Scaffold hopping approaches for the exploration of herbicidally active compounds inhibiting Acyl-ACP Thioesterase.

BACKGROUND: The sustainable control of weed populations is a significant challenge facing farmers around the world. Although various methods for the control of weeds exist, the use of small molecule herbicides remains the most effective and versatile approach. Striving to find novel herbicides that combat resistant weeds via the targeting of plant specific modes of action (MoAs), we further investigated the bicyclic class of acyl-acyl carrier protein (ACP) thioesterase (FAT) inhibitors in an effort to find safe and efficacious lead candidates. RESULTS: Utilizing scaffold hopping and bioisosteric replacements strategies, we explored new bicyclic inhibitors of FAT. Amongst the investigated compounds we identified new structural motifs that showed promising target affinity coupled with good in vivo efficacy against commercially important weed species. We further studied the structure-activity relationship (SAR) of the novel dihydropyranopyridine structural class which showed promise as a new type of FAT inhibiting herbicides. CONCLUSION: The current work presents how scaffold hopping approaches can be implemented to successfully find novel and efficacious herbicidal structures that can be further optimized for potential use in sustainable agricultural practices. The identified dihydropyranopyridine bicyclic class of herbicides were demonstrated to have in vitro inhibitory activity against the plant specific MoA FAT as well as showing promising control of a variety of weed species, particularly grass weeds in greenhouse trials on levels competitive with commercial standards. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors.

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines were prepared via an optimized BH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops.

Linking QKD Testbeds across Europe.

Quantum-key-distribution (QKD) networks are gaining importance and it has become necessary to analyze the most appropriate methods for their long-distance interconnection. In this paper, four different methods of interconnecting remote QKD networks are proposed. The methods are used to link three different QKD testbeds in Europe, located in Berlin, Madrid, and Poznan. Although long-distance QKD links are only emulated, the methods used can serve as a blueprint for the secure interconnection of distant QKD networks in the future. Specifically, the presented approaches combine, in a transparent way, different fiber and satellite physical media, as well as common standards of key delivery interfaces. The testbed interconnections are designed to increase the security by utilizing multipath techniques and multiple hybridizations of QKD and post-quantum cryptography (PQC) algorithms.

A Study in Scaffold Hopping: Discovery and Optimization of Thiazolopyridines as Potent Herbicides That Inhibit Acyl-ACP Thioesterase.

In the search for new chemical entities that can control resistant weeds by addressing novel modes of action (MoAs), we were interested in further exploring a compound class that contained a 1,8-naphthyridine core. By leveraging scaffold hopping methodologies, we were able to discover the new thiazolopyridine compound class that act as potent herbicidal molecules. Further biochemical investigations allowed us to identify that the thiazolopyridines inhibit acyl-acyl carrier protein (ACP) thioesterase (FAT), with this being further confirmed via an X-ray cocrystal structure. Greenhouse trials revealed that the thiazolopyridines display excellent control of grass weed species in pre-emergence application coupled with dose response windows that enable partial selectivity in certain crops.

Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.

Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.

Systematic Review on Saliva Biomarkers in Patients Diagnosed with Morbus Alzheimer and Morbus Parkinson.

Extracellular plaques composed of the hydrophobic peptide amyloid-ß and intraneuronal accumulation of the hyperphosphorylated protein tau (p-tau) are pathological hallmarks found in the brains of most people affected by Alzheimer's disease (AD). In Parkinson's disease (PD), Lewy bodies, i.e., intraneuronal protein deposits comprising the protein α-synuclein, are a typical disease feature. As these hallmarks located in the brain are hardly traceable, reliable biomarkers from easily accessible body fluids are key for accurate diagnosis. The aim of the present work was to review the available literature regarding potential biomarkers of AD and PD in the saliva. The databases PubMed, Google Scholar, LILACS, LIVIVO, VHL regional portal, Cochrane Library, eLIBRARY, and IOS Press were consulted for the literature search. Screening of titles and abstracts followed the PRISMA guidelines, while data extraction and the assessment of full texts were carried out in accordance with the Newcastle-Ottawa Scale assessment. The review shows significant increases in levels of the amyloid-ß Aß1-42 and elevated p-tau to total tau (t-tau) ratios in salivary samples of AD patients, in comparison with healthy controls. In PD patients, levels of α-synuclein in salivary samples significantly decreased compared to healthy controls, whereas oligomeric α-synuclein and the ratio of oligomeric α-synuclein to total α-synuclein markedly increased. Salivary biomarkers represent a promising diagnostic tool for neurodegenerative diseases. Further high-quality case-control studies are needed to substantiate their accuracy.

Longitudinal monitoring of SARS-CoV-2 spike protein-specific antibody responses in Lower Austria.

The Lower Austrian Wachau region was an early COVID-19 hotspot of infection. As previously reported, in June 2020, after the first peak of infections, we determined that 8.5% and 9.0% of the participants in Weißenkirchen and surrounding communities in the Wachau region were positive for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies against the receptor-binding domain of the spike protein of SARS-CoV-2, respectively. Here, we present novel data obtained eight months later (February 2021) from Weißenkirchen, after the second peak of infection, with 25.0% (138/552) and 23.6% (130/552) of participants that are positive for IgG and IgA, respectively. In participants with previous IgG/IgA positivity (June 2020), we observed a 24% reduction in IgG levels, whereas the IgA levels remained stable in February 2021. This subgroup was further analyzed for SARS-CoV-2 induced T cell activities. Although 76% (34/45) and 76% (34/45) of IgG positive and IgA positive participants, respectively, showed specific T cell activities (upon exposure to SARS-CoV-2 spike protein-derived peptides), those were not significantly correlated with the levels of IgG or IgA. Thus, the analyses of antibodies cannot surrogate the measurement of T cell activities. For a comprehensive view on SARS-CoV-2-triggered immune responses, the measurement of different classes of antibodies should be complemented with the determination of T cell activities.

The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.

Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

Persistence of humoral response upon SARS-CoV-2 infection.

SARS-CoV-2 continues to leave its toll on global health and the economy. Management of the pandemic will rely heavily on the degree of adaptive immunity persistence following natural SARS-CoV-2 infection. Along with the progression of the pandemic, more literature on the persistence of the SARS-CoV-2-specific antibody response is becoming available. Here, we summarize findings on the persistence of the humoral, including neutralizing antibody, response at three to eight months post SARS-CoV-2 infection in non-pregnant adults. While the comparability of the literature is limited, findings on the detectability of immunoglobulin G class of antibodies (IgG) were most consistent and were reported in most studies to last for six to eight months. Studies investigating the response of immunoglobins M and A (IgM, IgA) were limited and reported mixed results, in particular, for IgM. The majority of studies observed neutralizing antibodies at all time points tested, which in some studies lasted up to eight months. The presence of neutralizing antibodies has been linked to protection from re-infection, suggesting long-term immunity to SARS-CoV-2. These neutralizing capacities may be challenged by emerging virus variants, but mucosal antibodies as well as memory B and T cells may optimize future immune responses. Thus, further longitudinal investigation of PCR-confirmed seropositive individuals using sensitive assays is warranted to elucidate the nature and duration of a more long-term humoral response.

Persisting Antibody Response to SARS-CoV-2 in a Local Austrian Population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic recently. The prevalence and persistence of antibodies following a peak SARS-CoV-2 infection provides insights into the potential for some level of population immunity. In June 2020, we succeeded in testing almost half of the population of an Austrian town with a higher incidence of COVID-19 infection. We performed a follow-up study to reassess the prevalence of SARS-CoV-2-specific IgA and IgG antibodies with 68 participants of the previous study. We found that the prevalence of IgG or IgA antibodies remained remarkably stable, with 84% of our cohort prevailing SARS-CoV-2-specific antibodies (only a slight decrease from 93% 4 months before). In most patients with confirmed COVID-19 seroconversion potentially provides immunity to reinfection. Our results suggest a stable antibody response observed for at least 6 months post-infection with implications for developing strategies for testing and protecting the population.

SARS-CoV-2-Specific Antibody Prevalence and Symptoms in a Local Austrian Population.

Background: Since December 2019 the novel coronavirus (SARS-CoV-2) is the center of global attention due to its rapid transmission and toll on health care systems and global economy. Population-based serosurveys measuring antibodies for SARS-CoV-2 provide one method for estimating previous infection rates including the symptom-free courses of the disease and monitoring the progression of the epidemic. Methods: In June 2020 we succeeded in testing almost half of the population of an Austrian township (1,359 inhabitants) with a reported higher incidence for COVID-19 infections (17 PCR positive cases have been officially reported until the date of sample collection, i.e., 1.2% of the total population). We determined the prevalence of SARS-CoV-2-specific antibodies in this population, factors affecting, and symptoms correlated with prior infection. Antibodies were determined using a CE-certified quality-controlled ELISA test for SARS-CoV-2-specific IgG and IgA antibodies. Results: We found a high prevalence of 9% positive antibodies among the town population in comparison to 6% of the neighboring villages. This was considerably higher than the officially known RT-PCR-approved COVID-19 cases (1.2%) in the town population. Twenty percent of SARS-CoV-2-antibody positive cases declared being asymptomatic in a questionnaire. On the other hand, we identified six single major symptoms, including anosmia/ageusia, weight loss, anorexia, general debility, dyspnea, and fever, and especially their combination to be of high prognostic value for predicting SARS-CoV-2 infection in a patient. Conclusions: This population study demonstrated a high prevalence of antibodies to SARS-CoV-2 as a marker of past infections in an Austrian township. Several symptoms revealed a diagnostic value especially in combination.

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol.

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

Loss of Olfactory Function-Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders.

The loss of the senses of smell (anosmia) and taste (ageusia) are rather common disorders, affecting up to 20% of the adult population. Yet, this condition has not received the attention it deserves, most probably because per se such a disorder is not life threatening. However, loss of olfactory function significantly reduces the quality of life of the affected patients, leading to dislike in food and insufficient, exaggerated or unbalanced food intake, unintentional exposure to toxins such as household gas, social isolation, depression, and an overall insecurity. Not only is olfactory dysfunction rather prevalent in the healthy population, it is, in many instances, also a correlate or an early indicator of a panoply of diseases. Importantly, olfactory dysfunction is linked to the two most prominent neurodegenerative disorders, Parkinson's disease and Alzheimer's disease. Anosmia and hyposmia (reduced sense of smell) affect a majority of patients years before the onset of cognitive or motor symptoms, establishing olfactory dysfunction as early biomarker that can enable earlier diagnosis and preventative treatments. In the current health crisis caused by SARS-CoV2, anosmia and dysgeusia as early-onset symptoms in virus-positive patients may prove to be highly relevant and crucial for pre-symptomatic Covid-19 detection from a public health perspective, preceding by days the more classical respiratory tract symptoms such as cough, tightness of the chest or fever. Thus, the olfactory system seems to be at the frontline of pathologic assault, be it through pathogens or insults that can lead to or at least associate with neurodegeneration. The aim of this review is to assemble current knowledge from different medical fields that all share a common denominator, olfactory/gustatory dysfunction, and to distill overarching etiologies and disease progression mechanisms.

Activation of the Unfolded Protein Response and Proteostasis Disturbance in Parkinsonism-Dementia of Guam.

Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles composed of hyperphosphorylated tau, marked deposition of transactive response DNA-binding protein 43 kDa (TDP-43), and neuronal loss. The mechanisms that underlie neurodegeneration in G-PD are poorly understood. Here, we report that the unfolded protein response (UPR) is activated in G-PD brains. Specifically, we show that the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa and phosphorylated (activated) ER stress sensor protein kinase RNA-like ER kinase accumulate in G-PD brains. Furthermore, proteinaceous aggregates in G-PD brains are found to contain several proteins related to the ubiquitin-proteasome system (UPS) and the autophagy pathway, two major mechanisms for intracellular protein degradation. In particular, a mutant ubiquitin (UBB+1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBB+1 is a potent modifier of TDP-43 aggregation and cytotoxicity in vitro. Overall, these data suggest that UPR activation and intracellular proteolytic pathways are intimately connected with the accumulation of aggregated proteins in G-PD.

Endolysosomal pathway activity protects cells from neurotoxic TDP-43.

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP 43). Using a yeast model for TDP 43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP 43. This clearance occurred via TDP 43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP 43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP 43. In contrast, enhanced autophagy contributed to TDP 43 cytotoxicity, despite being involved in TDP 43 degradation. TDP 43's interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP 43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP 43-associated diseases.

TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity.

TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies.