Keystroke Biometrics as a Tool for the Early Diagnosis and Clinical Assessment of Parkinson's Disease.

(1) Background: Parkinson's disease (PD) is the second most common neurodegenerative disease. Early diagnosis and reliable clinical assessments are essential for appropriate therapy and improving patients' quality of life. Keystroke biometrics, which capture unique typing behavior, have shown potential for early PD diagnosis. This study aimed to evaluate keystroke biometric parameters from two datasets to identify indicators that can effectively distinguish de novo PD patients from healthy controls. (2) Methods: Data from natural typing tasks in Physionet were analyzed to estimate keystroke biometric parameters. The parameters investigated included alternating-finger tapping (afTap) and standard deviations of interkey latencies (ILSD) and release latencies (RLSD). Sensitivity rates were calculated to assess the discriminatory ability of these parameters. (3) Results: Significant differences were observed in three parameters, namely afTap, ILSD, and RLSD, between de novo PD patients and healthy controls. The sensitivity rates were high, with values of 83%, 88%, and 96% for afTap, ILSD, and RLSD, respectively. Correlation analysis revealed a significantly negative correlation between typing speed and number of words typed with the standard motor assessment for PD, UPDRS-III, in patients with early PD. (4) Conclusions: Simple algorithms utilizing keystroke biometric parameters can serve as effective screening tests in distinguishing de novo PD patients from healthy controls. Moreover, typing speed and number of words typed were identified as reliable tools for assessing clinical statuses in PD patients. These findings underscore the potential of keystroke biometrics for early PD diagnosis and clinical severity assessment.

Piperic acid derivative as a molecular modulator to accelerate the IAPP aggregation process and alter its antimicrobial activity.

Piperic acid derivatives were found to affect the islet amyloid polypeptide (IAPP) aggregation process. Structure-activity relationship studies revealed that PAD-13 was an efficient molecular modulator to accelerate IAPP fibril formation by promoting primary and secondary nucleation and reducing its antimicrobial activity.

Molecular Engineering to Boost the Photo-Oxidase Activity of Molecular Rotors in Colorimetric Sensing of Temperatures.

Some organic dyes and photosensitizers with strong visible absorption can behave as photo-responsive oxidase mimics. However, the relationship between the photo-oxidase activity and molecular structure remains unclear to date. In this work, a new type of photosensitizer with the characteristics of molecular rotors, namely DPPy, served as the molecular scaffold for further investigation. To adjust the photocatalytic oxidation ability, DAPy and CBPy were designed and synthesized based on the enhancement and diminishment of the intramolecular charge transfer (ICT) process, respectively. Kinetic studies revealed that DAPy and CBPy both exhibited highly efficient photo-activated oxidase-like activity with 3,3',5,5'-tetramethylbenzidine (TMB) as the substrate, which were in good accordance with their molecular engineering to promote either type I or type II reactive oxygen species (ROS) generation. Impressively a colorimetric method based on the visible light induced oxidase-like activity of molecular rotors was developed to determine the environmental temperature for the first time. Both DAPy and CBPy showed distinct sensitivities toward temperature as compared with several molecular rotors based on the typical fluorimetric detection. This work provides a new strategy for the application of molecular rotors to overcome the non-emissive challenge in temperature sensing.

Noncovalent Association Thermodynamics of Turn-On Fluorescent Probes with Human Serum Albumin: Dual-Concentration Ratio Method.

Efficient quantification of the affinity of a drug and the targeted protein is critical for strategic drug design. Among the various molecules, turn-on fluorescent probes are the most promising signal transducers to reveal the binding strength and site-specificity of designed drugs. However, the conventional method of measuring the binding ability of turn-on fluorescent probes by using the fractional occupancy under the law of mass action is time-consuming and a massive sample is required. Here, we report a new method, called dual-concentration ratio method, for quantifying the binding affinity of fluorescent probes and human serum albumin (HSA). Temperature-dependent fluorescence intensity ratios of a one-to-one complex (L ⋅ HSA) for a turn-on fluorescent probe (L), e. g., ThT (thioflavin T) or DG (dansylglycine), with HSA at two different values of [L]0 /[HSA]0 under the constraint [HSA]0 >[L]0 were collected. The van't Hoff analysis on these association constants further resulted in the thermodynamic properties. Since only two samples at different [L]0 /[HSA]0 are required without the need of [L]0 /[HSA]0 at a wide range, the dual-concentration ratio method is an easy way to greatly reduce the amounts of fluorescent probes and proteins, as well as the acquisition time.

Enantioselective Nickel-Catalyzed Reductive anti-Arylative Annulation of Alkyne-Tethered Malononitriles to Construct Quaternary Stereocenters.

A nickel-catalyzed reductive desymmetrizing annulation of alkyne-tethered malononitriles and (hetero)aryl iodides is reported for the access of cyclohexenones containing an α-all-carbon quaternary stereocenter. The use of a nickel catalyst derived from an electron-rich phosphinooxazoline ligand combined with iron powder as a reductant is crucial to the success of this transformation.

An environmentally sensitive molecular rotor as a NIR fluorescent probe for the detection of islet amyloid polypeptide.

The deposits of human islet amyloid polypeptide (IAPP), also called amylin, in the pancreas have been postulated to be a factor of pancreatic ß-cell dysfunction and is one of the common pathological hallmarks of type II diabetes mellitus (T2DM). Therefore, it is imperative to gain an in-depth understanding of the formation of these aggregates. In this study, we demonstrate a rationally-designed strategy of an environmentally sensitive near-infrared (NIR) molecular rotor utilizing thioflavin T (ThT) as a scaffold for IAPP deposits. We extended the π delocalized system not only to improve the viscosity sensitivity but also to prolong the emission wavelength to the NIR region. A naphthalene moiety was also introduced to adjust the sensitivity of our designed probes to differentiate the binding microenvironment polarity of different targeted proteins. As a result, a novel NIR fluorogenic probe toward IAPP aggregates, namely AmySP-4-Nap-Ene, was first developed. When attached to different protein aggregates, this probe exhibited distinct fluorescence emission profiles. In a comparison with ThT, the fluorescence emission of non-ionic AmySP-4-Nap-Ene exhibits a significant difference between the presence of non-fibrillar and fibrillar IAPP and displays a higher binding affinity toward IAPP fibrils. Further, the AmySP-4-Nap-Ene can be utilized to monitor IAPP accumulating process and image fibrils both in vitro and in living cells.

Highly flexible and superhydrophobic MOF nanosheet membrane for ultrafast alcohol-water separation.

High-performance pervaporation membranes have potential in industrial separation applications, but overcoming the permeability-selectivity trade-off is a challenge. We report a strategy to create highly flexible metal-organic framework nanosheet (MOF-NS) membranes with a faveolate structure on polymer substrates for alcohol-water separation. The controlled growth followed by a surface-coating method effectively produced flexible and defect-free superhydrophobic MOF-NS membranes. The reversible deformation of the flexible MOF-NS and the vertical interlamellar pathways were captured with electron microscopy. Molecular simulations confirmed the structure and revealed transport mechanism. The ultrafast transport channels in MOF-NS exhibited an ultrahigh flux and a separation factor of 8.9 in the pervaporation of 5 weight % ethanol-water at 40°C, which can be used for biofuel recovery. MOF-NS and polydimethylsiloxane synergistically contribute to the separation performance.

Surgical outcome of benign cases with pelvic adhesions undergoing robotic total hysterectomy.

BACKGROUND: Robotic total hysterectomies have been considered contraindicated for patients with intra-abdominal adherences, but the evidence for this is not strong, and we hypothesized that the procedure can be of benefit even in these cases. In our research, we analyzed how the severity of pelvic adhesions affects robotic total hysterectomy, and by comparing different types of adhesions, we can further identify the outcomes differences in between, which may aid in future surgical decision making. METHODS: Prospective cohort study (Canadian Task Force classification II-2). All 410 patients with uterine myoma or adenomyosis undergoing robotic total hysterectomies between 2011 and 2016 using the da Vinci Si system by the same surgeon in Taipei Medical University Hospital were included in the study. RESULTS: Baseline characteristics, blood loss, docking time, operation time, time to perform uterine artery ligation (UAL), pain score, hospital stay, complication rate, and laparotomy conversion rate were analyzed between benign cases with or without pelvic adhesions undergoing robotic total hysterectomy. Furthermore, in our subgroups analysis, we have divided the patients with adhesion into different groups according to the severity of adhesion. The abdomen and pelvic cavity was divided into nine sections, and the outcomes of different adhesion condition were compared. We found that patients with adhesions had increased docking time and operation time, but other differences between groups were not statistically significant. The results of the adhesion group showed no significant increases in blood loss, intra- and postoperative complications, and length of hospital stay. Only significantly longer surgical time compared with the normal group was noted. CONCLUSION: Our results suggest that robotic total hysterectomies with UAL are effective and safe for patients with benign gynecologic conditions, and the surgical method should be considered even for patients with adhesion risks.

Comparison of Survival Outcomes between Minimally Invasive Surgery and Open Radical Hysterectomy in Early-Stage Cervical Cancer.

OBJECTIVES: To compare the survival outcomes between minimally invasive surgery (MIS) and laparotomy radical hysterectomy in patients with early-stage cervical cancer. METHODS: We conducted a retrospective study involving women who received a radical hysterectomy for cervical cancer, stage IA1 with lymphovascular invasion, IA2, IB1, IB2, or IIA from 2008 to 2016. Clinicopathologic and perioperative outcomes were compared using appropriate statistical methodologies. RESULTS: Oncologic survival outcomes were analyzed using the Kaplan-Meier method. Among the 105 cases identified, 58 (55.2%) and 47 (44.8%) women underwent MIS and open radical hysterectomy, respectively. Over a median follow-up period of 62 months, women who underwent MIS and open radical hysterectomy had a 5-year overall survival rate of 87.9% and 89.4% (p = 0.845) and a 5-year disease-free survival rate of 82.5% and 86.7% (p = 0.624), respectively. CONCLUSIONS: For early-stage cervical cancer, patients who underwent MIS radical hysterectomy had survival outcomes that were comparable to those who underwent open surgery at our institute.

Novel Application of Multiscale Cross-Approximate Entropy for Assessing Early Changes in the Complexity between Systolic Blood Pressure and ECG R-R Intervals in Diabetic Rats.

Cardiac autonomic neuropathy (CAN) is a common complication of diabetes mellitus, and can be assessed using heart rate variability (HRV) and the correlations between systolic blood pressure (SBP) and ECG R-R intervals (RRIs), namely baroreflex sensitivity (BRS). In this study, we propose a novel parameter for the nonlinear association between SBP and RRIs based on multiscale cross-approximate entropy (MS-CXApEn). Sixteen male adult Wistar Kyoto rats were equally divided into two groups: streptozotocin-induced diabetes and age-matched controls. RRIs and SBP were acquired in control rats and the diabetic rats at the onset of hyperglycemia and insulin-treated euglycemia to determine HRV by the ratio of low-frequency to high-frequency power (LF/HF) and Poincaré plot as SSR (SD1/SD2), BRS, and MS-CXApEn. SSR and BRS were not significantly different among the three groups. The LF/HF was significantly higher in the hyperglycemic diabetics than those in the controls and euglycemic diabetic rats. MS-CXApEn was higher in the diabetic hyperglycemic rats than the control rats from scales 2 to 10, and approached the values of controls in diabetic euglycemic rats at scales 9 and 10. Conclusions: We propose MS-CXApEn as a novel parameter to quantify the dynamic nonlinear interactions between SBP and RRIs that reveals more apparent changes in early diabetic rats. Furthermore, changes in this parameter were related to correction of hyperglycemia and could be useful for detecting and assessing CAN in early diabetes.

