Ferulic acid reinstates mitochondrial dynamics through PGC1α expression modulation in 6-hydroxydopamine lesioned rats.

Disruption of the tightly regulated mitochondrial dynamics and energy homeostasis leads to oxidative stress and apoptotic cell death, as observed in neurodegenerative disorders such as Parkinson's disease (PD). Polyphenolic plant derivatives have been shown to alleviate such pathological features and have been used in models of neurodegenerative disorders in previous reports. In the current study, we utilized a 6-hydroxydopamine (6-OHDA) lesioned rat model of PD to explore the protective efficacy of polyphenolic phytochemical ferulic acid (FA) against mitochondrial dysfunction and explored its effect on gene and protein expression of mitochondrial dynamics regulators dynamin-related protein 1 (Drp1)/mitofusin 2 (Mfn2) in lesioned animals. We also evaluated its effect on expression of mitochondrial biogenesis regulator PGC1α and apoptotic regulators BAX, cyt c, p53, and cleaved PARP. We found that oral FA supplementation alleviated 6-OHDA induced oxidative stress, DNA fragmentation, morphological changes, and blocked apoptotic cascade. FA also reduced mitochondrial Drp1 expression and increased gene and protein expression of PGC1α, thereby regulating expression of its downstream target Mfn2 and restoring mitochondrial dynamics in lesioned animals. Our data suggest that targeting mitochondrial dynamics through modulation of PGC1α can prove to be a potent preventive strategy against PD pathology.

Over expression of a synthetic gene encoding interferon lambda using relative synonymous codon usage bias in Escherichia coli.

Interferon Lambda (IFN-λ) is a type III interferon which belongs to a novel family of cytokines and possesses antiviral and antitumor properties. It is unique in its own class of cytokines; because of the specificity towards its heterodimer receptors and its structural similarities with cytokines of other classes. This renders IFN-λ a better choice for the treatment against many diseases including viral hepatitis and human coronavirus (HCoV-EMC). The present study describes a computational approach known as relative synonymous codon usage (RSCU); used to enhance the expression of IFN-λ protein in a eukaryotic expression system. Manually designed and commercially synthesized IFN-λ gene was cloned into pET-22b expression plasmid under the control of inducible T7-lac promoter. Maximum levels of IFN-λ expression was observed with 0.4 mM IPTG in transformed E. coli incubated for 4 hours in LB medium. Higher concentrations of IPTG had no or negative effect on the expression of IFN-λ. This synthetically over expressed IFN-λ can be tested as a targeted treatment option for viral hepatitis after purification.

Virtual reality in post-stroke neurorehabilitation - a systematic review and meta-analysis.

BACKGROUND: Stroke is a neurological disorder and one of the leading causes of disability worldwide. The patient may lose the ability to adequately move the extremities, perceive sensations, or ambulate independently. Recent experimental studies have reported the beneficial influence of virtual reality training strategies on improving overall functional abilities for stroke survivors. METHODS: Conducted a systematic review of the literature using the following keywords to retrieve the data: stroke, virtual reality, motor deficits, neurorehabilitation, cognitive impairments, and sensory deficits. A random-effect meta-analysis was performed for seven scales - one cognitive (MMSE) and six motor (Fugl-Meyer, Berg Balance Scale, Time up and go, Wolf motor function, 10 m walk, Brunnstrom score). OBJECTIVE: To organize and compare all the available data regarding the effectiveness of virtual reality for stroke rehabilitation. RESULTS: This literature reviewed 150 studies and included 46 for qualitative and 27 for quantitative analysis. There was no statistically significant difference between groups in MMSE score (MD = 0.24, 95%CI = ((-0.42) -(0.9)), p = .47, I2 = 0%) and Fugl-Meyer score (MD = (-0.38), 95%CI = ((-12.88)-(12.11)), p = .95, I2 = 98%) . The statistical significance was not reached in any of the other outcomes. CONCLUSIONS: This review supports that stroke rehabilitation programs incorporating virtual reality are associated with improved functional outcomes, but there is no statistically significant difference compared to standard therapy.

What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior.

Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.

Co-infections as Modulators of Disease Outcome: Minor Players or Major Players?

Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.

Respiratory Co-Infections: Modulators of SARS-CoV-2 Patients' Clinical Sub-Phenotype.

Co-infection with ancillary pathogens is a significant modulator of morbidity and mortality in infectious diseases. There have been limited reports of co-infections accompanying SARS-CoV-2 infections, albeit lacking India specific study. The present study has made an effort toward elucidating the prevalence, diversity and characterization of co-infecting respiratory pathogens in the nasopharyngeal tract of SARS-CoV-2 positive patients. Two complementary metagenomics based sequencing approaches, Respiratory Virus Oligo Panel (RVOP) and Holo-seq, were utilized for unbiased detection of co-infecting viruses and bacteria. The limited SARS-CoV-2 clade diversity along with differential clinical phenotype seems to be partially explained by the observed spectrum of co-infections. We found a total of 43 bacteria and 29 viruses amongst the patients, with 18 viruses commonly captured by both the approaches. In addition to SARS-CoV-2, Human Mastadenovirus, known to cause respiratory distress, was present in a majority of the samples. We also found significant differences of bacterial reads based on clinical phenotype. Of all the bacterial species identified, ∼60% have been known to be involved in respiratory distress. Among the co-pathogens present in our sample cohort, anaerobic bacteria accounted for a preponderance of bacterial diversity with possible role in respiratory distress. Clostridium botulinum, Bacillus cereus and Halomonas sp. are anaerobes found abundantly across the samples. Our findings highlight the significance of metagenomics based diagnosis and detection of SARS-CoV-2 and other respiratory co-infections in the current pandemic to enable efficient treatment administration and better clinical management. To our knowledge this is the first study from India with a focus on the role of co-infections in SARS-CoV-2 clinical sub-phenotype.

Perillyl Alcohol Mitigates Behavioural Changes and Limits Cell Death and Mitochondrial Changes in Unilateral 6-OHDA Lesion Model of Parkinson's Disease Through Alleviation of Oxidative Stress.

In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.

Threading the Pieces Together: Integrative Perspective on SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has challenged the research community globally to innovate, interact, and integrate findings across hierarchies. Research on SARS-CoV-2 has produced an abundance of data spanning multiple parallels, including clinical data, SARS-CoV-2 genome architecture, host response captured through transcriptome and genetic variants, microbial co-infections (metagenome), and comorbidities. Disease phenotypes in the case of COVID-19 present an intriguing complexity that includes a broad range of symptomatic to asymptomatic individuals, further compounded by a vast heterogeneity within the spectrum of clinical symptoms displayed by the symptomatic individuals. The clinical outcome is further modulated by the presence of comorbid conditions at the point of infection. The COVID-19 pandemic has produced an expansive wealth of literature touching many aspects of SARS-CoV-2 ranging from causal to outcome, predisposition to protective (possible), co-infection to comorbidity, and differential mortality globally. As challenges provide opportunities, the current pandemic's challenge has underscored the need and opportunity to work for an integrative approach that may be able to thread together the multiple variables. Through this review, we have made an effort towards bringing together information spanning across different domains to facilitate researchers globally in pursuit of their response to SARS-CoV-2.

Megaloblastic anemia: A common but often neglected cause of pyrexia of unknown origin.

OBJECTIVE: The objective was to study megaloblastic anemia as a cause of pyrexia of unknown origin (PUO). MATERIALS AND METHODS: We conducted a study on 15 patients of megaloblastic anemia associated with fever, attending our hospital clinics over a period of 6 months. RESULTS: While 11 patients had symptoms suggesting foci of infection and responded well to intravenous antibiotics, 4 patients had neither any evidence of infection nor responded with empirical broad spectrum antibiotic treatment. They were treated with vitamin B12/folate therapy which led to marked improvement in fever within 48 h. Presenting complaints of the patients and severity/duration of fever along with other epidemiological data were also studied in each case. CONCLUSION: The present study led us to conclude that megaloblastic anemia forms an important and reversible cause of fever and should be ruled out in all patients presenting with PUO. This knowledge would help the physicians in adequate and timely management of these patients.