Non-structural protein NS4B: HCV replication web inducer

Hepatitis C virus (HCV) genome consists of a positive strand RNA encoding a polyprotein, having 3 structural and 6 non-structural components including non structural protein 4B (NS4B). NS4B is a 27 KDa protein, of 261 amino acids, released after polyprotein cleavage by NS3 serine protease and localized on endoplasmic reticulum (ER). NS4B has 2 alpha helices each in its N and C terminal domains and 4 transmembrane domains in its central region. N-terminal domain resides in the ER-lumen while C-terminal domain resides in the cytoplasm. Around its middle it has a nucleotide binding motif (NBM) which plays a role in ATP and GTP hydrolysis. It is involved in hyperphosphorylation of the NS5A protein and is also thought to be involved in production of various cytokines by the activation of NF-kB pathway. NS4B plays a major role in HCV replication by inducing membranous web and facilitating other HCV proteins necessary for replication. Here we discuss various functional aspects of this protein and their potential for targeted antiviral approaches.     

Accuracy of 64-slice multidetector computed tomography scan in detection of the point of transition of small bowel obstruction

Purpose  

To determine the accuracy of 64-slice multidetector computed tomography scans in detecting the point of transition of small bowel obstruction by using surgical findings as the gold standard.     

Sperm retrieval rate and reproductive outcome of infertile men with azoospermia factor c deletion

To evaluate the success rate in sperm retrieval (SR) through microdissection testicular sperm extraction (micro‐TESE) in infertile azoospermia factor c (AZFc)‐deleted men and determining their reproductive outcomes following ICSI, medical records of couples with AZFc‐deleted male partners were reviewed on patient's age, serum hormone levels, karyotype, testicular pathology and pregnancy outcomes. A comparison on age and serum hormone level was conducted between groups with positive and negative sperm retrieval in both azoospermic and oligozoospermic AZFc‐deleted men. Of 225 who had AZFc deletion, 195 cases followed clinical treatments. From 195 cases, 116 were azoospermic, 79 were oligozoospermic. Pathology profile was available in 103 of 195 subjects which the predominant trait was SCOS and was seen in 66.9% of cases (69 of 103). Success rate of sperm retrieval in azoospermic patients who underwent micro‐TESE was 36.3% (28/77). Forty‐three oligozoospermic and 17 azoospermic patients started ART cycle. Pregnancy rate in oligozoospermic group was 35.4% (17 cases), whilst there was no clinical pregnancy in azoospermic group. In conclusion, the pregnancy and delivery in oligozoospermic patients with AZFc deletion are comparable with other studies, but despite of sperm retrieval in azoospermic patients with AZFc deletion, the chance of pregnancy or delivery in these patients was very low.     

Recessive mutations of <Emphasis Type="Italic">TMC1</Emphasis> associated with moderate to severe hearing loss

TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404?+?1G?>?T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404?+?1G?>?T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.     

Oxidative and carbonyl stress in pregnant women with obstructive sleep apnea

Sleep and Breathing - Pregnant women are particularly susceptible to sleep-disordered breathing. Obstructive sleep apnea (OSA) in pregnancy is associated with poor pregnancy and fetal outcomes....     

<Emphasis Type="Italic">TOX3</Emphasis> Variants Are Involved in Restless Legs Syndrome and Parkinson’s Disease with Opposite Effects

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p?=?0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p?=?0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05–2.54, p?=?0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD.     