Silencing of transcription factor E93 inhibits adult morphogenesis and disrupts cuticle, wing and ovary development in Locusta migratoria.

Ecdysone-induced protein 93F (E93) plays important roles during the metamorphosis process in insects. In this study, a cDNA of the LmE93 gene was identified from the transcriptome of Locusta migratoria, which consists of the 3378-nucleotide open-reading frame (ORF) and encodes 1125 amino acids with helix-turn-helix (HTH) motifs. Reverse transcription quantitative polymerase chain reaction analysis revealed that LmE93 was highest expressed in ovary. The LmE93 expression level was markedly low from the 3rd to 4th instar nymphs, and greatly increased in 1-day-old 5th instar nymphs with a peak on middle nymphal days, then declined in the late nymphal days. Moreover, injected dsLmE93 into 4th and 5th instar nymphs greatly reduced LmE93 transcripts, respectively, and prevented the process of metamorphosis, causing supernumerary nymphal stages. Hematoxylin-eosin staining of the integument showed that the apolysis occurred in advance in 4th instar nymphs, and old cuticle degradation was decreased in dsLmE93-injected locusts of 5th instar nymphs. Smaller and no fully developed wings with reduced columns between the anterior and posterior regions were found in N6 and N7 supernumerary nymphs. In addition, the development of the ovary in dsLmE93-injected locusts was severely blocked, the yolk was almost not formed and there was no development of ovarioles. The results indicated that LmE93 play key roles in the metamorphosis, cuticle, wing and ovarian development of locusts.

Dynamic Changes and Temporal Association with Ambient Temperatures: Nonlinear Analyses of Stroke Events from a National Health Insurance Database.

BACKGROUND: The associations between ambient temperatures and stroke are still uncertain, although they have been widely studied. Furthermore, the impact of latitudes or climate zones on these associations is still controversial. The Tropic of Cancer passes through the middle of Taiwan and divides it into subtropical and tropical areas. Therefore, the Taiwan National Health Insurance Database can be used to study the influence of latitudes on the association between ambient temperature and stroke events. METHODS: In this study, we retrieved daily stroke events from 2010 to 2015 in the New Taipei and Taipei Cities (the subtropical areas) and Kaohsiung City (the tropical area) from the National Health Insurance Research Database. Overall, 70,338 and 125,163 stroke events, including ischemic stroke and intracerebral hemorrhage, in Kaohsiung City and the Taipei Area were retrieved from the database, respectively. We also collected daily mean temperatures from the Taipei and Kaohsiung weather stations during the same period. The data were decomposed by ensemble empirical mode decomposition (EEMD) into several intrinsic mode functions (IMFs). There were consistent 6-period IMFs with intervals around 360 days in most decomposed data. Spearman's rank correlation test showed moderate-to-strong correlations between the relevant IMFs of daily temperatures and events of stroke in both areas, which were higher in the northern area compared with those in the southern area. CONCLUSIONS: EEMD is a useful tool to demonstrate the regularity of stroke events and their associations with dynamic changes of the ambient temperature. Our results clearly demonstrate the temporal association between the ambient temperature and daily events of ischemic stroke and intracranial hemorrhage. It will contribute to planning a healthcare system for stroke seasonally. Further well-designed prospective studies are needed to elucidate the meaning of these associations.

Calculation of CYP450 protein-ligand binding and dissociation free energy paths.

