Accelerated and intensified manufacturing of an adenovirus-vectored vaccine to enable rapid outbreak response.

The Coalition for Epidemic Preparedness Innovations' "100-day moonshot" aspires to launch a new vaccine within 100 days of pathogen identification, followed by large-scale vaccine availability within the "second hundred days." Here, we describe work to optimize adenoviral vector manufacturing for rapid response, by minimizing time to clinical trial and first large-scale supply, and maximizing output from the available manufacturing footprint. We describe a rapid virus seed expansion workflow that allows vaccine release to clinical trials within 60 days of antigen sequence identification, followed by vaccine release from globally distributed sites within a further 40 days. We also describe a perfusion-based upstream production process, designed to maximize output while retaining simplicity and suitability for existing manufacturing facilities. This improves upstream volumetric productivity of ChAdOx1 nCoV-19 by approximately fourfold and remains compatible with the existing downstream process, yielding drug substance sufficient for 10,000 doses from each liter of bioreactor capacity. This accelerated manufacturing process, along with other advantages such as thermal stability, supports the ongoing value of adenovirus-vectored vaccines as a rapidly adaptable and deployable platform for emergency response.

Alleviation potential of green-synthesized selenium nanoparticles for cadmium stress in Solanum lycopersicum L: modulation of secondary metabolites and physiochemical attributes.

KEY MESSAGE: Selenium nanoparticles reduce cadmium absorption in tomato roots, mitigating heavy metal effects. SeNPs can efficiently help to enhance growth, yield, and biomolecule markers in cadmium-stressed tomato plants. In the present study, the effects of selenium nanoparticles (SeNPs) were investigated on the tomato plants grown in cadmium-contaminated soil. Nanoparticles were synthesized using water extract of Nigella sativa and were characterized for their size and shape. Two application methods (foliar spray and soil drench) with nanoparticle concentrations of 0, 100, and 300 mg/L were used to observe their effects on cadmium-stressed plants. Growth, yield, biochemical, and stress parameters were studied. Results showed that SeNPs positively affected plant growth, mitigating the negative effects of cadmium stress. Shoot length (SL), root length (RL), number of branches (NB), number of leaves per plant (NL), and leaf area (LA) were significantly reduced by cadmium stress but enhanced by 45, 51, 506, 208, and 82%, respectively, by soil drench treatment of SeNPs. Similarly, SeNPs increased the fruit yield (> 100%) and fruit weight (> 100%), and decreased the days to fruit initiation in tomato plants. Pigments were also positively affected by the SeNPs, particularly in foliar treatment. Lycopene content was also enhanced by the addition of NPs (75%). Furthermore, the addition of SeNPs improved the ascorbic acid, protein, phenolic, flavonoid, and proline contents of the tomato plants under cadmium stress, whereas stress enzymes also showed enhanced activities under cadmium stress. It is concluded from the present study that the addition of selenium nanoparticles enhanced the growth and yield of Cd-stressed plants by reducing the absorption of cadmium and increasing the stress management of plants.

Neural alterations in working memory of mild-moderate TBI: An fMRI study in Malaysia.

Working memory (WM) encompasses crucial cognitive processes or abilities to retain and manipulate temporary information for immediate execution of complex cognitive tasks in daily functioning such as reasoning and decision-making. The WM of individuals sustaining traumatic brain injury (TBI) was commonly compromised, especially in the domain of WM. The current study investigated the brain responses of WM in a group of participants with mild-moderate TBI compared to their healthy counterparts employing functional magnetic resonance imaging. All consented participants (healthy: n = 26 and TBI: n = 15) performed two variations of the n-back WM task with four load conditions (0-, 1-, 2-, and 3-back). The respective within-group effects showed a right hemisphere-dominance activation and slower reaction in performance for the TBI group. Random-effects analysis revealed activation difference between the two groups in the right occipital lobe in the guided n-back with cues, and in the bilateral occipital lobe, superior parietal region, and cingulate cortices in the n-back without cues. The left middle frontal gyrus was implicated in the load-dependent processing of WM in both groups. Further group analysis identified that the notable activation changes in the frontal gyri and anterior cingulate cortex are according to low and high loads. Though relatively smaller in scale, this study was eminent as it clarified the neural alterations in WM in the mild-moderate TBI group compared to healthy controls. It confirmed the robustness of the phenomenon in TBI with the reproducibility of the results in a heterogeneous non-Western sample.

Thematic analysis of multiple sclerosis research by enhanced strategic diagram.

Recent interest in multiple sclerosis research warrants literature analysis to evaluate the current state of the discipline and new research domains. This bibliometric review summarised the research trends and analysed research areas in multiple sclerosis over the last decade. The documents containing the term 'multiple sclerosis' in the article title were retrieved from the Scopus database. We used Harzing's Publish or Perish and VOSviewer for citation analysis and data visualisation, respectively. We found a total of 18,003 articles published in journals in the English language between 2012 and 2021. The emerging keywords identified utilising the enhanced strategic diagram were 'covid-19', 'teriflunomide', 'clinical trial', 'microglia', 'b cells', 'myelin', 'brain', 'white matter', 'functional connectivity', 'pain', 'employment', 'health-related quality of life', 'meta-analysis' and 'comorbidity'. This study demonstrates the tremendous growth of multiple sclerosis literature worldwide, which is expected to grow more than double during the next decade especially in the identified emerging topics.

The role of mTOR signalling pathway in hypoxia-induced cognitive impairment.

Hypoxia has been associated with cognitive impairment. Many studies have investigated the role of mTOR signalling pathway in cognitive functions but its role in hypoxia-induced cognitive impairment remains controversial. This review aimed to elucidate the role of mTOR in the mechanisms of cognitive impairment that may pave the way towards the mechanistic understanding and therapeutic intervention of hypoxia-induced cognitive impairment. mTORC1 is normally regulated during mild or acute hypoxic exposure giving rise to neuroprotection, whereas it is overactivated during severe or chronic hypoxia giving rise to neuronal cells death. Thus, it is worth exploring the possibility of maintaining normal mTORC1 activity and thereby preventing cognitive impairment during severe or chronic hypoxia.

Tualang Honey: A Decade of Neurological Research.

Tualang honey has been shown to protect against neurodegeneration, leading to improved memory/learning as well as mood. In addition, studies have also demonstrated its anti-inflammatory and antioxidant properties. However, a substantial part of this research lacks systematization, and there seems to be a tendency to start anew with every study. This review presents a decade of research on Tualang honey with a particular interest in the underlying mechanisms related to its effects on the central nervous system. A total of 28 original articles published between 2011 and 2020 addressing the central nervous system (CNS) effects of Tualang honey were analysed. We identified five main categories, namely nootropic, antinociceptive, stress-relieving, antidepressant, and anxiolytic effects of Tualang honey, and proposed the underlying mechanisms. The findings from this review may potentially be beneficial towards developing new therapeutic roles for Tualang honey and help in determining how best to benefit from this brain supplement.

Parcellation of the Hippocampus According to Its Connection Probability with Prefrontal Cortex Subdivisions in a Malaysian Malay Population: Preliminary Findings.

BACKGROUND: Lesion studies have shown distinct roles for the hippocampus, with the dorsal subregion being involved in processing of spatial information and memory, and the ventral aspect coding for emotion and motivational behaviour. However, its structural connectivity with the subdivisions of the prefrontal cortex (PFC), the executive area of the brain that also has various distinct functions, has not been fully explored, especially in the Malaysian population. METHODS: We performed diffusion magnetic resonance imaging with probabilistic tractography on four Malay males to parcellate the hippocampus according to its relative connection probability to the six subdivisions of the PFC. RESULTS: Our findings revealed that each hippocampus showed putative connectivity to all the subdivisions of PFC, with the highest connectivity to the orbitofrontal cortex (OFC). Parcellation of the hippocampus according to its connection probability to the six PFC subdivisions showed variability in the pattern of the connection distribution and no clear distinction between the hippocampal subregions. CONCLUSION: Hippocampus displayed highest connectivity to the OFC as compared to other PFC subdivisions. We did not find a unifying pattern of distribution based on the connectivity-based parcellation of the hippocampus.

Six Months Guided Exercise Therapy Improves Motor Abilities and White Matter Connectivity in Children with Cerebral Palsy.

BACKGROUND: Diffusion magnetic resonance imaging (dMRI) provides the state of putative connectivity from lesioned areas to other brain areas and is potentially beneficial to monitor intervention outcomes. This study assessed the effect of a 6 months guided exercise therapy on motor abilities and white matter diffusivity in the brains of cerebral palsy (CP) children. METHODS: This is a single arm pre-and post-test research design involving 10 spastic CP children, aged 8-18 years and whose Gross Motor Function Classification System Expanded and Revised (GMFCS-E & R) at least Level 21 with the ability to ambulate independently. They were recruited from Paediatric Neurology Clinic, Hospital Universiti Sains Malaysia (HUSM) from December 2015-December 2016. All participants underwent 6 months of therapist-guided exercise session comprising progressive strength training at a frequency of twice a week, 1 h duration per session. The effect of exercise on motor abilities was assessed using the Gross Motor Function Measures (GMFM)-88. Six out of the 10 children consented for dMRI. Probabilistic tractography of the corticospinal tract (CST) was performed to determine the connectivity index of the tracts pre-and post-intervention. RESULTS: All the participants displayed statistically significant increment in GMFM-88 scores pre-to post-exercise intervention. This improvement was concurrent with increased connectivity index in the CST of upper limbs and lower limbs in the brain of these children. CONCLUSION: Our findings demonstrated that 6 months guided exercise therapy improves motor abilities of CP children concurrent with strengthening the connectivities of the motor pathways in the brain.

Opioid-Independent and Opioid-Mediated Modes of Pain Modulation.

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

Characterisation of the Corticospinal Tract Using Diffusion Magnetic Resonance Imaging in Unilateral and Bilateral Cerebral Palsy Patients.

BACKGROUND: Neuroimaging is increasingly used to locate the lesion that causes cerebral palsy (CP) and its extent in the brains of CP patients. Conventional structural magnetic resonance imaging (MRI) does not indicate the connectional pattern of white matter; however, with the help of diffusion MRI, fibre tracking of white matter can be done. METHODS: We used diffusion MRI and probabilistic tractography to identify the putative white matter connectivity in the brains of 10 CP patients. We tracked the corticospinal tract (CST) of the patients' upper and lower limbs and calculated the white matter connectivity, as indexed by streamlines representing the probability of connection of the CST. RESULTS: Our results show that diffusion MRI with probabilistic tractography, while having some relation with the clinical diagnosis of CP, reveals a high degree of individual variation in the streamlines representing the CST for upper and lower limbs. CONCLUSION: Diffusion MRI with probabilistic tractography provides the state of connectivity from lesioned areas to other parts of the brain and is potentially beneficial to be used as an adjunct to the clinical management of CP, providing a means to monitor intervention outcomes.

Neutrophil to lymphocyte ratio predicts disease progression following intra-arterial therapy of hepatocellular carcinoma.

BACKGROUND: Prospectively predicting response to intra-arterial therapy for hepatocellular carcinoma (HCC) is challenging. Neutrophil/lymphocyte ratio (NLR) is a serum biomarker that is associated with survival for multiple malignancies. It was hypothesized that increased NLR would be associated with early disease progression after intra-arterial therapy of HCC. METHODS: The outcomes of 86 treatment-naïve patients who had chemoembolization or radioembolization of HCC between July 2013-July 2014 were reviewed. Pre-treatment laboratory tests and imaging were used to measure NLR, Child-Pugh (CP) score, tumor number and tumor size. High/low NLR groups were defined as >3 and <3 respectively. Follow-up imaging at two months with assessed response using modified response criteria in solid tumors (mRECIST). RESULTS: NLR >3 was seen in 25/86 patients (range 3.0-21.6). NLR >3 patients had a significantly higher baseline CP score. Comorbidities were otherwise similar between groups as was tumor number/size. Disease control was significantly worse (p = 0.014) with NLR >3. Logistic regression for tumor response revealed NLR >3 as the best predictor of early progression (p < 0.0001). DISCUSSION: NLR may be a serologic biomarker of early progressive disease after intra-arterial therapy of HCC. Future research should focus on outcomes by treatment type or potentially combining arterial therapies with ablation and/or targeted biologic agents.

Love as a Modulator of Pain.

Pain is modulated by various factors, the most notable of which is emotions. Since love is an emotion, it can also modulate pain. The answer to the question of whether it enhances or reduces pain needs to be determined. A review was conducted of animal and human studies in which this enigmatic emotion and its interaction with pain was explored. Recent advances in neuroimaging have revealed similarities in brain activation relating to love and pain. At the simplest level, this interaction can be explained by the overlapping network structure in brain functional connectivity, although the explanation is considerably more complex. The effect of love can either result in increased or decreased pain perception. An explanation of the interaction between pain and love relates to the functional connectivity of the brain and to the psychological construct of the individual, as well as to his or her ability to engage resources relating to emotion regulation. In turn, this determines how a person relates to love and reacts to pain.

Pain in Times of Stress.

Stress modulates pain perception, resulting in either stress-induced analgesia or stress-induced hyperalgesia, as reported in both animal and human studies. The responses to stress include neural, endocrine, and behavioural changes, and built-in coping strategies are in place to address stressors. Peculiar to humans are additional factors that modulate pain that are experienced in times of stress, notably psychological factors that potentially influence the directionality of pain perception.

Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen.

A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17 ß -estradiol (E2) on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX) rats. The animals were divided into six groups: (i) nonstressed sham-operated control, (ii) stressed sham-operated control, (iii) nonstressed OVX, (iv) stressed OVX, (v) stressed OVX treated with E2 (20 µg daily, sc), and (vi) stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally). Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH) and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.

The brain in pain.

Pain, while salient, is highly subjective. A sensation perceived as painful by one person may be perceived as uncomfortable, not painful or even pleasant to others. Within the same person, pain may also be modulated according to its threat value and the context in which it is presented. Imaging techniques, such as functional magnetic resonance imaging and positron emission tomography, have identified a distributed network in the brain, the pain-relevant brain regions, that encode the sensory-discriminative aspect of pain, as well as its cognitive and affective/emotional factors. Current knowledge also implicates the prefrontal cortex as the modulatory area for pain, with its subdivisions forming the cortico-cortical pathway, an alternative pain modulatory pathway distinct from the descending modulatory pathway of pain. These findings from neuroimaging in human subjects have paved the way for the molecular mechanisms of pain modulation to be explored in animal studies.

Global research Activity on olfactory marker protein (OMP): A bibliometric and visualized analysis.

Olfactory marker protein (OMP) is extensively studied in mature olfactory receptor neurons (ORNs) for understanding olfaction physiology. However, no bibliometric analysis on this topic exists. We conducted a bibliometric analysis of OMP research articles, wherein the publication count was assessed by year, country, journal, and author, collaboration by country, and productivity of the authors. Additionally, key terms and research themes were identified. Using the search phrase "olfactory marker protein" in Scopus, we retrieved 691 original research articles by 2487 authors since 1974. Publications showed an increasing trend, with the United States leading in quantity and collaboration. Our thematic map highlights "Olfactory bulb, regeneration, olfactory" as the primary research domain, while "olfaction, olfactory sensory neuron, glomerulus" and "olfactory receptor neurons, apoptosis, olfactory dysfunction" emerge as essential future research topics. These bibliometric findings offer insights into the global OMP research landscape, guiding researchers in potential collaborations and intriguing future research fields.

Electroencephalography and mild cognitive impairment research: A scoping review and bibliometric analysis (ScoRBA).

Mild cognitive impairment (MCI) is often considered a precursor to Alzheimer's disease (AD) and early diagnosis may help improve treatment effectiveness. To identify accurate MCI biomarkers, researchers have utilized various neuroscience techniques, with electroencephalography (EEG) being a popular choice due to its low cost and better temporal resolution. In this scoping review, we analyzed 2310 peer-reviewed articles on EEG and MCI between 2012 and 2022 to track the research progress in this field. Our data analysis involved co-occurrence analysis using VOSviewer and a Patterns, Advances, Gaps, Evidence of Practice, and Research Recommendations (PAGER) framework. We found that event-related potentials (ERP), EEG, epilepsy, quantitative EEG (QEEG), and EEG-based machine learning were the primary research themes. The study showed that ERP/EEG, QEEG, and EEG-based machine learning frameworks provide high-accuracy detection of seizure and MCI. These findings identify the main research themes in EEG and MCI and suggest promising avenues for future research in this field.

Emerging trends in gene and bipolar disorder research: a bibliometric analysis and network visualisation.

This study aims to use a bibliometric technique to evaluate the scientific output of gene and bipolar disorder research. The search query related to gene and bipolar disorder from the Scopus database identified 1848 documents from 1951 to 2020. The growth in the publications increased since early 1990, peaked in 2011, and started to decline thereafter. High occurrence in author keywords suggests that some research topics, such as "polymorphism", "linkage" and "association study" have waned over time, whereas others, such as "DNA methylation," "circadian rhythm," "" and "meta-analysis," are now the emerging trends in gene and bipolar disorder research. The USA was the country with the highest production followed by the UK, Canada, Italy and Germany. The leading institutions were Cardiff University in the UK, the National Institute of Mental Health (NIMH) in the USA, King's College London in the UK and the University of California, San Diego in the USA. The leading journals publishing gene and bipolar literature were the American Journal of Medical Genetics Neuropsychiatric Genetics, Molecular Psychiatry and Psychiatric Genetics. The top authors in the number of publications were Craddock N, Serretti A and Rietschel M. According to the co-authorship network analysis of authors, the majority of the authors in the same clusters were closely linked together and originated from the same or neighbouring country. The findings of this study may be useful in identifying emerging topics for future research and promoting research collaboration in the field of genetic studies related to bipolar disorder.

Global trends and themes in genetic counseling research.

This article seeks to highlight the most recent trends and themes in genetic counseling that are of broad interest. A total of 3505 documents were published between 1952 and 2021, with a trend toward increase in paper/year. The most common documents are original articles (2515, 71.8%), followed by review articles (341, 9.7%). Journal of Genetic Counseling publishes the highest number of genetic counseling articles (587, 16.7%), followed by Clinical Genetics (103, 2.9%) and the South American Journal of Medical Genetics (95, 2.7%). Co-occurrence analysis revealed five research themes: genetic testing, cancer, genetic counselor, prenatal diagnosis, and psychiatry. The genetic counselor theme contained most of the recent keywords, including "covid-19," "underrepresented population," "service delivery models," "workforce," "disparities," "service delivery," "professional development," "cultural competence," "access," "diversity," "telemedicine," and "health literacy." Genetic counseling researchers may use these keywords to find topics pertinent to their future research and practice.

Gene and schizophrenia in the pregenome and postgenome-wide association studies era: a bibliometric analysis and network visualization.

This study aimed to perform a bibliometric analysis on genetic studies in schizophrenia in the pregenome-wide association studies (GWAS) and post-GWAS era. We searched the literature on genes and schizophrenia using the Scopus database. The documents increased with time, especially after the human genome project and International HapMap Project, with the highest citation in 2008. The top occurrence author keywords were discovered to be different in the pre-GWAS and post-GWAS eras, reflecting the progress of genetic studies connected to schizophrenia. Emerging keywords highlighted a trend towards an application of precision medicine, showing an interplay of environmental exposures as well as genetic factors in schizophrenia pathogenesis, progression, and response to therapy. In conclusion, the gene and schizophrenia literature has grown rapidly after the human genome project, and the temporal variation in the author keywords pattern reflects the trend of genetic studies related to schizophrenia in the pre-GWAS and post-GWAS era.