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Mitochondria are referred to as the energy centers of cells, and mitochondrial DNA are known to alter the mitochondrial respiratory chain, which reduces cellular energy and causes ion-channel malfunction and neuronal cell death. As majority of the cells contain mitochondria, these disorders involve multiple systems. Since the energy requirements of different tissues vary, their vulnerability to mitochondrial dysfunction also varies in terms of threshold. This causes these disorders to appear clinically in a variety of ways and with significant phenotypic overlap. The genotypic and phenotypic definitions of some specific symptoms are, nevertheless, well established. Potentially deadly mitochondrial toxins are present in some epileptic medications and early diagnosis of the condition can help prevent serious morbidities. We describe a typical case of sodium valproate and lamotrigine-induced fast multiaxial worsening in a patient with myoclonic epilepsy with red ragged fibers (MERRF) as these drugs act as mitochondrial poisons and could prove life threatening for patients with mitochondrial diseases. When mitochondrial cocktail was introduced and the problematic medicines were removed, the symptoms were somewhat reversed. MERRF in progeny of non- consanguineous parents is a rare occurrence resulting in poor prognosis of the disease. Epileptic drugs lamotrigine and sodium valproate should be avoided as these drugs worsen myoclonus and cause mitochondrial toxicities. With knowledge of the information in this scenario, further harm to the patient can be prevented.

An ideal bone regeneration scaffold system needs to meet the high compressive properties of the bone. The stiffness of the scaffold extracellular matrix determines the cell's fate via cell adhesion migration and differentiation in-vitro and in-vivo. This study aims to investigate the effect of hydrothermal treatment on polyelectrolyte complex (PEC) fibrous biomaterials and its effect on scaffold morphology, cell viability, and function in-vitro. FTIR analysis revealed the ability of the thermal treatment to set the interaction of HAp with polymeric PEC fibers. FESEM analysis showed that with an increase in temperature, the interconnectivity and pore size increased (control-82.38 ± 12.92 μm; at 120°C-335.48 ± 85.10 μm). Mechanical tests showed that the scaffolds heated at 90°C showed the highest stiffness in both dry and wet states (dry state: 1.82 ± 0.07 MPa, wet state: 122 ± 1.78 kPa). Additionally, the hydrothermal treatment also improved the aqueous stability as well as swelling capacity. According to the experimental findings, hydrothermal treatment is a useful technique for crosslinker-free gelation with improved mechanical strength and nanofibrous structure. Furthermore, the cell adhesion, proliferation, and osteogenic differentiation of the MG63 cells on the hydrogel scaffolds in-vitro were evaluated by MTT assay, confocal imaging, alkaline phosphatase assay, and collagen estimation. The in-vitro study showed that scaffolds fabricated at 90°C promoted better MG63 cell attachment, proliferation, and differentiation. These results suggest the potential use of hydrothermal treated chitosan-polygalacturonic acid (PgA) fibrous scaffolds in bone tissue engineering.

Dandruff is one of the commonest scalp disorders of high cosmetic value. The clinical features include skin flaking, pruritus, irritation, feeling of a tight or dry scalp and hairfall. These symptoms are mentioned in Ayurveda classics as Twak Sphutana, Kandu, Kesha Bhoomi Rukshata, Keshachyuti in Darunaka described under Kapaalaroga by Acharya Vagbhata. Contemporary treatment of Dandruff advocates prescription that is highly expensive. Thus, there is a need for cost effective, simple and safe intervention in the management of the same. In the present study, a 26-year-old female having the features of Chronic Dandruff was treated with Masha Kanji Shirolepa. Marked improvement in the signs and symptoms were observed after treatment.