The function of an enzyme depends on its dynamic structure, and the catalytic mechanism has long been an active focus of research. The principle for interpreting protein selectivity and fidelity stems from optimization of the active site upon protein-substrate complexation, i.e., a lock-and-key configuration, on which most protein-substrate molecule binding recognition, and hence drug discovery, relies. Yet another thought has been to incorporate the protein folding interior tunnels for stereo- and regio-selectivity along the protein-substrate or protein-ligand/inhibitor binding process. Free energy calculations provide valuable information for molecular recognition and protein-ligand binding dynamics and kinetics. In this study, we focused on the kinetics of cytochrome P450 proteins (CYP450s) and the protein interior tunnel structure-dynamics relationship in terms of the substrate binding and leaving mechanism. A case in point is given by the prostaglandin H2 (PGH2) homologous isomerase of prostacyclin synthase. To calculate the reactant and product traversing the tunnels to and from the heme site, the free energy paths and tunnel potentials of mean force are constructed from steered molecular dynamics simulations and adaptive basing force umbrella sampling simulations. We explore the binding tunnels and critical residue lining characteristics for the ligand traverse and the underlying mechanism of CYP450 activity. Our theoretical analysis provides insights into the decisive role of the substrate tunnel binding process of the CYP450 mechanism and may be useful in drug design and protein engineering contexts.

Learning Curve of Robotic-assisted Hysterectomy With Pelvic Lymphadenectomy for Early Stage Endometrial Cancer: Analysis of 81 Cases.

BACKGROUND/AIM: The purpose of this study was to evaluate the learning curve of robotic hysterectomy and pelvic lymphadenectomy for early-stage endometrial carcinoma. PATIENTS AND METHODS: A retrospective chart review was performed on the first 81 surgeries performed by a single surgeon. The 81 cases were divided into three groups; 4 subgroups of 20 cases each, 3 subgroups of 27 cases each, and 2 subgroups of 40 cases each. The surgical outcomes in each group were analyzed, using operative time, estimated blood loss, and the number of lymph nodes resected. RESULTS: The median operating time, estimated blood loss, and number of pelvic lymph nodes were 147 min, 50 g and 23, respectively. The estimated blood loss improved over time significantly, when dividing by every 27 and 40 cases. No statistical significance was shown regarding operative time and the number of lymph nodes. CONCLUSION: Approximately, 30 cases were needed to gain proficiency in the surgical technique.

Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision.

Intrauterine adhesion (IUA), and its severe form Asherman syndrome (Asherman's syndrome), is a mysterious disease, often accompanied with severe clinical problems contributing to a significant impairment of reproductive function, such as menstrual disturbance (amenorrhea), infertility or recurrent pregnancy loss. Among these, its correlated infertility may be one of the most challenging problems. Although there are many etiologies for the development of IUA, uterine instrumentation is the main cause of IUA. Additionally, more complicated intrauterine surgeries can be performed by advanced technology, further increasing the risk of IUA. Strategies attempting to minimize the risk and reducing its severity are urgently needed. The current review will expand the level of our knowledge required to face the troublesome disease of IUA. It is separated into six sections, addressing the introduction of the normal cyclic endometrial repairing process and its abruption causing the formation of IUA; the etiology and prevalence of IUA; the diagnosis of IUA; the classification of IUA; the pathophysiology of IUA; and the primary prevention of IUA, including (1) delicate surgical techniques, such as the use of surgical instruments, energy systems, and pre-hysteroscopic management, (2) barrier methods, such as gels, intrauterine devices, intrauterine balloons, as well as membrane structures containing hyaluronate-carboxymethylcellulose or polyethylene oxide-sodium carboxymethylcellulose as anti-adhesive barrier.

Dipylidium caninum draft genome - a new resource for comparative genomic and genetic explorations of flatworms.

Here, we present a draft genome of the tapeworm Dipylidium caninum (family Dipylidiidae) and compare it with other cestode genomes. This draft genome of D. caninum is 110 Mb in size, has a repeat content of ~13.4% and is predicted to encode ~10,000 protein-coding genes. We inferred excretory/secretory molecules (representing the secretome), other key groups of proteins (including peptidases, kinases, phosphatases, GTPases, receptors, transporters and ion-channels) and predicted potential intervention targets for future evaluation. Using 144 shared single-copy orthologous sequences, we investigated the genetic relationships of cestodes for which nuclear genomes are available. This study provides first insights into the molecular biology of D. caninum and a new resource for comparative genomic and genetic explorations of this and other flatworms.

