Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through ...whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.
Efficient and reliable power electronic converters are desired to integrate renewable energy sources into households or the grid. Multilevel inverters for their benefits are being explored for ...low-power applications. In this work, recently introduced 9-level T-Type switched-capacitor multilevel inverters are explored for 11-level operation, increasing their reliability in high-temperature conditions. The operation makes it capable of generating more voltage levels than the prior technology and diminishes capacitor inrush currents. Eventually, in 9-level operation, the undesired continuous high inrush current peaks are inevitable, which heat the capacitors due to electrolytic series resistance (ESR). This leads to early electrolyte evaporation and thus results in capacitance variation and an increase of ESR with time. In order to suppress the capacitor inrush currents, additional inductance of small value in the charging circuit is sought to mitigate these currents, but that leads to increased losses and increased switch ringing effect. In this work, the modulation of the inverter is performed to produce 11-levels at the inverter output. Inverter redundant states are so employed that the capacitors are always charged and discharged through the load. This results in reduction of inrush current peaks by approximately 20 times, thereby increasing the reliability and life of the inverter and making them more suitable for Solar PV applications in harsh weather conditions. This structure and modulation strategy also achieves lower switch voltage and current stresses. The improved topology and the modulation strategy are validated on the controller hardware-in-the-loop (CHIL) setup and PLECS environments. Further, the topologies are experimentally validated on a laboratory prototype.
A paradigm shift in power engineering transforms conventional fossil fuel-based power systems gradually into more sustainable and environmentally friendly systems due to more renewable energy source ...(RES) integration. However, the control structure of high-level RES integrated system becomes complex, and the total system inertia is reduced due to the removal of conventional synchronous generators. Thus, such a system poses serious frequency instabilities due to the high rate of change of frequency (RoCoF). To handle this frequency instability issue, this work proposes an optimized fractional-order proportional integral (FOPI) controller-based superconducting magnetic energy storage (SMES) approach. The proposed FOPI-based SMES technique to support virtual inertia is superior to and more robust than the conventional technique. The FOPI parameters are optimized using the particle swarm optimization (PSO) technique. The SMES is modeled and integrated into the optimally designed FOPI to support the virtual inertia of the system. Fluctuating RESs are considered to show the effectiveness of the proposed approach. Extensive time-domain simulations were carried out in MATLAB Simulink with different load and generation mismatch levels. Systems with different inertia levels were simulated to guarantee the frequency stability of the system with the proposed FOPI-based SMES control technique. Several performance indices, such as overshoot, undershoot, and settling time, were considered in the analysis.
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and ...perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.
A climate change workshop for the Middle East brought together scientists and data for the region to produce the first area‐wide analysis of climate extremes for the region. This paper reports trends ...in extreme precipitation and temperature indices that were computed during the workshop and additional indices data that became available after the workshop. Trends in these indices were examined for 1950–2003 at 52 stations covering 15 countries, including Armenia, Azerbaijan, Bahrain, Cyprus, Georgia, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, and Turkey. Results indicate that there have been statistically significant, spatially coherent trends in temperature indices that are related to temperature increases in the region. Significant, increasing trends have been found in the annual maximum of daily maximum and minimum temperature, the annual minimum of daily maximum and minimum temperature, the number of summer nights, and the number of days where daily temperature has exceeded its 90th percentile. Significant negative trends have been found in the number of days when daily temperature is below its 10th percentile and daily temperature range. Trends in precipitation indices, including the number of days with precipitation, the average precipitation intensity, and maximum daily precipitation events, are weak in general and do not show spatial coherence. The workshop attendees have generously made the indices data available for the international research community.
The variants of electron transfer flavoprotein (
,
) and ETF dehydrogenase (
) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six ...variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (
:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the
:p.Gly472Arg, and
:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant
:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The
:p.Arg41Leu, and
:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants.
Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1–L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a–e) in 4 steps with overall 23% ...yields. An in situ generated L-Cu(OAc)2·H2O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a–m) producing chiral nitroaldols product (8a–m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc)2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry reaction.