BackgroundDuring the intra-erythrocytic proliferation ofPlasmodium falciparum, the host erythrocyte invasion is regarded as a complex and tightly regulated process comprising multiple receptor-ligand interactions, and numerous secretory molecules. Proteins secreted sequentially from apical organelles of merozoites serve as adhesins that play a crucial role in RBC invasion and can serve as vaccine and therapeutic targets.MethodsPurified merozoites were triggered to discharge apical organelle contents by exposure to ionic conditions mimicking that of blood plasma. The secreted proteins were subjected to tandem mass spectrometry, and a well-characterized invasion ligand, RhopH3, was identified. A novel RhopH3 receptor, 14-3-3□ was unearthed using a Bacterial two-hybrid approach. This interaction was confirmed using multiple biophysical and biochemical approaches. We were successful in disrupting this interaction using a de novo peptide binder of 14-3-3□, and we subsequently assessed its effect on merozoite invasion.ResultsA total of 66 proteins were identified in the secretory fraction with apical organellar or merozoite membrane localization. The well-known adhesin, RhopH3 was also identified and its interaction with the host phosphopeptide-binding protein, 14-3-3□ was established. We also discovered a de novo peptide with the potency to disrupt this crucial interaction, thereby blocking merozoite invasion.ConclusionWe, for the first time, report the secretory repertoire of plasmodium merozoite. Our study shows the importance of the erythrocyte protein, 14-3-3□ during the invasion process and paves the way for developing anti-malarial peptides or small molecules that inhibit the host-pathogen interaction, hence abrogating the invasion process.

Sphingolipid is an 18-carbon amino-alcohol-containing lipid with a sphingosine backbone, which when phosphorylated by sphingosine kinase 1 (SphK-1), generates sphingosine-1-phosphate (S1P), an essential lipid signaling molecule. Dysregulation of S1P function has been observed in a variety of pathologies, including severe malaria.

The changing pattern of climate variables has caused extreme weather events and severe disasters especially in mountainous regions. Such events have a detrimental impact on resources, environment and society. Thus, it has become imperative to examine trends and forecast of meteorological variables using scientific modeling approach at micro level. This study makes an attempt to examine trend in temperature and rainfall using Modified Mann–Kendall test and Sen’s slope estimator during 1980–2021. A Bagging-REPTree machine learning model was utilized for forecasting temperature and rainfall trend for the next 20 years (2022–2041) to understand the temporal dynamics in Shimla district of Indian Himalayan state. Correlation coefficient (R), mean squared error (MSE), mean absolute error (MAE), and root mean squared error mean (RMSE) performance were determined to assess effectiveness and precision of the model. The findings revealed that the frequency of intense rainfall in the district has increased, especially during the monsoon season (June–September) during 1980–2021. Annual maximum, minimum, and mean temperatures have exhibited significant variability while annual rainfall has shown a decreasing trend. The forecast analysis revealed significant trend for rainfall during monsoon season and increasing trend in the maximum temperature has been observed during summer and winter seasons. The analysis has provided sufficient evidence of variability and uncertainty in the behavior of meteorological variables. The outcome of the study may help in devising suitable adaptation and mitigation strategies to combat the effect of climate change in the hilly regions. The methodology adopted in the study may help in future progression of the research in different geographical regions of Western Himalayas.

Furunculosis (Localized Otitis externa) is a condition that causes localized inflammation of external ear. Ear pain (Otalgia), redness (erythema) and edema are the most common symptoms found in localized otitis externa. Clinical features of furunculosis can be analyzed under the Lakshanas (signs and symptoms) of Karnashoola (Otalgia). Karnashoola is described as a symptom and as a separate disease entity in Ayurveda. Acharya Sushruta has mentioned about Arkankura (tender leaves of Arka) in the form of eardrop to treat the Karnashoola. This paper aims to highlight the clinical efficacy of Arka patra (leaves of Calotropis gigantea Linn.B.Rr) in Arka (distilled product) form as Karnapichu (aural pack) in the management of localized otitis externa. Arka patra is selected because of its Katu rasa, Tikshna guna, Ushna veerya, Kaphavatahara and Shothahara property. The paper makes a short discussion on the mode of action of Arka patra Arka in the form of Karnapichu based on its bio availability. The present case study highlights all the above said points. Significant changes in reduction of pain and edema were observed.

Acharya Vagbhata has explained about 18 Nasa rogas and Nasanaha is one among them. It occurs due to vitiation of Vata and Kapha and the treatments mentioned in the classics for Nasanaha include Snehapana, Nasya, and Dhoomapana. This case study is of a female patient who complained of recurrent nasal obstruction, watery nasal discharge and headache. Use of nasal decongestants gives her temporary relief from nasal obstruction and she came to the OPD for further management. In the present study, Nasya with Yashtimadhu taila is proved to give good results in Nasanaha.

