Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit ...of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.
Intestinal worms, or soil-transmitted helminths (STHs), affect hundreds of millions of people in all tropical and subtropical regions of the world. The most prevalent STH is Ascaris lumbricoides. ...Through large-scale deworming programs, World Health Organization aims to reduce morbidity, caused by moderate-to-heavy intensity infections, below 2%. In order to monitor these control programs, stool samples are examined microscopically for the presence of worm eggs. This procedure requires well-trained personnel and is known to show variability between different operators interpreting the slides. We have investigated whether ABA-1, one of the excretory-secretory products of A. lumbricoides can be used as a coproantigen marker for infection with this parasite. Polyclonal antibodies were generated and a coproantigen ELISA was developed. Using this ELISA, it was found that ABA-1 in stool detected Ascaris infection with a sensitivity of 91.5% and a specificity of 95.3%. Our results also demonstrate that there is a correlation between ABA-1 levels in stool and A. lumbricoides DNA detected in stool. Using a threshold of 18.2 ng/g stool the ABA-1 ELISA correctly assigned 68.4% of infected individuals to the moderate-to-heavy intensity infection group, with a specificity of 97.1%. Furthermore, the levels of ABA-1 in stool were shown to rapidly and strongly decrease upon administration of a standard anthelminthic treatment (single oral dose of 400 mg albendazole). In an Ascaris suum infection model in pigs, it was found that ABA-1 remained undetectable until day 28 and was detected at day 42 or 56, concurrent with the appearance of worm eggs in the stool. This report demonstrates that ABA-1 can be considered an Ascaris -specific coproantigen marker that can be used to monitor infection intensity. It also opens the path for development of point-of-care immunoassay-based tests to determine A. lumbricoides infection in stool at the sample collection site.
The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a ...prefusion-stabilized conformation.
In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10
viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.
The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval CI, 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% adjusted 95% CI, 54.6 to 89.1 for onset at ≥14 days and 85.4% adjusted 95% CI, 54.2 to 96.9 for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).
A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).
In magnetic multilayer systems, a large spin-orbit coupling at the interface between heavy metals and ferromagnets can lead to intriguing phenomena such as the perpendicular magnetic anisotropy, the ...spin Hall effect, the Rashba effect, and especially the interfacial Dzyaloshinskii-Moriya (IDM) interaction. This interfacial nature of the IDM interaction has been recently revisited because of its scientific and technological potential. Here we demonstrate an experimental technique to straightforwardly observe the IDM interaction, namely Brillouin light scattering. The non-reciprocal spin wave dispersions, systematically measured by Brillouin light scattering, allow not only the determination of the IDM energy densities beyond the regime of perpendicular magnetization but also the revelation of the inverse proportionality with the thickness of the magnetic layer, which is a clear signature of the interfacial nature. Altogether, our experimental and theoretical approaches involving double time Green's function methods open up possibilities for exploring magnetic hybrid structures for engineering the IDM interaction.
Advancements in wireless sensor network technologies have enabled the proliferation of miniaturized body-worn sensors, capable of long-term pervasive biomedical signal monitoring. Remote ...cardiovascular monitoring has been one of the beneficiaries of this development, resulting in non-invasive, photoplethysmography (PPG) sensors being used in ambulatory settings. Wrist-worn PPG, although a popular alternative to electrocardiogram, suffers from motion artifacts inherent in daily life. Hence, in this paper, we present a novel deep learning framework (CorNET) to efficiently estimate heart rate (HR) information and perform biometric identification (BId) using only a wrist-worn, single-channel PPG signal collected in ambulant environment. We have formulated a completely personalized data-driven approach, using a four-layer deep neural network. Two convolution neural network layers are used in conjunction with two long short-term memory layers, followed by a dense output layer for modeling the temporal sequence inherent within the pulsatile signal representative of cardiac activity. The final dense layer is customized with respect to the application, functioning as: regression layer-having a single neuron to predict HR; classification layer-two neurons that identify a subject among a group. The proposed network was evaluated on the TROIKA dataset having 22 PPG records collected during various physical activities. We achieve a mean absolute error of 1.47 ± 3.37 beats per minute for HR estimation and an average accuracy of 96% for BId on 20 subjects. CorNET was further evaluated successfully in an ambulant use-case scenario with custom sensors for two subjects.
