFM data acquired pixel by pixel. We first tested the method using a toy model of a diffusing cone, showing that the Kalman smoother method outperforms to reproduce the ground-truth movie. We then applied the Kalman smoother to a synthetic movie for conformational change dynamics of a motor protein, i.e., dynein, confirming the superiority of the Kalman smoother. Finally, we applied the Kalman smoother to two real HS-AFM movies, FlhA
C
and centralspindlin, reducing distortion and noise in the AFM movies. The method is general and can be applied to any HS-AFM movies.
Summary
Purpose
KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the ...clinical spectrum of EOEE associated with KCNQ2 mutation.
Methods
A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high‐resolution melting (HRM) analysis or whole‐exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation.
Key Findings
A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression‐burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate‐to‐profound intellectual disability was found in all except one patient who died at 3 months.
Significance
De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression‐burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.
Previous studies have unravelled glycolytic oscillations in cancer cells, such as HeLa cervical and DU145 prostate cancer cells, using a monolayer culture system. Here, we demonstrate glycolytic ...oscillations in HeLa cervical cancer cell spheroids. Experiments revealed that a small number of HeLa cells in spheroids exhibited heterogeneous oscillations with a higher frequency than those in monolayers. Model analyses and our previous experiments indicated that the higher frequencies of oscillations in spheroids were mostly due to the increase in glycolytic enzyme activity in the cells, and to the decrease in glucose concentration by diffusional transport of glucose from the surface to inside the spheroids, as well as the increase in cell density through spheroid formation. These results and our previous studies imply that more malignant cancer cells tend to exhibit glycolytic oscillations with higher frequencies than less malignant cells. Adjacent cells in spheroids oscillated within a 10% difference in frequency, but did not synchronize with each other. This suggests that weak cell‐to‐cell interactions might exist among HeLa cells connected with cadherins in the spheroid microenvironment; however, the interactions were not strong enough to induce synchronization of glycolytic oscillations.
Glycolytic oscillations are demonstrated in HeLa cervical cancer cell spheroids. Spheroids are often used to model the in vivo microenvironment of tumours. The properties of spheroids, in particular their metabolic properties, including glycolysis, are reported to be different from those in monolayer cells. The present experimental and mathematical studies revealed the quantitative glycolytic dynamics of HeLa spheroids, which could shed light on the pathophysiological characteristics of cancer.
We propose an empirical procedure for verifying the factor price equalization (FPE) condition. The FPE condition defined by Deardorff (J Int Econ 36:167–175,
1994
) is converted to a standard linear ...programming problem. Although the procedure does not provide a graphical representation, it can be applied for any number of primary factors of production. In addition, based on the solution vector of the linear programming problem, we can find what quantities of the primary factors of production should be reallocated between which regions to satisfy the FPE condition when the condition does not hold.
Lung, gastric, colorectal, pancreatic, and esophageal cancers, as well as hepatocellular carcinoma (HCC), were the six most common and highly fatal cancers for Japanese men in Japan in 2003, while ...for women uterine cervical cancer could also be added to this list. To identify diagnostic or therapeutic biomarkers for these cancers, investigators are nowadays performing proteomic analyses of cancer tissues and cells, and revealing a large number of molecules which are diagnostic, prognostic and informative of carcinogenesis. From reports of proteomic analyses of cancerous tissues and noncancerous tissues sampled from HCC, and pancreatic, esophageal, gastric, colorectal, lung and uterine cervical cancers, we classified the proteins into digestive enzymes, growth factors, cell adhesion molecules, calcium‐binding proteins, proteases, protease inhibitors, transporter proteins, structural molecules, apoptosis inhibitor, molecular chaperone, as well as proteins related to cell growth, cell differentiation, cell transformation, tumor invasion, carcinogen metabolism, and others. The aim of this study was to understand carcinogenesis of major cancers from a proteomics perspective using samples from cancer patients, and to elucidate their tumor biomarkers.
In a factory production line, if abnormal signals can be automatically detected from time-series fluctuations in power consumption, the defect rate of products can be reduced, and productivity can be ...improved. Individual period estimation is often needed to detect the abnormals because deviations from the mean period provide valuable information about the failures and the abnormals. This study proposes an online system that estimates individual cycles and detects anomalies from quasi-periodic time series data represented by energy consumption data. The proposed system extracts local patterns by convolution and identifies individual cycles and abnormal signals based on similarity vectors calculated by an attention mechanism. Experimental results show that the proposed system outperforms existing methods on several simulated data sets.
Abstract Slingshot-1L (SSH1L), a cofilin-phosphatase, plays a role in actin dynamics and cell migration by reactivating cofilin-1. However, the expression of SSH1L in malignant diseases is poorly ...understood. The overexpression of SSH1L in cancerous tissue compared to the matched surrounding non-cancerous tissues from patients with late stages (III–IV) of PC was detected in 90% (9/10) of cases by western blotting. The expression of SSH1L was shown to be upregulated in tumor cells from 10.7% (11/102) of patients with pancreatic cancer (PC) by immunohistochemistry (IHC). The positive rate of SSH1L in patients with PC at stage VI (TNM) categorized as grade 3 was of 50% (2/4) and 15% (6/40), respectively. Moreover, SSH1L expression was shown to be up-regulated in the PC cell lines (KLM1, PANC-1 and MIAPaCa-2) with high metastatic potential. Loss of SSH1L expression was associated with an increase in the phosphorylation of cofilin-1 at serine-3 and further inhibited cell migration (but not proliferation) in KLM1, PANC-1 and MIAPaCa-2. Actin polymerization inhibitor cytochalasin-D was sufficient to abrogate cell migration of PC without changing SSH1L expression. These results reveal that SSH1L is upregulated in a subset of PCs and that the SSH1L/cofilin-1 signal pathway is associated positively in PC with cell migration. Our study may thus provide potential targets to prevent and/or treat PC invasion and metastasis in patients with SSH1L-positive PC.
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