A survey was conducted in Al-Kharj governorate, Riyadh region to identify viruses causing variety of virus-like symptoms on tomato plants. A total of 135 samples were collected from symptomatic ...tomato plants. Symptoms included mottling, deformation, necrosis of leaves and fruits. Eighteen viruses were tested by DAS-ELISA. Tomato black ring virus (TBRV) was the virus of concern as it was not detected in Saudi Arabia before and was detected in 52.6% of the collected samples in this study. RT-PCR was used to confirm detection of TBRV and to sequence the amplified products to determine molecular characteristics of this virus. In the host range test study that was performed using a purified isolate of TBRV, sixteen out of the twenty two tested plants showed symptoms. Brassica oleracea was not infected by this virus. Gel electrophoreses (2% agarose) yielded fragments of 978 bp of coat protein gene of TBRV. Nucleotide sequences of purified RT-PCR products for three TBRV Saudi isolates were deposited in the GenBank with the following accession numbers MT274656, MT274657, and MT274658. These isolates of TBRV indicated a close Phylogenetic relationship of (99–100%) among themselves and with five isolates from Poland (95–98%) but a distant relationship of 85% with isolates from England and Lithuania deposited in the GenBank. This is the first report for detection and molecular characterization of TBRV infecting tomato plants in Saudi Arabia.
Drug induced hepatocyte death is a major contributor to acute liver failure. We aimed to determine whether β-sitosterol conjugated silver nanoparticles (BSAgNPs) could ameliorate carbon tetrachloride ...(CCl4)-induced liver injury in Swiss albino mice.
Biogenic silver nanoparticles were synthesized from β-sitosterol to produce β-sitosterol (BS) conjugated silver nanoparticles. Serum liver function assays in mice model with CCl4-induced liver injury revealed that alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin and cholesterol levels decreased markedly after treatment with β-sitosterol and BSAgNPs. In vivo liver enzymatic assays, including superoxide dismutase (SOD), catalase and reduced glutathione (GSH) were conducted to assess the antioxidant activity of the treatments.
Liver tissue from BSAgNP treated mice displayed significantly elevated SOD activity (73.57 ± 1.48%) when compared to positive control group with silymarin treatment. Catalase activity decreased drastically in CCl4 treated mice (47.14 ± 1.08%), but increased with the administration of BSAgNPs (72.24 ± 2.25%). An increase in transforming growth factor β (TGF-β1) in liver tissue homogenate accompanied a reduction in nuclear factor erythroid-2-related factor 2 (Nrf2) in CCl4 treated mice. β-sitosterol and BSAgNPs mediated the reduction of TGF-β1. In the BSAgNPs treated mice, Nrf2 level was significantly elevated; however, no change was detected following β-sitosterol treatment.
Our findings reveal that β-sitosterol conjugated silver nanoparticles (BSAgNPs) may cause activation of the Nrf2 gene, through potential inhibition of TGF β1/Smad signaling. Antifibrotic effect of BSAgNPs may promote the lowering of chronic inflammation, oxidative stress and collagen deposition. Nanoparticle-mediated drug delivery of β-sitosterol may therefore have therapeutic promise against hepatic complications.
Prior acute coronary syndrome (ACS) registries in Saudi Arabia might not have accurately described the true demographics and cardiac care of patients with ACS. We aimed to evaluate the clinical ...characteristics, management, and outcomes of a representative sample of patients with acute myocardial infarction (AMI) in Saudi Arabia.
We conducted a 1-month snap-shot, prospective, multi-center registry study in 50 hospitals from various health care sectors in Saudi Arabia. We followed patients for 1 month and 1 year after hospital discharge. Patients with AMI included those with or without ST-segment elevation (STEMI or NSTEMI, respectively). This program survey will be repeated every 5 years.
Between May 2015 and January 2017, we enrolled 2233 patients with ACS (mean age was 56 standard deviation = 13 years; 55.6% were Saudi citizens, 85.7% were men, and 65.9% had STEMI). Coronary artery disease risk factors were high; 52.7% had diabetes mellitus and 51.2% had hypertension. Emergency Medical Services (EMS) was utilized in only 5.2% of cases. Revascularization for patients with STEMI included thrombolytic therapy (29%), primary percutaneous coronary intervention (PCI); (42.5%), neither (29%), or a pharmaco-invasive approach (3%). Non-Saudis with STEMI were less likely to undergo primary PCI compared to Saudis (35.8% vs. 48.7%; respectively, p <0.001), and women were less likely than men to achieve a door-to-balloon time of <90 min (42% vs. 65%; respectively, p = 0.003). Around half of the patients with NSTEMI did not undergo a coronary angiogram. All-cause mortality rates were 4%, 5.8%, and 8.1%, in-hospital, at 1 month, and at 1 year, respectively. These rates were significantly higher in women than in men.
There is an urgent need for primary prevention programs, improving the EMS infrastructure and utilization, and establishing organized ACS network programs. AMI care needs further improvement, particularly for women and non-Saudis.
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