Synthesis of 4-thiol-furanosidic uronate via hydrothiolation reaction.

Uronic acids are not only important building blocks of polysaccharides and oligosaccharides but also are widely used in the food and pharmaceutical industries. Inspired by the structure of natural products, here, we disclosed base-mediated and radical-mediated hydrothiolation reactions for the preparation of thiol-contained uronates. In comparison with base-mediated reaction, radical-mediated hydrothiolation is inefficient due to the electron-withdrawing group on the ethylene group; nevertheless, the adduct had excellent stereoselectivity at both C-4 and C-5 positions. For the alkaline approach, thiols as nucleophiles can regioselectively and stereoselectively attach to the C-4 position of Δ-4,5-unsaturated uronate with moderate to good yields. However, poor stereoselectivity at the C-5 position was observed due to retro thiol-Michael addition. After removing the protecting group of the thiol, the thiol adduct was isomerized to the furanosidic form and the 4-thiol-furanosidic uronate derivative was synthesized for the first time.

Roles of LmCDA1 and LmCDA2 in cuticle formation in the foregut and hindgut of Locusta migratoria.

Chitin deacetylases (CDAs, including CDA1 and CDA2) are considered key enzymes for body cuticle formation and tracheal morphogenesis in various insect species. However, their functions in the formation of the cuticular intima of the foregut and hindgut are unclear. Here, we investigated the roles of their respective genes LmCDA1 and LmCDA2 in this process, in the hemimetabolous insect Locusta migratoria. Transcripts of LmCDA1 and LmCDA2 were highly expressed both before and after molting in the foregut. In the hindgut, their expression was high only before molting. In both the foregut and hindgut, LmCDA1 protein was localized in the basal half of the chitin matrix (procuticle), whereas LmCDA2 was detected in the upper half of the procuticle. Knockdown of LmCDA1 by RNA interference (RNAi) in 5th-instar nymphs caused no visible defects of the hindgut cuticle. By contrast, the chitinous lamellae of the cuticular intima in the foregut of knockdown animals were less compact than in control animals. RNAi against LmCDA2 led to thickening of both the foregut and hindgut cuticles, with a greater number of thinner laminae than in the respective control cuticles. Taken together, our results show that LmCDA1 and LmCDA2 have distinct, but overlapping, functions in chitin organization in the foregut cuticle. However, in the hindgut, this process seems independent of LmCDA1 activity but requires LmCDA2 function. Thus, the CDAs reflect tissue-specific differences in cuticular organization and function, which need further detailed molecular and histological analyses for full comprehension.

LmIntegrinß-PS is required for wing morphogenesis and development in Locusta migratoria.

Wings are an important flight organ of insects and their morphogenesis depends on a series of cell-to-cell and cell-to-extracellular matrix interactions. Integrin as a transmembrane protein receptor mediates cell-to-cell adhesion, cell-to-extracellular matrix interactions and signal transduction. In the present study, we characterized an integrin gene that encodes integrinß-PS protein in Locusta migratoria. LmIntegrinß-PS is highly expressed in the wing pads and the middle stages of 5th instar nymphs. Immunohistochemical analysis revealed that the LmIntegrinß-PS protein was localized at the cell base of the two layers of wings. After suppression of LmIntegrinß-PS by RNA interference, the wing pads or wings were unable to form normally, with a blister wing appearance during nymph to nymph transition and nymph to adult transition. We further found that the dorsal and ventral epidermis of the wings after dsLmIntegrinß-PS injection were improperly connected and formed huge cavities revealed by hematoxylin and eosin staining. Furthermore, the morphology and structure of the wing cuticle was significantly disturbed which affected the stable arrangement and attachments of the wing epidermis. Moreover, the expression of related cell adhesion genes was significantly decreased in LmIntegrinß-PS-suppressed L. migratoria, suggesting that LmIntegrinß-PS is required for the morphogenesis and development of wings during molting by stabilizing cell adhesion and maintaining the cytoskeleton of these cells.