Abstract
As the advent of next-generation sequencing (NGS) technology, various de novo assembly algorithms based on the de Bruijn graph have been developed to construct chromosome-level sequences. ...However, numerous technical or computational challenges in de novo assembly still remain, although many bright ideas and heuristics have been suggested to tackle the challenges in both experimental and computational settings. In this review, we categorize de novo assemblers on the basis of the type of de Bruijn graphs (Hamiltonian and Eulerian) and discuss the challenges of de novo assembly for short NGS reads regarding computational complexity and assembly ambiguity. Then, we discuss how the limitations of the short reads can be overcome by using a single-molecule sequencing platform that generates long reads of up to several kilobases. In fact, the long read assembly has caused a paradigm shift in whole-genome assembly in terms of algorithms and supporting steps. We also summarize (i) hybrid assemblies using both short and long reads and (ii) overlap-based assemblies for long reads and discuss their challenges and future prospects. This review provides guidelines to determine the optimal approach for a given input data type, computational budget or genome.
Frailty is defined as a reduced physiologic reserve vulnerable to external stressors. For older individuals, frailty plays a decisive role in increasing adverse health outcomes in most clinical ...situations. Many tools or criteria have been introduced to define frailty in recent years, and the definition of frailty has gradually converged into several consensuses. Frail older adults often have multi-domain risk factors in terms of physical, psychological, and social health. Comprehensive geriatric assessment (CGA) is the process of identifying and quantifying frailty by examining various risky domains and body functions, which is the basis for geriatric medicine and research. CGA provides physicians with information on the reversible area of frailty and the leading cause of deterioration in frail older adults. Therefore frailty assessment based on understanding CGA and its relationship with frailty, can help establish treatment strategies and intervention in frail older adults. This review article summarizes the recent consensus and evidence of frailty and CGA.
With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. ...With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases.
New, more effective pharmacologic treatments for epilepsy are needed, as a substantial portion of patients (>30%) are refractory to currently available anti-epileptic drugs. Cenobamate (YKP3089) is ...an investigational anti-epileptic drug in clinical development. Two completed adequate and well-controlled studies demonstrated a significant reduction in focal seizures with cenobamate in patients with epilepsy. In this study, we characterized the effects of cenobamate on voltage-gated Na+ channels in acutely isolated rat hippocampal CA3 neurons using a whole-cell patch-clamp technique. While cenobamate had little effect on the peak component of transient Na+ current (INaT) induced by brief depolarizing step pulses, it potently inhibited the non-inactivating persistent component of INa (INaP). In addition, cenobamate potently inhibited the current by slow voltage-ramp stimuli. Cenobamate significantly shifted the steady-state fast inactivation relationship toward a hyperpolarizing range, indicating that cenobamate binds to voltage-gated Na+ channels at the inactivated state with a higher affinity. Cenobamate also accelerated the development of inactivation and retarded recovery from inactivation of voltage-gated Na+ channels. In current clamp experiments, cenobamate hyperpolarized membrane potentials in a concentration-dependent manner, and these effects were mediated by inhibiting the INaP. Cenobamate also increased the threshold for generation of action potentials, and decreased the number of action potentials elicited by depolarizing current injection. Given that the INaP plays a pivotal role in the repetitive and/or burst generation of action potentials, the cenobamate-mediated preferential blockade of INaP might contribute to anti-epileptic activity.
In this paper, we investigate the behavior of monomials in the q-characters of the fundamental modules over a quantum affine algebra of untwisted type C. As a result, we give simple closed formulae ...for the q-characters of the fundamental modules in terms of sequences of vertices in
R
2
, so-called paths, with an admissible condition. This may be viewed as a type C analog of the path description of q-characters in types A and B due to Mukhin-Young.
Degenerative disc disease is a leading cause of chronic back pain in the aging population in the world. Sinuvertebral nerve and basivertebral nerve are postulated to be associated with the pain ...pathway as a result of neurotization. Our goal is to perform a prospective study using radiofrequency ablation on sinuvertebral nerve and basivertebral nerve; evaluating its short and long term effect on pain score, disability score and patients' outcome. A review in literature is done on the pathoanatomy, pathophysiology and pain generation pathway in degenerative disc disease and chronic back pain. 30 patients with 38 levels of intervertebral disc presented with discogenic back pain with bulging degenerative intervertebral disc or spinal stenosis underwent Uniportal Full Endoscopic Radiofrequency Ablation application through either Transforaminal or Interlaminar Endoscopic Approaches. Their preoperative characteristics are recorded and prospective data was collected for Visualized Analogue Scale, Oswestry Disability Index and MacNab Criteria for pain were evaluated. There was statistically significant Visual Analogue Scale improvement from preoperative state at post-operative 1wk, 6 months and final follow up were 4.4 ± 1.0, 5.5 ± 1.2 and 5.7 ± 1.3, respectively,
< 0.0001. Oswestery Disability Index improvement from preoperative state at 1week, 6 months and final follow up were 45.8 ± 8.7, 50.4 ± 8.2 and 52.7 ± 10.3,
< 0.0001. MacNab criteria showed excellent outcomes in 17 cases, good outcomes in 11 cases and fair outcomes in 2 cases Sinuvertebral Nerve and Basivertebral Nerve Radiofrequency Ablation is effective in improving the patients' pain, disability status and patient outcome in our study.