Under‐reporting of sudden unexpected death in epilepsy

Aims. The identification and characterization of sudden unexpected deaths in epilepsy (SUDEP) may be improved, helping to optimize prevention and intervention. We set out to assess the frequency and demographic and clinical characteristics of SUDEP cases in a sudden death cohort. Methods. All out‐of‐hospital deaths were investigated from March 1, 2013 to February 28, 2015 in Wake County, NC, attended by the Emergency Medical Services. Cases were screened and adjudicated by three physicians to identify sudden death cases from any cause among free‐living adults, aged 18–64. In total, 399 sudden death victims were identified during this two‐year period. Seizure history, demographic and clinical characteristics, and healthcare utilization patterns were assessed from death records, emergency response scene reports, and medical records. Sudden death cases with a history of seizures were summarized by an experienced chart abstractor (SC) and adjudicated by an experienced neurologist (OD). We then compared demographic and clinical characteristics and healthcare utilization patterns of neurologist‐identified SUDEP cases to other sudden death victims in our population‐based registry of sudden death from any cause. Results. SUDEP accounted for 5.3% of sudden deaths. However, seizures or complications of seizures were only considered the primary cause of death on death certificates in 1.5% of sudden deaths. SUDEP cases were more likely to have a history of alcohol abuse. Mental health disorders and a low level of medication compliance and healthcare utilization were common among SUDEP victims. Conclusions. SUDEP accounts for approximately 5.3% of sudden deaths from any cause in individuals aged between 18 and 64. Death certificates underestimate the burden of sudden death in epilepsy, attributing only 1.5% of sudden deaths to seizures or complications of seizures. Accurate documentation of epileptic disorders on death certificates is essential for the surveillance of SUDEP. Further, interventions that promote better use of medical services and patient engagement with healthy living practices may reduce sudden deaths in epilepsy.     

Valveless microliter combustion for densely packed arrays of powerful soft actuators

Existing tactile stimulation technologies powered by small actuators offer low-resolution stimuli compared to the enormous mechanoreceptor density of human skin. Arrays of soft pneumatic actuators initially show promise as small-resolution (1- to 3-mm diameter), highly conformable tactile display strategies yet ultimately fail because of their need for valves bulkier than the actuators themselves. In this paper, we demonstrate an array of individually addressable, soft fluidic actuators that operate without electromechanical valves. We achieve this by using microscale combustion and localized thermal flame quenching. Precisely, liquid metal electrodes produce sparks to ignite fuel lean methane–oxygen mixtures in a 5-mm diameter, 2-mm tall silicone cylinder. The exothermic reaction quickly pressurizes the cylinder, displacing a silicone membrane up to 6 mm in under 1 ms. This device has an estimated free-inflation instantaneous stroke power of 3 W. The maximum reported operational frequency of these cylinders is 1.2 kHz with average displacements of ∼100 µm. We demonstrate that, at these small scales, the wall-quenching flame behavior also allows operation of a 3 × 3 array of 3-mm diameter cylinders with 4-mm pitch. Though we primarily present our device as a tactile display technology, it is a platform microactuator technology with application beyond this one.

Through the senses, human beings constantly gain rich information about the external world; ultimately, everything one knows comes from what one first learns through one’s sense powers (1). Though sight is generally considered to be our strongest sensorial asset, touch (pressure, pain, vibration, temperature, etc.) intimately connects us with our nearby environment and our own bodies. Touch is, perhaps, more necessary for survival than any other sense (2–8). It is unsurprising, then, that our skin is our bodies’ largest organ (9, 10), comprising in part a diverse array of mechanoreceptive organelles, allowing people to feel skin deformations of different types, durations, and intensities (11). For example, human fingertips have over 200 mechanoreceptive units per square centimeter (10), perceiving static deformations of down to 0.1 mm (12) and vibrations of up to 400 Hz (10, 13).Despite the importance of touch, our visual and auditory senses dominate the experience of digital information. The most proliferate form of haptic actuation is vibrotactile, but this technique does not allow the type of displacement and persistence of touch required to provide a natural experience. Vibrations alone cannot meaningfully recreate the pressure felt from a bag on the shoulders or the impact of a ball caught in the hands. Because of this lack of haptic experience, at least two societal needs remain unfulfilled: artificial touch recreation in immersive virtual reality (VR) and braille displays that compete with analogous visual media. For braille, specifically, there are no full-page, affordable, portable, refreshable displays on the market (14).The dearth of available tactile display options is not from lack of trying; manufacturing arrays of actuators at the size and density suitable for reading computer information from a tactile screen requires reducing actuator volume, weight, power draw, and cost, all together. The diverse set of designs conceived to achieve this haptic challenge have employed an equally numerous suite of physical principles, and each actuation method has presented its own failure mode (14). For example, thermal actuators usually take seconds (without thermal management accessories) (15) to finish a work loop because of heat transport limitations (16). Pulsed electromagnetic systems suffer from low actuation forces and interference between individual actuators (crosstalk) when made close to the size of a braille dot (17). Piezoelectric devices have large production costs at scale (HyperBraille systems cost ∼$50,000), also needing long cantilevered geometries that impede their ability to be densely arranged (14, 18).Fluidic elastomer actuators (FEAs) displace rubber forms with liquids and gases, showing promise as dense actuator arrays because of their manufacturing simplicity and favorable mechanical characteristics (19). An elastomeric membrane ∼1 mm in diameter can displace more than 0.5 mm as was previously shown by ref. 20 in which a 1.5-mm diameter viscoelastic membrane displaced 0.56 mm in about 1 s. Beyond simplicity, these soft haptic devices also have the convenient ability to conform to complex body shapes (21). For example, HaptX has developed a commercial, tethered VR glove technology that integrates 130 individually addressable fluidic actuators into each glove (22). This paper’s lead author has experienced this technology and testifies to its natural feel (23). As designed, the glove’s microfluidic channels are tethered to a large box housing a pump and many valves, limiting the user’s range of motion. One major deficiency of FEAs is how the system scales with actuator number density: there is generally a linear relationship between the number of valves and actuators. As electromechanical valves are themselves actuators, the size, weight, power, and cost (SWaP-C) requirements of FEA arrays soon become untenable for portable tactile display systems. For example, the most popular valve choice for FEAs is the Parker X-Valve, with dimensions of 7.87 × 23.37 × 12.30 mm³ at a unit cost of ∼$40 (24); if a single, six-dot braille cell (∼6 × 10 × 10 mm³) was controlled by six valves, that is, one valve per actuator, the array of valves would take up 18.4 times the cell area and cost $240 (14). Though there are multiplexing solutions to the valving challenge (25), we are currently unaware of any high-resolution tactile interaction being enabled by these methods.Counterintuitively, microscale combustion could provide an alternative actuation motif for haptic arrays, given its own engineering tradeoffs. Combining high-energy density fuels (26, 27) with small-volume mechanical elements results in a potentially safe and enduring actuation mechanism. Previously, microscale combustion research primarily focused on replacing batteries with high–power density micro-electromechanical systems (MEMS) thermoelectric generators (28). These systems may have failed to become practical because of unwanted flame extinction, thermal degradation, and frictional wear (29). More recently, combustion has been used in FEAs for macroscale soft robots and pumps (30–34). A spark ignites a combustible gas mixture that rapidly heats the product gas and expands the soft FEA cavity to move a robot or separate fluid. This research direction, however, has not been previously expanded into the realm of small gas-powered FEAs (35).In this paper, we make two contributions: 1) the use of combustion in microliter-scale FEAs for powerful, high-stroke, millimeter-scale actuations and 2) the exploitation of rapid thermal quenching at these scales to individually actuate fluidically coupled arrays without valving. As we no longer need valves, we can space the actuators more closely because their flow and electrical control components occupy less area than the actuator footprint. Primarily composed of molded silicone and microfluidic liquid metal (LM) traces, our design is an inexpensive, thin rubber sheet that provides more favorable SWaP-C scaling than prior FEA systems. We elementally characterize our device’s mechanical performance as a general microactuation strategy. As tactile display systems represent one of the oldest, broadest, and most contemporary microactuator research initiatives, we focus our discussion and demonstration on this system’s potential to serve a similar purpose.