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关键词： Human Genetics   Molecular Medicine   Gene Function   Metabolic Diseases  

摘要： The discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology.

关键词： G protein-coupled receptors   motif   nociceptin receptor   opioid receptors   post-translational modification   trafficking  

摘要： Over the past several years, studies have highlighted the delta-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management. While exhibiting milder undesired effects than most currently prescribed opioids, its specific agonists elicit effective analgesic responses in numerous animal models of chronic pain, including inflammatory, neuropathic, diabetic, and cancer-related pain. However, as compared with the extensively studied mu-opioid receptor, the molecular mechanisms governing its trafficking remain elusive. Recent advances have denoted several significant particularities in the regulation of DOPr intracellular routing, setting it apart from the other members of the opioid receptor family. Although they share high homology, each opioid receptor subtype displays specific amino acid patterns potentially involved in the regulation of its trafficking. These precise motifs or "barcodes" are selectively recognized by regulatory proteins and therefore dictate several aspects of the itinerary of a receptor, including its anterograde transport, internalization, recycling, and degradation. With a specific focus on the regulation of DOPr trafficking, this review will discuss previously reported, as well as potential novel trafficking barcodes within the opioid and nociceptin/orphanin FQ opioid peptide receptors, and their impact in determining distinct interactomes and physiological responses.

关键词： Diabetes   Sex   Training adaptations   Vascular control   Muscle contractions  

摘要： Aims: We tested the hypotheses that exercise training improves the peak and dynamic responses of leg vascular conductance (LVC) in males and females with type 2 diabetes (T2DM). Methods: Forty-one males and females with T2DM were assigned to two training groups and two control groups. Twelve weeks of aerobic/resistance training was performed three times per week, 60-90 min per session. Responses of calf muscle blood flow and systemic arterial pressure during incremental and constant-load (30% maximal voluntary contraction) intermittent plantar-flexion protocols in the supine position were recorded. Results: Training significantly increased peak LVC in males (4.86 +/- 1.88 to 6.06 +/- 2.06 ***(-1).mm Hg-1) and females (3.91 +/- 1.13 to 5.40 +/- 1.38 ***(-1).mm Hg-1) with no changes in control groups. For dynamic responses, training significantly increased the amplitude of the fast growth phase of LVC (1.81 +/- 1.12 to 2.68 +/- 1.01 ***(-1).mm Hg-1) and decreased the time constant of the slow growth phase (43.6 +/- 46.4 s to 16.1 14.0 s) in females, but no improvements were observed in control females or in any of the two male groups. Conclusions: These data suggest that training increases the peak vasodilatory response in males and females, whereas the speed of the dynamic response of vasodilation is improved in females but not males.

关键词： CMOS 65-nm   digital-controlled VGA   Ka-band  

摘要： This paper presents a 35 GHz differential variable gain amplifier (VGA) with 4-bit digital-controlled gain-tuning using 65-nm CMOS process. Using the proposed miniaturized differential matching inductors, a core size of the VGA is only 0.53 x 0.26 mm. The digital gain control mechanism is achieved using the digital version current steering topology. The measured gain control range of the VGA is from 17.4 to 9 dB at 35 GHz with 16 different linear-in-dB gain states. Thus, this work achieves the maximum peak gain per unit core size and maintains a much better gain control range per unit core size. The measured root mean square gain error is 4.6 degrees from 34 to 36.5 GHz.

关键词： Pulmonary arterial hypertension   IPAH   HDL-C   LDL-C   Cholesterol   Serum lipids   Congenital heart disease  

摘要： Lipid homeostasis is dysregulated in pulmonary arterial hypertension (PAH). A decrease in serum high-and low density lipoprotein cholesterol (HDL-C and LDL-C) is significantly associated with the worse prognosis of PAH. However, no study has investigated the differential distribution of lipids in various PAH subtypes. We enrolled 190 patients in this retrospective study, which includes 20 patients with congenital heart disease without PAH (CHD-nonPAH), 101 patients with PAH associated with congenital heart disease (CHD-PAH), 69 patients with idiopathic PAH (IPAH) and 81 healthy controls. Laboratory parameters such as liver and renal function, serum lipids, C-reactive protein, N-terminal pro-brain natriuretic peptide (NT-proBNP), echocardiography, right heart catheterization and 6-min walk distance (6-MWD) were performed. All types of cholesterol including HDL-C, LDLC and total cholesterol (CHOL) were significantly lower in IPAH patients in association with right heart function. Although LDL-C and CHOL were lower in CHD-PAH, they were not associated with disease severity or heart failure. Thus, we conclude that IPAH and CHD-PAH patients exhibited a differential distribution pattern of serum lipids.