Menthol-a natural organic compound-is widely used for relieving various pain conditions including migraine. However, a high dose of menthol reportedly decreases pain thresholds and enhances pain ...responses. Accordingly, in the present study, we addressed the effect of menthol on the excitability of acutely isolated dural afferent neurons, which were identified with a fluorescent dye, using the whole-cell patch-clamp technique. Under a voltage-clamped condition, menthol altered the holding current levels in a concentration-dependent manner. The menthol-induced current (I
) remained unaffected by the addition of selective transient receptor potential melastatin 8 antagonists. Moreover, the reversal potential of I
was similar to the equilibrium potential of K
. I
was accompanied by an increase in input resistance, thereby suggesting that menthol decreases the leak K
conductance. Under a current-clamped condition, menthol caused depolarization of the membrane potential and decreased the threshold for the generation of action potential. While the I
was substantially inhibited by 10 μM XE-991, a selective K
7 blocker, the M-current mediated by K
7 was not detected in the nociceptive neurons tested in the present study. Moreover, I
decreased under acidic extracellular pH conditions or in the presence of 3 μM A-1899, a selective K2P3.1 and K2P9.1 blocker. The present results suggest that menthol inhibits leak K
channels, possibly acid-sensitive two-pore domain K
channels, thereby increasing the excitability of nociceptive sensory neurons. The resultant increase in neuron excitability may partially be responsible for the pronociceptive effect mediated by high menthol doses.
BACKGROUND/OBJECTIVES
To evaluate the long‐term association between a multicomponent intervention program and disability in socioeconomically vulnerable older adults.
DESIGN
This was a nonrandomized ...prospective intervention trial.
SETTING
The setting was a community.
PARTICIPANTS
Participants included older Koreans living alone or receiving government assistance from a low‐income program.
INTERVENTION
The intervention was a 24‐week multicomponent program compromising group exercise, nutritional supplementation, management of depression, deprescribing, and home hazard reduction (n = 187) versus usual care (n = 196).
MEASUREMENTS
The number of dependencies in 17 basic and instrumental activities of daily living was measured every 3 months for 30 months (range: 0–17; greater values indicated worse disability). Inverse probability weighting Poisson regression was used to model the number of dependencies to adjust for confounding bias and higher dropout rates of those with greater disability.
RESULTS
The study population had a mean age of 76 years, and 26% were men. During the 30‐month follow up, 17 died (n = 8, intervention; n = 9, control), 62 (n = 16, intervention; n = 46, control) were institutionalized or received nursing home care, and 34 (n = 15, intervention; n = 19, control) were lost to follow up. After inverse probability weighting, the mean number of dependencies at baseline was 1.21 and 1.29 for the intervention group and the control group, respectively (P = .80). The intervention group had fewer dependencies than the control group, but the difference was attenuated over time: 1.08 versus 1.60 at 6 months (P = .04), 1.29 versus 1.87 at 12 months (P = .03), 1.62 versus 2.17 at 18 months (P = .06), 2.08 versus 2.51 at 24 months (P = .18), and 2.73 versus 2.90 at 30 months (P = .67).
CONCLUSION
A 24‐week multicomponent intervention was associated with a slower progression of disability; however, the diminishing association from 24 months and beyond suggests that reassessment and intervention may be necessary. Due to a lack of randomization, our findings should be interpreted with caution.
Spherical tip nanoindentation experiments on two typical face-centered cubic high-entropy alloys (HEAs), CoCrFeNi and CoCrFeMnNi in as-solutionized and aged conditions were performed using tips of ...two different radii. Large datasets of the strength at the first pop-in were obtained and their statistical nature were analyzed to gain insights into the micromechanisms responsible for the onset of incipient plasticity in HEAs that are notionally monophasic. In all the cases examined, the probability density distributions were bimodal in nature. The deconvoluted distributions were utilized to estimate the activation volumes of the underlying deformation mechanisms. They show that when the probed material's volume is relatively small, heterogeneous dislocation nucleation aided by monovacancies occurs at lower indentation stresses; this followed by homogeneous dislocation nucleation at high loads, resulting in strengths corresponding to the theoretical strengths. When a substantially larger volume is sampled, by using a larger radius tip, either the preexisting dislocation mediated ones at low stresses or vacancy cluster /grain boundary aided heterogeneous dislocations nucleation at higher stresses become dominant. Increasing the chemical short-range order in the alloy via high temperature aging leads to overall strengthening of the alloy by enhancing stress required for the homogeneous dislocation nucleation. Implications of such plurality of mechanisms with overlapping strength distributions at HEA's disposal in imparting high strength-ductility combinations are discussed.
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Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively ...expressed channelrhodopsin‐2 (ChR2), a light‐sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole‐cell patch‐clamp recordings in two functionally distinct types of VLPO neurons: sleep‐promoting GABAergic projection neurons and non‐sleep‐promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non‐sleep‐promoting neurons and excitation of sleep‐promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue‐nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin‐negative VLPO neurons, but not in galanin‐positive sleep‐promoting projection neurons. Taken together, these results suggest that astrocyte‐derived ATP is converted into adenosine by TNAP in non‐sleep‐promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep‐promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte‐neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep‐promoting VLPO neurons, and thus decreases neuronal excitability in arousal‐related areas of the brain.
Main Points
Astrocyte‐derived adenosine decreased the excitability of local GABAergic neurons, and indirectly excited sleep‐promoting neurons within the VLPO.
The present results provide a novel mechanism of astrocyte‐neuron interactions in sleep regulation.
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