The synergistic potential of biochar and nanoparticles in phytoremediation and enhancing cadmium tolerance in plants.

Cadmium (Cd) is classified as a heavy metal (HM) and is found into the environment through both natural processes and intensified anthropogenic activities such as industrial operations, mining, disposal of metal-laden waste like batteries, as well as sludge disposal, excessive fertilizer application, and Cd-related product usage. This rising Cd disposal into the environment carries substantial risks to the food chain and human well-being. Inadequate regulatory measures have led to Cd bio-accumulation in plants, which is increasing in an alarming rate and further jeopardizing higher trophic organisms, including humans. In response, an effective Cd decontamination strategy such as phytoremediation emerges as a potent solution, with innovations in nanotechnology like biochar (BC) and nanoparticles (NPs) further augmenting its effectiveness for Cd phytoremediation. BC, derived from biomass pyrolysis, and a variety of NPs, both natural and less toxic, actively engage in Cd removal during phytoremediation, mitigating plant toxicity and associated hazards. This review scrutinizes the application of BC and NPs in Cd phytoremediation, assessing their synergistic mechanism in influencing plant growth, genetic regulations, structural transformations, and phytohormone dynamics. Additionally, the review also underscores the adoption of this sustainable and environmentally friendly strategies for future research in employing BC-NP microaggregates to ameliorate Cd phytoremediation from soil, thereby curbing ecological damage due to Cd toxicity.

The Multifaceted Role of Jasmonic Acid in Plant Stress Mitigation: An Overview.

Plants, being sessile, have developed complex signaling and response mechanisms to cope with biotic and abiotic stressors. Recent investigations have revealed the significant contribution of phytohormones in enabling plants to endure unfavorable conditions. Among these phytohormones, jasmonic acid (JA) and its derivatives, collectively referred to as jasmonates (JAs), are of particular importance and are involved in diverse signal transduction pathways to regulate various physiological and molecular processes in plants, thus protecting plants from the lethal impacts of abiotic and biotic stressors. Jasmonic acid has emerged as a central player in plant defense against biotic stress and in alleviating multiple abiotic stressors in plants, such as drought, salinity, vernalization, and heavy metal exposure. Furthermore, as a growth regulator, JA operates in conjunction with other phytohormones through a complex signaling cascade to balance plant growth and development against stresses. Although studies have reported the intricate nature of JA as a biomolecular entity for the mitigation of abiotic stressors, their underlying mechanism and biosynthetic pathways remain poorly understood. Therefore, this review offers an overview of recent progress made in understanding the biosynthesis of JA, elucidates the complexities of its signal transduction pathways, and emphasizes its pivotal role in mitigating abiotic and biotic stressors. Moreover, we also discuss current issues and future research directions for JAs in plant stress responses.

Thirty novel sequence variants impacting human intracranial volume.

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Assessing the performance of sustainable entrepreneurship and environmental corporate social responsibility: revisited environmental nexus from business firms.

Society is currently contemplating sustainable growth strategies, which have become somewhat apprehensive by associating entrepreneurship, innovation, and sustainable development. In this perspective, this article's objective is to connect sustainable development to environmentally sensitive entrepreneurship via scientific proof of developing nations. Therefore, this research objective is to confirm the hypothesis of corporate social responsibility (CSR) to confirm that Pakistan achieves its objectives for sustainable development. The combined average estimator and pooled mean group (PMG) model of the self-release lag model determines a lengthy-term combination of factors and environmental analysis in the Kuznets. We can see the U-shaped ecological arcs in Pakistan. Further results show that the pooled mean group autoregressive distributed lag (PMG-ARDL) estimator has a long-term relationship. This indicates that a 1% rise in per-capita income at some stage of industrial growth will reduce environmental emissions by 2.88%, 4.54%, and 2.48%. The results show that (1) CSR has a substantial and robust link to the two factors of organizational success (employee engagement and credibility); (ii) respectively socio-cultural and ecological CSR make a positive contribution to the success of Pakistani companies; (iii) the ecological dimensions of CSR being the essential relevance to Pakistani companies' credibility and engagement of employees. This research attempts to include additional analytical information on the contribution of CSR to profitable growth. This also has academic and empirical ramifications, showing how domestic and international companies in developing countries can do CSR. This research is expected to give guidance to policymakers.

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo.

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

How well has economic strategy changed CO2 emissions? Evidence from China's largest emission province.

In recent years, Shandong Province became one of China's largest carbon emitters; however, existing studies failed to capture the recent trends and the key driving factors behind it at the city level. In this study, we computed the city-level CO2 emission by employing accounting methods and Logarithmic Mean Divisia Index (LMDI) to provide a holistic picture and measure the contributing factors CO2 emissions across 16 cities in Shandong Province during 2010-2018. Research outcomes indicate that Shandong's CO2 emissions showed an increasing trend during 2010-2018, except in 2013. Shandong Province's GDP per capita and population size promote energy-related CO2 emissions from 2010 to 2018. Energy intensity is the main driving force behind Shandong's significant CO2 emission growth, followed by the energy consumption structure. Emission intensity and regional structure partly offset the CO2 emission increase. Industrial structure is the most important driving factor in reducing emissions; however, its emission reduction effect is not stable in some cities and sectors, especially for the nonmetal and metal industry, petroleum and chemical industry, and energy sector. Dongying is the top emitter across Shandong from 2010 to 2018. Its emissions mainly come from the petroleum and chemical industry. The largest driving factors are the energy intensity and industrial structure. Investigating CO2 emissions at the city level yields a strong recommendation that Shandong Province's regions cooperate to improve development patterns.

A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy.

Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10-11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.

Large genome-wide association study identifies three novel risk variants for restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10-18), rs10068599-T (OR = 1.09, P = 6.9 × 10-10) and rs10769894-A (OR = 0.90, P = 9.4 × 10-14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

China's seaborne oil import and shipping emissions: The prospect of belt and road initiative.

China's seaborne foreign oil supply through the Malacca Strait is facing security challenges due to territorial disputes, pirate attacks, and geopolitics. To overcome these challenges, China plans to import oil through one of the corridors of the Belt and Road Initiative (BRI)-the China-Pakistan Economic Corridor (CPEC). This study estimated and compared ship emissions and their externalities associated with seaborne oil supply from the top five oil suppliers to China through the existing shipping route via the Malacca Strait and proposed route via CEPC. Ship activity-based methodology is applied to estimate the emissions of air pollutants (CO2, NOx, SO2, PM10, and CO) during cruising, maneuvering, and hoteling periods. The results show that the total ship emissions of China's seaborne oil supply can be significantly reduced from 6.2 million tons to 2.1 million tons via the CPEC route. While external cost can be reduced up to 65.9% via the CPEC route.

COVID-19 pandemic and environmental pollution: A blessing in disguise?

In late 2019, a novel infectious disease with human to human transmission (COVID-19) was identified in Wuhan China, which now has turned into a global pandemic. Countries all over the world have implemented some sort of lockdown to slow down its infection and mitigate it. Lockdown due to COVID-19 has drastic effects on social and economic fronts. However, this lockdown also has some positive effect on natural environment. Recent data released by NASA (National Aeronautics and Space Administration) and ESA (European Space Agency) indicates that pollution in some of the epicenters of COVID-19 such as Wuhan, Italy, Spain and USA etc. has reduced up to 30%. This study compiled the environmental data released by NASA and ESA before and after the coronavirus pandemic and discusses its impact on environmental quality.

Different impacts of export and import on carbon emissions across 7 ASEAN countries: A panel quantile regression approach.

ASEAN (Association of Southeast Asian Nations) has contributed numerous carbon emissions during the phase of industrialization. This study mainly compares the different effects of export and import on CO2 emissions across 7 ASEAN countries over 1990-2017. In addition, we investigate how technological innovation affects carbon emissions. Stationary tests are conducted through cross section dependence, unit root of panel data, and Westerlund cointegration. The results of panel quantile regression show that export and import both have adverse effects on CO2 emissions. EKC is valid in these countries. Moreover, population size and energy intensity increase carbon emissions. In particular, technology innovation significantly reduces carbon emissions by augmenting energy efficiency. It is important to improve eco-innovation, and expand knowledge-intensive industries in ASEAN countries.

In Silico Structure Modeling and Molecular Docking Analysis of Phosphoribosyl Pyrophosphate Amidotransferase (PPAT) with Antifolate Inhibitors.

BACKGROUND: Cancer remains one of the most serious disease worldwide. Robust metabolism is the hallmark of cancer. PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the first committed step of de novo purine biosynthesis. Hence PPAT, the key regulatory spot in De novo purine nucleotide biosynthesis, is an attractive and credible drug target for leukemia and other cancer therapeutics. OBJECTIVE: In the present study, detailed computational analysis has been performed for PPAT protein, the key enzyme in de novo purine biosynthesis which is inhibited by many folate derivatives, hence we aimed to investigate and gauge the inhibitory effect of antifolate derivatives; lomexterol (LTX) methotrexate (LTX), and pipretixin (PTX) with human PPAT to effectively capture and inhibit De novo purine biosynthesis pathway. METHODS: The sequence to structure computational approaches followed by molecular docking experiments was performed to gain insight into the inhibitory mode, binding orientation and binding affinities of selected antifolate derivatives against important structural features of PPAT. RESULTS: Results indicated a strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and electrostatic interactions. CONCLUSION: Conclusively, the strong physical interaction of selected antifolate inhibitors with human PPAT suggests the selective inhibition of De novo purine biosynthesis pathway by antifolate derivatives towards cancer therapeutics.

In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA.

In humans, purine de novo synthesis pathway consists of multi-functional enzymes. Nucleotide metabolism enzymes are potential drug targets for treating cancer and autoimmune diseases. Glycinamide ribonucleotide transformylase (GART) is one of the most important trifunctional enzymes involved in purine synthesis. Previous studies have demonstrated the role of folate inhibitors against tumor activity. In this present study, three components of GART enzyme were targeted as receptor dataset and in silico analysis was carried out with folate ligand dataset. To accomplish the task, Autodock 4.2 was used for determining the docking compatibilities of ligand and receptor dataset. Taken together, it has been suggested that folate ligands could be potentially used as inhibitors of GART.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Nanoneurotoxicity to nanoneuroprotection using biological and computational approaches.

Nanoparticles (NPs) that are ∼100 nm in diameter can potentially cause toxicity in the central nervous system (CNS). Although NPs exhibit positive aspects, these molecules primarily exert negative or harmful effects. Thus, the beneficial and harmful effects should be compared. The prevalence of neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and some brain tumors, has increased. However, the major cause of these diseases remains unknown. NPs have been considered as one of the major potential causes of these diseases, penetrating the human body via different pathways. This review summarizes various pathways for NP-induced neurotoxicity, suggesting the development of strategies for nanoneuroprotection using in silico and biological methods. Studies of oxidative stress associated with gene expression analyses provide efficient information for understanding neuroinflammation and neurodegeneration associated with NPs. The brain is a sensitive and fragile organ, and evolution has developed mechanisms to protect it from injury; however, this protection also hinders the methods used for therapeutic purposes. Thus, brain and CNS-related diseases that are the cause of disability and disorder are the most difficult to treat. There are many obstacles to drug delivery in the CNS, such as the blood brain barrier and blood tumor barrier. Considering these barriers, we have reviewed the strategies available to map NPs using biological techniques. The surface adsorption energy of NPs is the basic force driving NP gathering, protein corona formation, and many other interactions of NPs within biological systems. These interactions can be described using an approach named the biological surface adsorption index. A quantitative structural activity relationship study helps to understand different protein-protein or protein-ligand interactions. Moreover, equilibrium between cerebrovascular permeability is required when a drug is transferred via the circulatory system for the therapy of neurodegenerative diseases. Various drug delivery approaches, such as chemical drug delivery and carrier-mediated drug delivery, have been established to avoid different barriers inhibiting CNS penetration by therapeutic substances. Developing an improved understanding of drug receptors and the sites of drug action, together with advances in medicinal chemistry, will make it possible to design drugs with greatly enhanced activity and selectivity; this may result in a significant increase in the therapeutic index.