关键词： anococcygeal nerve   coccygectomy   neuroma   coccygeal plexus  

摘要： Background The plastic surgeon is often asked to reconstruct the sacral area related to pilonidal cysts or a tumor, or after other surgery, such as coccygectomy. When sitting pain is not due to the pudendal or posterior femoral cutaneous nerve injury, the anococcygeal nerve (ACN) must be considered. Clinically, its anatomy is not well known. Rather than consider coccygectomy when the traditional nonoperative treatment of coccydynia fails, resection of the ACN might be considered. Methods A review of traditional anatomy textbooks was used to establish classical thoughts about the ACN. A retrospective cohort of patients with sitting pain related to the coccyx was examined, and those operated on, by resecting the ACN, were examined for clinicopathologic correlations. Results When the ACN is described in anatomy textbooks, it is with varying distributions of innervated skin territory and nerve root composition. Most include an origin from sacral 5 and coccygeal 1 ventral roots. Most agree that the ACN forms on the ventral side of the sacrum/coccyx, alongside the coccygeus muscle, to emerge laterally and travel dorsally to innervate skin over the coccyx and lower sacrum. A review of 13 patients with sitting pain due to the ACN, from 2015 to 2019, demonstrated a mean age of 54.6 years. Eleven were female. The etiologies of ACN injury were falls (9), exercise (3), and complication from surgery (1). Six of the 9 patients who had surgery were able to be followed up with a mean length of 36.3 months (range, 11-63 months). Overall, 3 had an excellent result, 2 had a good result, and 1 was not improved. The one with a failed result showed improvement with coccygectomy. Conclusions The ACN must be included in the differential diagnosis of sitting pain. It is most often injured by a fall. The ACN can be evaluated with a diagnostic nerve block, can be identified at surgery, and can be resected, and its proximal end can be implanted into the coccygeus muscle. This surgery may prove

关键词： H-2 norm   differential algebraic equations   time-delay systems  

摘要： The H-2 norm of an exponentially stable system described by delay differential algebraic equations (DDAEs) might be infinite due to the existence of hidden feedthrough terms and, as shown in this article, it might become infinite as a result of infinitesimal changes to the delay parameters. We introduce the notion of strong H-2 norm of semi-explicit DDAEs, a robustified measure that considers delay perturbations, and we analyze its properties. We derive necessary and sufficient finiteness criteria for the strong H-2 norm in terms of a finite number of equalities involving multidimensional powers of a finite set of matrices. As the main contribution, we present a strengthened, sufficient, condition for finiteness of the strong H-2 norm, along with an algorithm for checking it, which has significantly better scalability properties in terms of both the system dimension and the number of delays. We show that the satisfaction of the novel condition is equivalent to the existence of a simultaneous block triangularization of the matrices of the delay difference equation associated with the DDAE. The latter is instrumental to a novel regularization procedure that allows us to transform the DDAE to a neutral-type system with the same transfer matrix, without any need for differentiation of inputs or outputs. This transformation enables computing of the strong H-2 norm using Lyapunov matrices. Finally, we show by a counterexample that the strengthened condition is, in general, not necessary, inducing open problems, but we also list several classes of DDAEs for which it is necessary and sufficient.

关键词： AM species   antioxidant defense   nitrogenase   soil enzyme activities   sucrose metabolism  

摘要： Arbuscular mycorrhizal (AM) fungi can improve nitrogen (N-2) fixing potential of legumes under metalloid stress by enhancing nutrient uptake and modulating antioxidant defense mechanisms. Diversity among AM species in imparting metalloid tolerance highlights the importance of selecting best host-fungal combinations. Therefore, effectiveness of AM species: Rhizoglomus intraradices (Ri), Funneliformis mosseae (Fm), and Claroideoglomus claroideum (Cc) in improving N-2 fixation was assessed in two differentially metalloid tolerant chickpea genotypes: HC 3 and C 235 under arsenate (AsV) and arsenite (AsIII) stress. Nodulation potential had a negative correlation with As, the impacts being more severe in C 235 than HC 3. AM species strengthened symbiotic process by enhancing availability of N, P and Fe to the nodules through increased soil enzymes activities. AM also accelerated the activities of sucrolytic enzymes in host nodules, for improved C accessibility to the bacterioids. Mycorrhization significantly increased the antioxidant enzyme activities as well as the concentrations of thiol derivatives. Ri was most efficient in improving functional efficiency of nodules, closely followed by Fm, with least positive impact of Cc, which could be related to their differential mycorrhizal colonizing abilities. Study highlighted importance of Ri inoculation for maximising the symbiotic efficiency of chickpea in As contaminated soils.

关键词： Measure of noncompactness   Darbo fixed point theorem   Monotonic integrable solutions   Hybrid implicit initial conditions   Riemann-Liouville fractional integral   Liouville-Caputo fractional derivative   Uniqueness of the solution   Continuous dependence of the solution   Arzela-Ascoli Theorem   Lebesgue Dominated Convergence Theorem  

摘要： Here, in this article, we study some existence results of monotonic integrable solutions for a nonlinear hybrid implicit functional differential inclusion of arbitrary fractional orders. We derive the sufficient conditions for the uniqueness of the solution. We also prove the continuous dependence of the solution which we have presented here.

关键词： autoregressive model   power spectral density estimation   Raman spectrum   spectrum denoising  

摘要： Although ultraviolet (UV) laser Raman spectroscopy offers the benefits of stronger signals, partial separation of fluorescence and Raman spectra, and increased eye safety, it suffers from excessive noise, poor resolution, low maturity level, and small intensities of remotely acquired signals and therefore needs to be used in combination with effective denoising techniques. Herein, a denoising approach denoted as iterative differential autoregressive spectrum estimation was developed relying on the assumption that more detailed Raman peaks can be obtained by dividing the Raman spectrum into multiple layers with different intensity levels and estimating the energy distribution of each layer. Specifically, each layer was computed from the difference between the upper layer spectrum and its autoregressive model estimation spectrum, and the energy distribution at progressively lower intensity levels was considered. Compared with traditional techniques, our method exhibited good noise suppression performance and an excellent Raman peak restoration ability while offering the advantages of decreased spectral resolution loss and stable robustness. Cutoff optimization strategies were proposed to improve convergence and noise suppression ability and thus decrease the calculation time to 0.18 s and meet the needs of remote Raman spectrometers for real-time denoising under the condition of long integration. The developed technique paves the way to Raman spectrum denoising based on power spectrum estimation, has a strong adaptive potential, and can be extended to other applications.