Faithful degradation of mRNAs is a critical step in gene expression, and eukaryotes share a major conserved mRNA decay pathway. In this major pathway, the two rate-determining steps in mRNA ...degradation are the initial gradual removal of the poly(A) tail, followed by removal of the cap structure. Removal of the cap structure is carried out by the decapping enzyme, containing the Dcp2 catalytic subunit. Although the mechanism and regulation of mRNA decay is well understood, the consequences of defects in mRNA degradation are less clear. Dcp2 has been reported as either essential or nonessential. Here, we clarify that Dcp2 is not absolutely required for spore germination and extremely slow growth, but in practical terms it is impossible to continuously culture
∆ under laboratory conditions without suppressors arising. We show that null mutations in at least three different genes are each sufficient to restore growth to a
∆, of which
∆ and
∆ appear the most specific. We show that
∆ and
∆ suppress
by mechanisms that are different from each other and from previously isolated
suppressors. The suppression mechanism for
is determined by the unique GAG anticodon of this tRNA, and thus likely by translation of some CUC or CUU codons. Unlike previously reported suppressors of decapping defects, these suppressors do not detectably restore decapping or mRNA decay to normal rates, but instead allow survival while only modestly affecting RNA homeostasis. These results provide important new insight into the importance of decapping, resolve previously conflicting publications about the essentiality of
, provide the first phenotype for a
mutant, and show that multiple distinct mechanisms can bypass Dcp2 requirement.
This paper describes a mixed-signal ECG System-on-Chip (SoC) that is capable of implementing configurable functionality with low-power consumption for portable ECG monitoring applications. A ...low-voltage and high performance analog front-end extracts 3-channel ECG signals and single channel electrode-tissue-impedance (ETI) measurement with high signal quality. This can be used to evaluate the quality of the ECG measurement and to filter motion artifacts. A custom digital signal processor consisting of 4-way SIMD processor provides the configurability and advanced functionality like motion artifact removal and R peak detection. A built-in 12-bit analog-to-digital converter (ADC) is capable of adaptive sampling achieving a compression ratio of up to 7, and loop buffer integration reduces the power consumption for on-chip memory access. The SoC is implemented in 0.18 μm CMOS process and consumes 32 μW from a 1.2 V while heart beat detection application is running, and integrated in a wireless ECG monitoring system with Bluetooth protocol. Thanks to the ECG SoC, the overall system power consumption can be reduced significantly.
This paper proposes a 3-channel biopotential monitoring ASIC with simultaneous electrode-tissue impedance measurements which allows real-time estimation of motion artifacts on each channel using an ...an external μC. The ASIC features a high performance instrumentation amplifier with fully integrated sub-Hz HPF rejecting rail-to-rail electrode-offset voltages. Each readout channel further has a programmable gain amplifier and programmable 4th order low-pass filter. Time-multiplexed 12 b SAR-ADCs are used to convert all the analog data to digital. The ASIC achieves >; 115 dB of CMRR (at 50/60 Hz), a high input impedance of >; 1 GΩ and low noise (1.3 μVrms in 100 Hz). Unlike traditional methods, the ASIC is capable of actual motion artifact suppression in the analog domain before final amplification. The complete ASIC core operates from 1.2 V with 2 V digital IOs and consumes 200 μW when all 3 channels are active.
This paper presents the design and implementation of an analog signal processor (ASP) ASIC for portable ECG monitoring systems. The ASP ASIC performs four major functionalities: 1) ECG signal ...extraction with high resolution, 2) ECG signal feature extraction, 3) adaptive sampling ADC for the compression of ECG signals, 4) continuous-time electrode-tissue impedance monitoring for signal integrity monitoring. These functionalities enable the development of wireless ECG monitoring systems that have significantly lower power consumption yet that are more capable than their predecessors. The ASP has been implemented in 0.5 μm CMOS process and consumes 30 μW from a 2 V supply. The noise density of the ECG readout channel is 85 nV/√Hz and the CMRR is better that 105 dB. The adaptive sampling ADC is capable of compressing the ECG data by a factor of 7 and the heterodyne chopper readout extracts the features of the ECG signals. Combination of these two features leads to a factor 4 reduction in the power consumption of a wireless ECG monitoring system. Furthermore, the proposed continuous-time impedance monitoring circuit enables the monitoring of the signal integrity.
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