Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family.

BACKGROUND: Joubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS, with an equal number of genes known so far for this phenotype. METHODS: Whole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9). RESULTS: A novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled-coil and C2 domains-containing the protein 2A (CC2D2A; NM_001080522) gene. The variant co-segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In silico analyses supported the pathogenic effect of the altered CC2D2A protein. CONCLUSIONS: To the best of our knowledge, this is the first report of CC2D2A alteration co-segragating with a JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variation pool. WES analysis is a successful molecular diagnostic tool for rare genetic disorders, especially in those populations where the marriage of cousins is more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful for patient management and for reducing the disease burden in future generations.

Thermoelectricity Generation and Electron-Magnon Scattering in a Natural Chalcopyrite Mineral from a Deep-Sea Hydrothermal Vent.

Current high-performance thermoelectric materials require elaborate doping and synthesis procedures, particularly in regard to the artificial structure, and the underlying thermoelectric mechanisms are still poorly understood. Here, we report that a natural chalcopyrite mineral, Cu1+x Fe1-x S2 , obtained from a deep-sea hydrothermal vent can directly generate thermoelectricity. The resistivity displayed an excellent semiconducting character, and a large thermoelectric power and high power factor were found in the low x region. Notably, electron-magnon scattering and a large effective mass was detected in this region, thus suggesting that the strong coupling of doped carriers and antiferromagnetic spins resulted in the natural enhancement of thermoelectric properties during mineralization reactions. The present findings demonstrate the feasibility of thermoelectric energy generation and electron/hole carrier modulation with natural materials that are abundant in the Earth's crust.

A wearable AuNP enhanced metal-organic gel (Au@MOG) sensor for sweat glucose detection with ultrahigh sensitivity.

The demand for sensitive and non-invasive sensors for monitoring glucose levels in sweat has grown considerably in recent years. This study presents the development of a wearable sensor for sweat glucose detection with ultrahigh sensitivity. The sensor was fabricated by embedding Au nanoparticles (AuNPs) and metal-organic gels (MOGs) on nickel foam (NF). A non-enzymatic electrocatalytic glucose sensor has been developed to combine the three-dimensional network of MOGs with more active sites favourable for glucose diffusion and the transfer of electrons from glucose to the electrode. These results show that the sensor has an ultrahigh sensitivity of 13.94 mA mM-1 cm-2, a linear detection range between 2 and 600 µM, and a lower detection limit as low as 1 µM (signal/noise = 3) with comparable accuracy and reliability under non-alkaline conditions to those of high-pressure ion chromatography (HPIC). Furthermore, a wearable sweat glucose sensor has been constructed by sputtering an Au conductive layer on a flexible polydimethylsiloxane (PDMS) substrate and coating it with Au@MOGs. Our work demonstrates that the combination of Au NPs and MOGs can enhance the sensitivity and activity of these materials, making them useful for electrocatalytic glucose monitoring with ultrahigh sensitivity.

Recent advancement, immune responses, and mechanism of action of various vaccines against intracellular bacterial infections.

Emerging and re-emerging bacterial infections are a serious threat to human and animal health. Extracellular bacteria are free-living, while facultative intracellular bacteria replicate inside eukaryotic host cells. Many serious human illnesses are now known to be caused by intracellular bacteria such as Salmonella enterica, Escherichia coli, Staphylococcus aureus, Rickettsia massiliae, Chlamydia species, Brucella abortus, Mycobacterium tuberculosis and Listeria monocytogenes, which result in substantial morbidity and mortality. Pathogens like Mycobacterium, Brucella, MRSA, Shigella, Listeria, and Salmonella can infiltrate and persist in mammalian host cells, particularly macrophages, where they proliferate and establish a repository, resulting in chronic and recurrent infections. The current treatment for these bacteria involves the application of narrow-spectrum antibiotics. FDA-approved vaccines against obligate intracellular bacterial infections are lacking. The development of vaccines against intracellular pathogenic bacteria are more difficult because host defense against these bacteria requires the activation of the cell-mediated pathway of the immune system, such as CD8+ T and CD4+ T. However, different types of vaccines, including live, attenuated, subunit, killed whole cell, nano-based and DNA vaccines are currently in clinical trials. Substantial development has been made in various vaccine strategies against intracellular pathogenic bacteria. This review focuses on the mechanism of intracellular bacterial infection, host immune response, and recent advancements in vaccine development strategies against various obligate intracellular bacterial infections.