In silico analysis of the amido phosphoribosyltransferase inhibition by PY873, PY899 and a derivative of isophthalic acid.

Selectively decreasing the availability of precursors for the de novo biosynthesis of purine nucleotides is a valid approach towards seeking a cure for leukaemia. Nucleotides and deoxynucleotides are required by living cells for syntheses of RNA, DNA, and cofactors such as NADP(+), FAD(+), coenzyme A and ATP. Nucleotides contain purine and pyrimidine bases, which can be synthesized through salvage pathway as well. Amido phosphoribosyltransferase (APRT), also known as glutamine phosphoribosylpyrophosphate amidotransferase (GPAT), is an enzyme that in humans is encoded by the PPAT (phosphoribosyl pyrophosphate amidotransferase) gene. APRT catalyzes the first committed step of the de novo pathway using its substrate, phosphoribosyl pyrophosphate (PRPP). As APRT is inhibited by many folate analogues, therefore, in this study we focused on the inhibitory effects of three folate analogues on APRT activity. This is extension of our previous wet lab work to analyze and dissect molecular interaction and inhibition mechanism using molecular modeling and docking tools in the current study. Comparative molecular docking studies were carried out for three diamino folate derivatives employing a model of the human enzyme that was built using the 3D structure of Bacillus subtilis APRT (PDB ID; 1GPH) as the template. Binding orientation of interactome indicates that all compounds having nominal cluster RMSD in same active site's deep narrow polar fissure. On the basis of comparative conformational analysis, electrostatic interaction, binding free energy and binding orientation of interactome, we support the possibility that these molecules could behave as APRT inhibitors and therefore may block purine de novo biosynthesis. Consequently, we suggest that PY899 is the most active biological compound that would be a more potent inhibitor for APRT inhibition than PY873 and DIA, which also confirms previous wet lab report.

Prediction of structure of human WNT-CRD (FZD) complex for computational drug repurposing.

The observed genetic alterations of various extracellular and intracellular WNT (Wingless, Int-1 proto-oncogene) signaling components can result in an increase or decrease in gene expression, and hence can be obstructed proficiently. These genetics target sites may include the prevention of WNT-FZD (Frizzled) binding, destruction of ß-catenin and formation of Axin, APC and GSK-3ß complex. Hence, the localized targeting of these interacting partners can help in devising novel inhibitors against WNT signaling. Our present study is an extension of our previous work, in which we proposed the co-regulated expression pattern of the WNT gene cluster (WNT-1, WNT-6, WNT-10A and WNT-10B) in human breast carcinoma. We present here the computationally modeled three dimensional structure of human WNT-1 in complex with the FZD-1 CRD (Cysteine Rich Domain) receptor. The dimeric cysteine-rich domain was found to fit into the evolutionarily conserved U-shaped groove of WNT protein. The two ends of the U- shaped cleft contain N-terminal and C-terminal hydrophobic residues, thus providing a strong hydrophobic moiety for the frizzled receptor and serving as the largest binding pocket for WNT-FZD interaction. Detailed structural analysis of this cleft revealed a maximum atomic distance of ~28 Å at the surface, narrowing down to ~17 Å and again increasing up to ~27 Å at the bottom. Altogether, structural prediction analysis of WNT proteins was performed to reveal newer details about post-translational modification sites and to map the novel pharmacophore models for potent WNT inhibitors.

Molecular interaction study of N1-p-fluorobenzyl-cymserine with TNF-α , p38 kinase and JNK kinase.

Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid- beta peptide (Aß) containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Aß and p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase- inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation,Aß and p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-α with respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation.