Invasive maize spotted stem borer Chilo partellus Swinhoe 1885 (Lepidoptera: Crambidae) is the dominant pest in maize agro-system in the Mediterranean Region of Turkey

The maize spotted stem borer Chilo partellus Swinhoe 1885 (Lepidoptera: Crambidae) was recorded for the first time in Turkey in 2014. This pest is described as invasive, especially in the current climate change dispensation. It is important to investigate the population dynamics of C. partellus for better management practices. We studied the species abundance distribution (SAD) models and some biodiversity indices of three major stem bores, C. partellus, Ostrinia nubilalis and Sesamia nonagrioides as these are the most common and major stem borers of maize in the Mediterranean Region. With the help of light traps, weekly catches of the three major maize stem borers were collected during two maize growing seasons (first cropping and second cropping seasons) in 2018 and 2019. The results showed that C. partellus emerged earlier (April-May) and was very dominant throughout the first cropping season of maize. Ostrinia nubilalis and S. nonagrioides emerged late in June-July, and its population remained low throughout the first cropping season. The population structure of all three stem borers was similar throughout the second cropping season of maize. The relative abundance (RA) of C. partellus was significantly higher than that of O. nubilalis and S. nonagrioides in the first cropping (p <.0001) when compared to the second cropping season (p >.05) for both years. In the first cropping season for both years, no SAD model fitted the observed species distribution, although Fisher’s log series was relatively similar. In the second cropping for both years, the geometric series distribution model fitted the observed SAD. The Berger-Parker dominance index was greater for the first cropping season than that of the second, whereas the opposite was true for the Simpson’s evenness and evenness of Pielou. High RA of C. partellus and the geometric series distribution observed in the second cropping are indicative of a possible dominant status of the C. partellus in the Mediterranean Region of Turkey. Our findings indicated that seasonality is a fundamental driving factor influencing the distribution of the three major stem borers of maize in the Mediterranean Region. In addition, the long and warmer winters could be the reason for the dominance of C. partellus as indicated by the diversity indices.     

Gait stride-to-stride variability and foot clearance pattern analysis in Idiopathic Parkinson’s Disease and Vascular Parkinsonism

The literature on gait analysis in Vascular Parkinsonism (VaP), addressing issues such as variability, foot clearance patterns, and the effect of levodopa, is scarce. This study investigates whether spatiotemporal, foot clearance and stride-to-stride variability analysis can discriminate VaP, and responsiveness to levodopa.Fifteen healthy subjects, 15 Idiopathic Parkinson's Disease (IPD) patients and 15 VaP patients, were assessed in two phases: before (Off-state), and one hour after (On-state) the acute administration of a suprathreshold (1.5 times the usual) levodopa dose. Participants were asked to walk a 30-meter continuous course at a self-selected walking speed while wearing foot-worn inertial sensors. For each gait variable, mean, coefficient of variation (CV), and standard deviations SD1 and SD2 obtained by Poincaré analysis were calculated. General linear models (GLMs) were used to identify group differences. Patients were subject to neuropsychological evaluation (MoCA test) and Brain MRI.VaP patients presented lower mean stride velocity, stride length, lift-off and strike angle, and height of maximum toe (later swing) (p < .05), and higher %gait cycle in double support, with only the latter unresponsive to levodopa. VaP patients also presented higher CV, significantly reduced after levodopa. Yet, all VaP versus IPD differences lost significance when accounting for mean stride length as a covariate.In conclusion, VaP patients presented a unique gait with reduced degrees of foot clearance, probably correlated to vascular lesioning in dopaminergic/non-dopaminergic cortical and subcortical non-dopaminergic networks, still amenable to benefit from levodopa. The dependency of gait and foot clearance and variability deficits from stride length deserves future clarification.     

Development of a novel MATLAB-based framework for implementing mechanical joint stability constraints within OpenSim musculoskeletal models

The Static Optimization (SO) solver in OpenSim estimates muscle activations and forces that only equilibrate applied moments. In this study, SO was enhanced through an open-access MATLAB interface, where calculated muscle activations can additionally satisfy crucial mechanical stability requirements. This Stability-Constrained SO (SCSO) is applicable to many OpenSim models and can potentially produce more biofidelic results than SO alone, especially when antagonistic muscle co-contraction is required to stabilize body joints. This hypothesis was tested using existing models and experimental data in the literature. Muscle activations were calculated by SO and SCSO for a spine model during two series of static trials (i.e. simulation 1 and 2), and also for a lower limb model (supplementary material 2). In simulation 1, symmetric and asymmetric flexion postures were compared, while in simulation 2, various external load heights were compared, where increases in load height did not change the external lumbar flexion moment, but necessitated higher EMG activations. During the tasks in simulation 1, the predicted muscle activations by SCSO demonstrated less average deviation from the EMG data (6.8% −7.5%) compared to those from SO (10.2%). In simulation 2, SO predicts constant muscle activations and forces, while SCSO predicts increases in the average activations of back and abdominal muscles that better match experimental data. Although the SCSO results are sensitive to some parameters (e.g. musculotendon stiffness), when considering the strategy of the central nervous system in distributing muscle forces and in activating antagonistic muscles, the assigned activations by SCSO are more biofidelic than SO.     

Autophagic dysfunction in Alzheimer’s disease: Cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis

Autophagy is a preserved cytoplasmic self-degradation process and endorses recycling of intracellular constituents into bioenergetics for the controlling of cellular homeostasis. Functional autophagy process is essential in eliminating cytoplasmic waste components and helps in the recycling of some of its constituents. Studies have revealed that neurodegenerative disorders may be caused by mutations in autophagy-related genes and alterations of autophagic flux. Alzheimer’s disease (AD) is an irrevocable deleterious neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles (NFTs) in the hippocampus and cortex. In the central nervous system of healthy people, there is no accretion of amyloid β (Aβ) peptides due to the balance between generation and degradation of Aβ. However, for AD patients, the generation of Aβ peptides is higher than lysis that causes accretion of Aβ. Likewise, the maturation of autophagolysosomes and inhibition of their retrograde transport creates favorable conditions for Aβ accumulation. Furthermore, increasing mammalian target of rapamycin (mTOR) signaling raises tau levels as well as phosphorylation. Alteration of mTOR activity occurs in the early stage of AD. In addition, copious evidence links autophagic/lysosomal dysfunction in AD. Compromised mitophagy is also accountable for dysfunctional mitochondria that raises Alzheimer’s pathology. Therefore, autophagic dysfunction might lead to the deposit of atypical proteins in the AD brain and manipulation of autophagy could be considered as an emerging therapeutic target. This review highlights the critical linkage of autophagy in the pathogenesis of AD, and avows a new insight to search for therapeutic target for blocking Alzheimer’s pathogenesis.     

Identification of human plasma C1 inhibitor as a target protein for staphylococcal superantigen-like protein 5 (SSL5)

The family of staphylococcal superantigen-like proteins (SSLs) have a structure similar to bacterial superantigens but exhibit no superantigenic activity. These exoproteins have recently been shown to disturb the host immune defense system. One family member, SSL5, was reported to bind to human leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) and matrix metalloproteinase-9 (MMP-9) and to interfere with leukocyte trafficking. In the present study, we explored human plasma proteins bound by glutathione S-transferase (GST)-tagged recombinant SSL5 (GST-SSL5) and identified plasma protease C1 inhibitor (C1Inh) as a major SSL5-binding protein based on the results of peptide mass fingerprinting analysis with MALDI-TOFMS. GST-SSL5 was found to attenuate the inhibitory activity of recombinant histidine-tagged C1Inh (C1Inh-His) toward complement C1s. We also observed that the treatment of C1Inh-His with neuraminidase markedly decreased its binding to GST-SSL5. Moreover, C1Inh-His produced by Lec2 mutant cells (deficient in sialic acid biosynthesis) showed much lower binding affinity for SSL5 than that produced by the wild-type CHO-K1 cells, as assessed by pull-down assay. These results suggest that SSL5 binds to C1Inh in a sialic acid-dependent fashion and modulates the host immune defense through perturbation of the complement system in association with S. aureus infection.     

The monoamine oxidase inhibition properties of C6-mono- and N3/C6-disubstituted derivatives of 4(3H)-quinazolinone

Parkinson’s disease is characterised by the death of the nigrostriatal neurons and depletion of striatal dopamine. The standard symptomatic therapy consists of dopamine replacement with l-dopa, the metabolic precursor of dopamine, which represents the most effective treatment. Since monoamine oxidase (MAO) B is a key dopamine metabolising enzyme in the brain, MAO-B inhibitors are often used as adjuvants to l-dopa. In addition to the symptomatic benefits offered by MAO-B inhibitors, these drugs may also possess neuroprotective properties and possibly delay the progression of Parkinson’s disease. Based on the therapeutic use of MAO-B inhibitors, the present study evaluates a series of mono- and disubstituted derivatives of 4(3H)-quinazolinone as potential inhibitors of recombinant human MAO-A and MAO-B. Twelve C6-monosubstituted and nine N3/C6-disubstituted 4(3H)-quinazolinone derivatives were synthesised, which led to the discovery of novel quinazolinone derivatives with micromolar and submicromolar activities as inhibitors of MAO-B. The most potent mono- and disubstituted derivatives exhibited IC₅₀ values of 6.35 μM (7f) and 0.685 μM (8b), respectively. This study identifies suitable substitution patterns for the design of 4(3H)-quinazolinone derivatives as MAO-B inhibitors.     

Expansion of the scaffold diversity for the development of highly selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits through the pharmacophore model generation,virtual screening and molecular dynamics simulation

Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer’s disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC₅₀ values in sub-micromolar range on eqBChE and three displayed IC₅₀ values < 2 μM on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD.     

Discovery of a novel DNA binding agent via design and synthesis of new thiazole hybrids and fused 1,2,4-triazines as potential antitumor agents: Computational,spectrometric and in silico studies

New series of furan–thiazole hybrids (3a-f), thiazolo[2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino[4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI₅₀ MG-MID = 14.22 µM) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb⁺³) probe revealed increased fluroresence of DNA-3d-Tb⁺³ mixture due to damage of the double-stranded DNA. Also, UV–vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04 ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski’s rule.     

α-bisabolol β-D-fucopyranoside as a potential modulator of β-amyloid peptide induced neurotoxicity: An in vitro & in silico study

Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder affecting the elderly people. For the AD treatment, there is inefficiency in the existing medication, as these drugs reduce only the symptoms of the disease. Since multiple pathological proteins are involved in the development of AD, searching for a single molecule targeting multiple AD proteins will be a new strategy for the management of AD. In view of this, the present study was designed to synthesize and evaluate the multifunctional neuroprotective ability of the sesquiterpene glycoside α-bisabolol β-D-fucopyranoside (ABFP) against multiple targets like acetylcholinesterase, oxidative stress and β-amyloid peptide aggregation induced cytotoxicity. In silico computational docking and simulation studies of ABFP with acetylcholinesterase (AChE) showed that it can interact with Asp74 and Thr75 residues of the enzyme. The in vitro studies showed that the compound possess significant ability to inhibit the AChE enzyme apart from exhibiting antioxidant, anti-aggregation and disaggregation properties. In addition, molecular dynamics simulation studies proved that the interacting residue between Aβ peptide and ABFP was found to be involved in Leu34 and Ile31. Furthermore, the compound was able to protect the Neuro2 a cells against Aβ_25-35 peptide induced toxicity. Overall, the present study evidently proved ABFP as a neuroprotective agent, which might act as a multi-target compound for the treatment of Alzheimer’s disease.     

A deuterohemin peptide protects a transgenic Caenorhabditis elegans model of Alzheimer’s disease by inhibiting Aβ1–42 aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease and is the most common cause of dementia in the elderly. The main hallmark of AD is the deposition of insoluble amyloid (Aβ) outside the neuron, leading to amyloid plaques and neurofibrillary tangles in the brain. Deuterohemin-Ala-His-Thr-Val-Glu-Lys (DhHP-6), a novel porphyrin-peptide, has both microperoxidase activity and cell permeability. In the present study, DhHP-6 efficiently inhibited the aggregation of Aβ and reduced the β-sheet percentage of Aβ from 89.1% to 78.3%. DhHP-6 has a stronger affinity (K_D = 100 ± 12 μM) for binding with Aβ at Phe⁴, Arg⁵, Val¹⁸, Glu¹¹ and Glu²². In addition, DhHP-6 (100 μM) significantly prolonged lifespan, alleviated paralysis and reduced Aβ plaque formation in the Aβ_1–42 transgenic Caenorhabditis elegans CL4176 model of AD. Our results demonstrate that DhHP-6 is a potential drug candidate that efficiently protects a transgenic C. elegans model of Alzheimer’s disease by inhibiting Aβ aggregation.