Phytoremediation of pollutants from wastewater: A concise review.

As there is a global water crisis facing the whole world, it is important to find alternative solutions to treat wastewater for reuse. Hence, plants have an effective role in removing pollutants from wastewater, which has been emphasized in this review article. Biological treatment of wastewater can be considered an eco-friendly and cost-effective process that depends on in the future. Living organisms, including plants, can remediate pollutants in wastewater, especially in agricultural fields, such as dyes, heavy metals, hydrocarbons, pharmaceuticals, and pesticides. This review discusses the different activities of plants in pollutant elimination from wastewater and sheds light on the utilization of plants in this scope. This review focuses on the remediation of the most common contaminants present in wastewater, which are difficult to the removal with microorganisms, such as bacteria, fungi, and algae. Moreover, it covers the major role of plants in wastewater treatment and the potential of phytoremediation as a possible solution for the global water crisis.

Reflections of Pro-Poor Growth across Agro-Climatic Zones for Farming and Non-Farming Communities: Evidence from Punjab, Pakistan.

The basic objective of the existing study was to inspect the triangular association between economic growth, poverty, and income disparity in farming and non-farming communities across agro-climatic zones in Punjab province, Pakistan. The cross-sectional Household Integrated Economic Survey (HIES) data and Poverty Equivalent Growth Rate (PEGR) methodology were applied from 2001-2002 to 2015-2016. Outcomes of the study found that in a short period, 2001-2002 to 2004-2005; 2004-2005 to 2005-2006; 2005-2006 to 2007-2008; 2007-2008 to 2010-2011; 2010-2011 to 2011-2012; 2011-2012 to 2013-2014; and 2013-2014 to 2015-2016, economic growth has presented hybrid (pro-poor and anti-poor) pattern across both communities of all agro-climatic zones of Punjab province in different periods. In the longer period of 2001-2002 to 2015-2016, economic growth has been pro-poor across both communities of all the zones apart from zone III (Cotton-Wheat Punjab); there is an anti-poor pattern of economic growth. Results for the decomposition of change in poverty further indicate that economic growth is a dominant factor in reducing poverty for all investigated zone. Moreover, a positive redistribution component reduces the beneficial impacts of economic growth for the poor more than for non-poor, that ultimately makes economic development patterns anti-poor in zone III. In the present study, we proposed two-fold policy implications. First, improve the living standard of households in each agro-climatic zone by increasing their incomes. Second, develop a precise taxation system that helps to reduce income disparities among upper-pro to lower-income groups.

Applications of Various Types of Nanomaterials for the Treatment of Neurological Disorders.

Neurological disorders (NDs) are recognized as one of the major health concerns globally. According to the World Health Organization (WHO), neurological disorders are one of the main causes of mortality worldwide. Neurological disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Prion disease, Brain tumor, Spinal cord injury, and Stroke. These diseases are considered incurable diseases because no specific therapies are available to cross the blood-brain barrier (BBB) and reach the brain in a significant amount for the pharmacological effect in the brain. There is a need for the development of strategies that can improve the efficacy of drugs and circumvent BBB. One of the promising approaches is the use of different types of nano-scale materials. These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity. Different types and shapes of nanomaterials have been widely used for the treatment of neurological disorders, including quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These nanoparticles have unique characteristics, including sensitivity, selectivity, and the ability to cross the BBB when used in nano-sized particles, and are widely used for imaging studies and treatment of NDs. In this review, we briefly summarized the recent literature on the use of various nanomaterials and their mechanism of action for the treatment of various types of neurological disorders.

Dynamic reflections of multidimensional health poverty in Pakistan.

The recent methodological development has entirely shifted the identification of poor in the multidimensional spectrum; thereby addressing the multiple health spheres. The present research primarily examines the dynamics of multidimensional health poverty on the basis of HIES & PSLM nationwide survey data from 2013-14 to 2018-19. The study employed Alkire & Foster Alkire, S (2007) Multidimensional Poverty Index to estimate the seven distinct dimensions of health aspects to identify the poor. The results of health poverty demonstrate a declining trend over time at national, provincial and regional level in Pakistan. Interestingly, the regional statistics indicated the poverty as a rural phenomenon of Pakistan. Comparative measures of provinces reveal that Baluchistan has been a severe victim of health poverty at overall as well as regional level during the study period. The population decomposition elaborates that individuals residing in two most populated provinces Punjab & Sindh, were the major contributor to overall profile of health poverty. Findings of dimensional decomposition exposes that five key dimensions i.e. use of health services, quality of health services, maternal health, child health and malnutrition have contributed to the overall profile of multidimensional health poverty.

Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review.

Nanotechnology is the fabrication, characterization, and potential application of various materials at the nanoscale. Over the past few decades, nanomaterials have attracted researchers from different fields because of their high surface-to-volume ratio and other unique and remarkable properties. Cobalt and cobalt oxide nanoparticles (NPs) have various biomedical applications because of their distinctive antioxidant, antimicrobial, antifungal, anticancer, larvicidal, antileishmanial, anticholinergic, wound healing, and antidiabetic properties. In addition to biomedical applications, cobalt and cobalt oxide NPs have been widely used in lithium-ion batteries, pigments and dyes, electronic thin film, capacitors, gas sensors, heterogeneous catalysis, and for environmental remediation purposes. Different chemical and physical approaches have been used to synthesize cobalt and cobalt oxide NPs; however, these methods could be associated with eco-toxicity, cost-effectiveness, high energy, and time consumption. Recently, an eco-friendly, safe, easy, and simple method has been developed by researchers, which uses biotic resources such as plant extract, microorganisms, algae, and other biomolecules such as starch and gelatin. Such biogenic cobalt and cobalt oxide NPs offer more advantages over other physicochemically synthesized methods. In this review, we have summarized the recent literature for the understanding of green synthesis of cobalt and cobalt oxide NPs, their characterization, and various biomedical applications.

Iron-doped zinc oxide nanoparticles-triggered elicitation of important phenolic compounds in cell cultures of Fagonia indica.

The callus cultures of Fagonia indica could prove as factories for the production of important phytochemicals when triggered through different types of stress. In this study, we initiated callus cultures from healthy stem explants in the presence of iron-doped zinc oxide nanoparticles (Fe-ZnO-NPs). We performed experiments with the callus cultures of F. indica to determine the impact of Fe-ZnO-NPs in concentrations (15.62-250 µg/mL) on biomass accumulation, production of important phenolic and flavonoids, and antioxidative potential. Our results showed that maximum callus biomass [Fresh weight (FW) = 13.6 g and Dry weight (DW) = 0.58 ± 0.01] was produced on day 40 when the media was supplemented with 250 µg/mL Fe-ZnO-NPs. Similarly, maximum total phenolic content (268.36 µg GAE/g of DW) was observed in 40 days old callus added with 125 µg/mL Fe-ZnO-NPs. Maximum total flavonoid content (78.56 µg QE/g of DW) was recorded in 20 days old callus grown in 62.5 µg/mL Fe-ZnO-NPs containing media. Maximum total antioxidant capacity (390.74 µg AAE/g of DW) was recorded in 40 days old callus with 125 µg/mL Fe-ZnO-NPs treated cultures, respectively. Similarly, the highest free radical scavenging activity (93.02%) was observed in callus derived from media having 15.62 µg/mL Fe-ZnO-NPs. The antioxidant potential was observed to have positive correlation with TPC (r = 0.44). HPLC analysis showed that Fe-ZnO-NPs produced compounds (e.g., Epigallocatechin gallate) that were either absent or in lesser quantities in the control group. These results showed that Fe-ZnO-NPs elicitors could increase the biomass and activate secondary metabolism in F. indica cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11240-021-02123-1.