Microbial Consortia: Promising Tool as Plant Bioinoculants for Agricultural Sustainability.

In the present scenario, growing population demands more food, resulting in the need for sustainable agriculture. Numerous approaches are explored in response to dangers and obstacles to sustainable agriculture. A viable approach is to be exploiting microbial consortium, which generate diverse biostimulants with growth-promoting characteristics for plants. These bioinoculants play an indispensable role in optimizing nutrient uptake efficiency mitigating environmental stress. Plant productivity is mostly determined by the microbial associations that exist at the rhizospheric region of plants. The engineered consortium with multifunctional attributes can be effectively employed to improve crop growth efficacy. A number of approaches have been employed to identify the efficient consortia for plant growth and enhanced crop productivity. Various plant growth-promoting (PGP) microbes with host growth-supporting characteristics were investigated to see if they might work cohesively and provide a cumulative effect for improved growth and crop yield. The effective microbial consortia should be assessed using compatibility tests, pot experimentation techniques, generation time, a novel and quick plant bioassay, and sensitivity to external stimuli (temperature, pH). The mixture of two or more microbial strains found in the root microbiome stimulates plant growth and development. The present review deals with mechanism, formulation, inoculation process, commercialization, and applications of microbial consortia as plant bioinoculants for agricultural sustainability.

Bacterial biopesticides: Biodiversity, role in pest management and beneficial impact on agricultural and environmental sustainability.

Agro-environmental sustainability is based upon the adoption of efficient resources in agro-practices that have a nominal impact on the ecosystem. Insect pests are responsible for causing severe impacts on crop productivity. Wide ranges of agro-chemicals have been employed over the last 50 years to overcome crop yield losses due to insect pests. But better knowledge about the hazards due to chemical pesticides and other pest resistance and resurgence issues necessitates an alternative for pest control. The applications of biological pesticides offer a best alternate that is safe, cost-effective, easy to adoption and successful against various insect pests and pathogens. Like other organisms, insects can get a wide range of diseases from various microbes, such as bacteria, fungi, viruses, protozoa, and nematodes. In order to create agricultural pest management practices that are environmentally beneficial, bacterial entomopathogens are being thoroughly studied. Utilization of bacterial biopesticides has been adopted for the protection of agricultural products. The different types of toxin complexes released by various microorganisms and their mechanisms of action are recapitulated. The present review described the diversity and biocontrol prospective of certain bacteria and summarised the potential of bacterial biopesticides for the management of agricultural pests, insects, and other phytopathogenic microorganisms in agricultural practices.

Silicon derived benefits to combat biotic and abiotic stresses in fruit crops: Current research and future challenges.

Fruit crops are frequently subjected to biotic and abiotic stresses that can significantly reduce the absorption and translocation of essential elements, ultimately leading to a decrease in crop yield. It is imperative to grow fruits and vegetables in areas prone to drought, salinity, and extreme high, and low temperatures to meet the world's minimum nutrient demand. The use of integrated approaches, including supplementation of beneficial elements like silicon (Si), can enhance plant resilience under various stresses. Silicon is the second most abundant element on the earth crust, following oxygen, which plays a significant role in development and promote plant growth. Extensive efforts have been made to explore the advantages of Si supplementation in fruit crops. The application of Si to plants reinforces the cell wall, providing additional support through enhancing a mechanical and biochemical processes, thereby improving the stress tolerance capacity of crops. In this review, the molecular and physiological mechanisms that explain the beneficial effects of Si supplementation in horticultural crop species have been discussed. The review describes the role of Si and its transporters in mitigation of abiotic stress conditions in horticultural plants.

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

Collaboration and knowledge integration for successful brain therapeutics - lessons learned from the pandemic.

Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as well as drug discovery paradigms in recent years, these have not been sufficiently translated into effective treatments. This Special Article expands on Keystone Symposia's pre- and post-pandemic panel discussions on translational neuroscience research. In the article, we discuss how lessons learned from the COVID-19 pandemic can catalyze critical progress in translational research, with efficient collaboration bridging the gap between basic discovery and clinical application. To achieve this, we must place patients at the center of the research paradigm. Furthermore, we need commitment from all collaborators to jointly mitigate the risk associated with the research process. This will require support from investors, the public sector and pharmaceutical companies to translate disease mechanisms into world-class drugs. We also discuss the role of scientific publishing in supporting these models of open innovation. Open science journals can now function as hubs to accelerate progress from discovery to treatments, in neuroscience in particular, making this process less tortuous by bringing scientists together and enabling them to exchange data, tools and knowledge effectively. As stakeholders from a broad range of scientific professions, we feel an urgency to advance brain disease therapies and encourage readers to work together in tackling this challenge.

A Comparative Analysis of Laser Additive Manufacturing of High Layer Thickness Pure Ti and Inconel 718 Alloy Materials Using Finite Element Method.

Investigation of the selective laser melting (SLM) process, using finite element method, to understand the influences of laser power and scanning speed on the heat flow and melt-pool dimensions is a challenging task. Most of the existing studies are focused on the study of thin layer thickness and comparative study of same materials under different manufacturing conditions. The present work is focused on comparative analysis of thermal cycles and complex melt-pool behavior of a high layer thickness multi-layer laser additive manufacturing (LAM) of pure Titanium (Ti) and Inconel 718. A transient 3D finite-element model is developed to perform a quantitative comparative study on two materials to examine the temperature distribution and disparities in melt-pool behaviours under similar processing conditions. It is observed that the layers are properly melted and sintered for the considered process parameters. The temperature and melt-pool increases as laser power move in the same layer and when new layers are added. The same is observed when the laser power increases, and opposite is observed for increasing scanning speed while keeping other parameters constant. It is also found that Inconel 718 alloy has a higher maximum temperature than Ti material for the same process parameter and hence higher melt-pool dimensions.

Video research visits for atypical parkinsonian syndromes among Fox Trial Finder participants.

BACKGROUND: Use of video research visits in neurologic conditions is rising, but their utility has not been assessed in atypical parkinsonian syndromes. We sought to evaluate the diagnostic concordance between video-based vs self-reported diagnoses of multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and corticobasal syndrome. We also assessed patient satisfaction with video-based visits. METHODS: We conducted a study of video-based research visits in individuals with an atypical parkinsonian syndrome enrolled in The Michael J. Fox Foundation's Fox Trial Finder. Participants completed a recorded real-time video visit with a remote evaluator who was blinded to the participant's self-reported diagnosis. The investigator conducted a structured interview and performed standard assessments of motor function. Following the visit, the investigator selected the most likely diagnosis. The recorded visit was reviewed by a second blinded investigator who also selected the most likely diagnosis. We evaluated diagnostic concordance between the 2 independent investigators and assessed concordance between investigator consensus diagnosis and self-reported diagnosis using Cohen's kappa. We assessed participant satisfaction with a survey. RESULTS: We enrolled 45 individuals with atypical parkinsonian syndromes, and 44 completed the investigator-performed video assessment. We demonstrated excellent concordance in diagnosis between the investigators (κ = 0.83) and good reliability of self-reported diagnosis (κ = 0.73). More than 90% of participants were satisfied or very satisfied with the convenience, comfort, and overall visit. CONCLUSIONS: Video research visits are feasible and reliable in those with an atypical parkinsonian syndrome. These visits represent a promising option for reducing burden and extending the reach of clinical research to individuals with these rare and disabling conditions.

Segmentation of Intra-Retinal Cysts From Optical Coherence Tomography Images Using a Fully Convolutional Neural Network Model.

Optical coherence tomography (OCT) is an imaging modality that is used extensively for ophthalmic diagnosis, near-histological visualization, and quantification of retinal abnormalities such as cysts, exudates, retinal layer disorganization, etc. Intra-retinal cysts (IRCs) occur in several macular disorders such as, diabetic macular edema, retinal vascular disorders, age-related macular degeneration, and inflammatory disorders. Automated segmentation of IRCs poses challenges owing to variations in the acquisition system scan intensities, speckle noise, and imaging artifacts. Several segmentation methods have been proposed in the literature for IRC segmentation on vendor-specific OCT images that lack generalizability across imaging systems. In this paper, we propose a fully convolutional network (FCN) model for vendor-independent IRC segmentation. The proposed method counteracts image noise variabilities and trains FCN models on OCT sub-images from the OPTIMA cyst segmentation challenge dataset (with four different vendor-specific images, namely, Cirrus, Nidek, Spectralis, and Topcon). Further, optimal data augmentation and model hyperparametrization are shown to prevent over-fitting for IRC area segmentation. The proposed method is evaluated on the test dataset with a recall/precision rate of 0.66/0.79 across imaging vendors. The Dice correlation coefficient of the proposed method outperforms that of the published algorithms in the OPTIMA cyst segmentation challenge with a Dice rate of 0.71 across the vendors.

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

OBJECTIVE: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials. METHODS: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org. RESULTS: Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01). INTERPRETATION: PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort.

OBJECTIVE: The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD. METHODS: We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures. RESULTS: A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P < .0001 for the change over time), with a steeper change in year 1. Dopaminergic therapy had a significant effect on the change of MDS-UPDRS. There was a significant longitudinal change in dopamine transporter binding in all striatal regions (P < .001). There was a significant but weak correlation between MDS-UPDRS and dopamine transporter binding at baseline and years 1, 2, and 4, but no correlation between the rate of change of the 2 variables. CONCLUSIONS: We present 5-year longitudinal data on the change of the MDS-UPDRS and other clinical and dopamine transporter imaging outcome measures in early PD. These data can be used for sample size estimates for interventional studies in the de novo PD population. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aß1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aß1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aß1-42, or highest t-tau/Aß1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aß1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

Feasibility of Virtual Research Visits in Fox Trial Finder.

BACKGROUND: Fox Trial Finder is an online registry for individuals with and without Parkinson disease (PD) interested in participating in PD research. However, distance or disability could prevent such individuals from participating in traditional, clinic-based research at major centers. OBJECTIVE: Use videoconferencing to connect participants to specialists to: (1) demonstrate feasibility of virtual research visits within this population (2) collect phenotypic data of the participants, (3) validate self-reported diagnosis, and (4) gauge interest in virtual research visits. METHODS: We solicited volunteers throughout the United States through Fox Trial Finder. Interested individuals with PD provided consent, were given web cameras if needed, completed baseline surveys, and downloaded videoconferencing software remotely. Participants had a test connection and assessment appointment which included the Montreal Cognitive Assessment (MoCA), then a virtual research visit with a neurologist who reviewed their history and assessed their PD using a modified Movement Disorders Society Unified Parkinson's Disease Rating Scale. Neurologists assessed PD diagnosis and symptomatology. Physicians and participants were surveyed about their experience. RESULTS: Of 204 individuals who consented, 166 (81% ) individuals from 39 states completed all visits. The mean age was 62 and mean disease duration was 8.0 years. Mean MoCA score was 26.5, and mean modified MDS-UPDRS motor score was 22.8 (out of a possible 124). Neurologists judged PD as the most likely diagnosis in 97% of cases. Overall satisfaction with the visits was 79% (satisfied or very satisfied) among neurologists and 93% among participants. CONCLUSIONS: Through virtual research visits, neurologists engaged, characterized, and validated self-reported diagnosis in individuals with PD over a broad geography. This model may facilitate future research participation.

Use of an online portal to facilitate clinical trial recruitment: a preliminary analysis of Fox Trial Finder.

BACKGROUND: As in other therapeutic areas, clinical studies in Parkinson's disease (PD) face significant recruitment challenges. However, qualitative surveys suggest that individuals with PD are willing to participate in clinical research. The Michael J. Fox Foundation therefore established Fox Trial Finder in 2011 to facilitate connection between PD research teams and volunteers. OBJECTIVE: Characterize the research volunteers (with and without PD) registered on Fox Trial Finder as of June 2014, and the published, recruiting studies to identify trends and highlight gaps between research requirements and available volunteers. METHODS: Profiles of volunteers with and without PD were analyzed to explore trends in geography, demographics, family history and, for those volunteers with PD, disease progression and treatment history. Clinical study profiles were analyzed to determine study type, phase, sponsor, focus, location and eligibility criteria. The analysis focused on volunteers and studies based in the United States. RESULTS: The database contained 26,261 US-based volunteers, including 19,243 volunteers (73%) with PD and 7,018 (27%) controls without PD. The average time since diagnosis for PD volunteers was 5.7 years and the average age at diagnosis was 58 years. Control volunteers were more likely than volunteers with PD to be female (67% vs. 35%) and to have a family history of PD (49% vs. 12%). CONCLUSIONS: Fox Trial Finder's registration history to date demonstrates the high level of willingness among individuals affected by PD to participate in clinical research and provide a significant amount of personal health information to facilitate that participation.

Association of cerebrospinal fluid ß-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease.

IMPORTANCE: We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not ß-amyloid 1-42 (Aß1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE: To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aß1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES: The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aß1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS: Slightly, but significantly, lower levels of Aß1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aß1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aß1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aß1-42 and P-tau181 concentrations were associated with the postural instability-gait disturbance-dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181. CONCLUSIONS AND RELEVANCE: In this first report of CSF biomarkers in PPMI study subjects,we found that measures of CSF Aß1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression

Overcoming obstacles in Parkinson's disease.

Improved symptomatic and disease-modifying treatments are needed for Parkinson's disease (PD). Although significant advances have been made in the understanding of PD etiology, the translation of these discoveries into novel transformative therapies has been limited as a result of systemic challenges in PD drug development. Preclinical testing lacks clear standards and prioritization criteria for advancing therapies to the clinic. Clinical testing is marked by expensive, long, and uninformative studies. In parallel to these scientific challenges, funding of late-stage drug development has become increasingly scarce and risk averse. In this context, novel models of collaboration and funding are opening up new avenues for pursuing treatments. This review will discuss the most critical challenges in PD drug development and the innovative approaches being developed to overcome these hurdles.

Biomarkers in Parkinson's disease: a funder's perspective.

Therapeutic development in Parkinson's disease is hampered by the paucity of well-validated biomarkers that can assist with diagnosis and/or tracking the progression of the disease. Since its inception, the Michael J Fox Foundation for Parkinson's Research has invested heavily in biomarker research and continues to prioritize discovery and development efforts. This article summarizes the history and evolution of the Michael J Fox Foundation's role in supporting biomarker research and lays out the current challenges in successfully developing markers that can be used to test therapies, while also providing a vision of future funding efforts in Parkinson's disease biomarkers.

Efficient mitigation strategies for epidemics in rural regions.

Containing an epidemic at its origin is the most desirable mitigation. Epidemics have often originated in rural areas, with rural communities among the first affected. Disease dynamics in rural regions have received limited attention, and results of general studies cannot be directly applied since population densities and human mobility factors are very different in rural regions from those in cities. We create a network model of a rural community in Kansas, USA, by collecting data on the contact patterns and computing rates of contact among a sampled population. We model the impact of different mitigation strategies detecting closely connected groups of people and frequently visited locations. Within those groups and locations, we compare the effectiveness of random and targeted vaccinations using a Susceptible-Exposed-Infected-Recovered compartmental model on the contact network. Our simulations show that the targeted vaccinations of only 10% of the sampled population reduced the size of the epidemic by 34.5%. Additionally, if 10% of the population visiting one of the most popular locations is randomly vaccinated, the epidemic size is reduced by 19%. Our results suggest a new implementation of a highly effective strategy for targeted vaccinations through the use of popular locations in rural communities.