The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water-soluble aggregation-induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1-Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission-blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell-based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial-dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next-generation antimalarial agents for treating multidrug resistant malaria parasites.

The emergence of Plasmodium falciparum resistance raises an urgent need to find new antimalarial drugs. Here, we report the rational repurposing of the anti-hepatitis C virus drug, alisporivir, a nonimmunosuppressive analog of cyclosporin A, against artemisinin-resistant strains of P. falciparum. In silico docking studies and molecular dynamic simulation predicted strong interaction of alisporivir with PfCyclophilin 19B, confirmed through biophysical assays with a K(d) value of 354.3 nM. Alisporivir showed potent antimalarial activity against chloroquine-resistant (PfRKL-9 with resistance index [Ri] 2.14 ± 0.23) and artemisinin-resistant (PfKelch13(R539T) with Ri 1.15 ± 0.04) parasites. The Ri is defined as the ratio between the IC(50) values of the resistant line to that of the sensitive line. To further investigate the mechanism involved, we analyzed the expression level of PfCyclophilin 19B in artemisinin-resistant P. falciparum (PfKelch13(R539T)). Semiquantitative real-time transcript, Western blot, and immunofluorescence analyses confirmed the overexpression of PfCyclophilin 19B in PfKelch13(R539T). A 50% inhibitory concentration in the nanomolar range, together with the targeting of PfCyclophilin 19B, suggests that alisporivir can be used in combination with artemisinin. Since artemisinin resistance slows the clearance of ring-stage parasites, we performed a ring survival assay on artemisinin-resistant strain PfKelch13(R539T) and found significant decrease in parasite survival with alisporivir. Alisporivir was found to act synergistically with dihydroartemisinin and increase its efficacy. Furthermore, alisporivir exhibited antimalarial activity in vivo. Altogether, with the rational target-based Repurposing of alisporivir against malaria, our results support the hypothesis that targeting resistance mechanisms is a viable approach toward dealing with drug-resistant parasite.

In this article, we use a factorial design of experiments to develop a three-way relationship between the 3-D printing parameters, the microstructural characteristics, and the hysteresis loss of binder jet printed iron silicon. Subsequent analysis of variance is used to validate the hypotheses between the printing process input factors and the output factors. The input factors in this work include the sintering temperature, the addition of boron, and the silicon content in the starting powder. The magnetic output factors of the printed iron silicon include the intrinsic coercivity and the hysteresis loss per cycle, which are extracted via the use of quasi-static magnetic characterization. Additionally, ac magnetic characterization is used to extract the total iron loss of the binder jet printed silicon. The microstructural output factors are extracted via the use of optical microscope. The established relationship can be used to reduce hysteresis loss in binder jet printed iron silicon.

A fast, simple and valued method is developed to observe the quality and quantity of different pharmaceutical brands of cefixime. A spectrophotometric method has been developed for analysis of cefixime (CFX) by reacting with 4-dimethylamino benzaldehyde (DAB) as derivatizing agent. The molar absorptivity of CFX-DAB, newly synthesized derivative was calculated as 3.2 x 105 L.mole-1cm-1 and λ maximum was 393 nm. The calibration curve was developed in range of 5-25 µg.mL-1as this concentration followed beers law. The derivatization reaction is stable and didn’t show any difference in absorbance with radiation interaction for up to one day. The percentage recovery of CFX was checked and calculated in different pharmaceuticals was within 95 to 99.5% with RSD value calculated in between RSD 0.69-0.96% (n=3), respectively. This newly developed and validated procedure was proved to be accurate and precise for the analysis of CFX. This method was successfully applied to check amount of CFX from 7 different brands of pharmaceutical preparations commercially available in Pakistan.

Cold shock proteins are well characterized in bacteria, plants and humans, however there is no information on their existence and role in malaria parasite. Here, we have delineated the function of a novel cold shock protein of Plasmodium falciparum (Pf) which we have annotated ‘PfCoSP’. Our results show that recombinant PfCoSP has both DNA and RNA binding activity, and also interacts with alpha and beta tubulin of Pf. PfCoSP binds with RNA and alpha tubulin simultaneously to form a complex. Expression of PfCoSP was found during asexual blood stages and gametocyte stages of malaria parasite. PfCoSP expression up-regulates many folds upon cold treatment, suggesting its role during hypothermic cold shock. Interestingly, PfCoSP showed binding with human cold shock protein LIN28A inhibitor ‘LI71’ that also inhibits PfCSP -alpha/beta tubulin interactions. LI71 showed antimalarial activity against asexual blood stage and gametocyte stage suggesting its multi-stage, transmission-blocking potential. We propose that PfCoSP may form a workbench for translation during cold stress via its interactions with target mRNAs and the cytoskeleton protein tubulin.

Histone deacetylases (HDACs) play a key role in cellular processes by the regulation of gene transcription. This study contributes a novel insight how Plasmodium falciparum HDAC (PfHDAC-1) is regulated by S1P produced by host erythrocyte SphK-1. The binding of S1P with endogenous nuclear extract PfHDAC-1 and recombinant PfHDAC-1 blocks their activity. A significant modulation in transcriptional regulation of P. falciparum HDAC regulated genes resulted upon inhibition of S1P production through blocking of hSphK-1 by clinical SphK-1 inhibitor PF-543. PF-543 led to profound decrease in S1P in the parasite’s nuclear fraction. The significant modulation of PfHDAC-1 regulated specific candidate genes related to gametocytogenesis, virulence and proliferation was observed in parasite treated with SphK-1 inhibitor, suggesting S1P targets PfHDAC-1 and participates in epigenetic regulation of these key cellular processes. The epigenetic modulation of parasite cell growth and differentiation by host provides a novel approach for the developmenthost-targeted therapeutics.

LAMP diagnosis of malaria is simple and cost-effective with acceptable sensitivity and specificity as compared to standard diagnostic modules such as microscopy, RDTs and nested PCR, and thus its deployment for onsite screening of malaria in resource-limited regions is under consideration. However, the requirement of an electricity-operated dry bath and bulky read-out unit is still a major concern. In an effort to simplify this limitation, we have developed a portable LAMP device and fluorescence readout unit which can be used in the rapid point-of-care diagnosis of malaria. We have developed a point-of-care diagnostic LAMP device that is easy to operate by a mobile application, and the results can be quantified with a fluorescent readout unit. The diagnostic performance of the device was evaluated in 90 P

Objective: COVID-19 has affected millions of people throughout the world and due to the high rate of its spread, it is very vital to protect the people who are at the frontlines of COVID-19 positive cases. In this study, we have analyzed the level of awareness among the Healthcare Workers (HCWs) and level of preparedness by the Healthcare Authorities (HCA) for the safety of HCWs. Study Design: Cross-sectional prospective study. Subjects and Methods: Study was conducted online, for 3 months, from July to September 2020, at various Health Care Facilities (HCF) of Sindh, Pakistan. The survey instrument was circulated among the HCWs and a total of 419 filled forms were received and analyzed using SPSS 24. Results: Out of 419 participants, 54.4% were male and 45.6% female. Half of the respondents were doctors (50.1%) with majority having 1-5 years (61.6%) of experience. It was found that the major sources of information of HCWs about COVID-19 was social media (80.4%) and only 18.6% of HCWs had trainings to deal with pandemics. HCA couldn’t manage to maintain adequate supply of personal protective equipment (PPE) as goggle/eye shields were available only to 20.5% HCWs, shoe covers to 24.3%, N95 masks to 28.5%. Conclusion: We identified serious concern in the source of information but despite that the knowledge and awareness level was quite acceptable among our study respondents. However, greater efforts to be taken for training campaigns for HCWs as well as supply of PPE.

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aβ) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aβ was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aβ in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-ὰ and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aβ deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodent's models.

Background: The frequency of hepatitis C virus infection along with tuberculosis has not been widely investigated and very low statistics on rates of hepatitis C virus co-infection in tuberculosis patients. Hepatotoxicity is the major side effect of anti-tuberculosis therapy hepatitis HCVliver disease elevates the chances of hepatotoxicity up-to five folds. Aim: To see the frequency of Hepatitis Cvirus infection amongst people with diagnosed Tuberculosis using gene X-pert technique. To evaluate the factors associated with HCVinfection in patients with MTBtuberculosis and to determine sensitivity and specificity of the tests. Study design: Comparative analytical study. Place and duration of study: Pathology Department, Civil Hospital Mirpur Khas Sindh from 1stJanuary 2017 to 31st December 2018. Methodology: Three hundred and thirteen patients of tuberculosis diagnosed by Genexpert included while testing hepatitis C virus using immunochromotography rapid test technique, enzyme linked immunosorbent assay method and polymerase chain reaction test for confirmation. Results:Higher frequency of tuberculosis infection in males 57.8%, 42.5% between 20-39 years and 22% of hepatitis C virus infection in tuberculosis patients.Sensitivity of rapid test and enzyme-linked immunosorbent assay was 79% and 96% respectively while the specificity of rapid test and enzyme-linked immunosorbent assay was 91% and 99% respectively. Conclusion: The high frequency of hepatitis C virus co-infection was found among tuberculosis cases in Mirpur Khas Division Sindh. Enzyme-linked immunosorbent assay method is more accurate, reliable as compared to rapid immunochromatographytest for hepatitis C virus and polymerase chain reaction is still gold standard. Keywords: TB, Hepatitis C virus, Mycobacterium tuberculosis,, PCR, Genexpert, Rapid test

Aim: It is estimated that more than half a million of people die worldwide due to various incidences of intentional and unintentional poisoning and of them 84% occur in low- and middle-income countries. The clinical presentation of poisoning cases differs by age group, reason of poisoning, geographic region, substances involved and economic development of the country. The aim of present research was to estimate the incidence of poisoning in Shaheed Benazirabad based on above reasons. Study Design: Cross-sectional prospective study. Place and Duration of Study: Over a period of 6 months between July to December 2019 in a tertiary care hospital in Sindh, Pakistan. Methodology: Study was carried out by enrolling poisoned patients admitted in a tertiary care hospital. A standardized questionnaire was designed based on different variables in surveys conducted by American Association of Poison Control Centers. In total 263 poisoning cases were presented during the study period. The data obtained was coded, entered and analyzed using SPSS 24. Results: It was found that poisoning was more common in male (58.9%) in the age group of 16 to 30 years (48.7%) and single individuals (56.3%) with uneducated (55.1%) and jobless (54%) background. The common reasons of poisoning were suicide (36.5%) and substance involved in poisoning cases were pesticides (42.6%). Of the total cases reported during study period, 17.5% were admitted in Intensive Care Unit and death was reported in 5.3% of cases. Conclusion: It was found that improved regulatory controls for hazardous chemicals, establishing poison control centers and decreasing exposure and reporting time can decrease poisoning cases.

This study focuses on the conversion of groundnut shell into activated carbons via chemical activation using H3PO4, ZnCl2 and KOH. 100 g of groundnut shell was used for activation at 1:1 impregnation ratio (feedstock to the activating agent). The yield (wt%) of activated carbon was in the range of 87–90 wt%. Highest BET surface area was obtained for KOH activated carbon sample (691.69 m2/g). In line with this, methylene blue number was higher in case of KOH activated carbon sample (332.20 mg/g) as compared to H3PO4 (270.20 mg/g) and ZnCl2 (291.20 mg/g) samples. Thermo-gravimetric analysis reveals that all activated carbon samples were thermal stable up to ~ 850 °C. FTIR spectrum shows appearances of minor functional groups in the activated carbons.

A study of the microstructural evolution of a Ni-based superalloy, Allvac 718Plus, in the forged condition, was performed by varying the solutionizing temperature. Different solutionizing temperatures were chosen to obtain different fractions of the gamma prime (Ni3(Al,Ti,Nb), γ′) and delta (Ni3Nb, δ) precipitates. The solutionizing temperatures ranged between 954 to 1100 °C based on the solvus temperature of the γ′ phase. The 954 °C solutionizing treatment resulted in incomplete dissolution of the γ′ phase and a relatively high-volume fraction of the δ phase, which formed preferentially at grain boundaries. The γ′ phase was completely dissolved during each of the other three solutionizing treatments (1000, 1050, and 1100 °C), while the fraction of the δ phase decreased with increasing solutionizing temperature. The 1100 °C solutionizing treatment led to significant grain growth of the matrix γ phase. After solutionizing, the samples were subjected to a standard two-step aging treatment (788 °C for 8 h followed by 704 °C for 8 h) to see the relative effect of the solutionizing on the precipitation during aging.