bluuebunny/crossref_metadata_2025 huggingface dataset:
Trait and state mindfulness modulate EEG microstates
Authors: Zarka D. , Cevallos C. , Ruiz P. , Cebolla A. M. , Petieau M. , Bengoetxea A. , Cheron G.
Published: November 2021

The present study aimed to characterize microstate dynamics induced by non-reactive attention underlying mindfulness. Electroencephalogram signals from eighteen trained meditators and a matched non-meditators group were recorded before, during, and after a non-reactive attention meditation or during three resting periods respectively, while they were passively exposed to auditory stimulation. In a multimodal approach, microstate cluster decompositions, personality trait questionnaires, phenomenological ratings, and microstates sources localization were analyzed. Our results revealed that temporal parameters of microstates A and C at rest were negatively correlated to mindfulness traits across all participants. After meditation, the frequency of microstate A and C was decreased while microstate B was of longer duration, in meditators. Source localization analysis revealed that the non-reactive trait effect on microstate C at rest was explained by a modified activity of the salience network (identified by the anterior cingulate cortex, thalamus, and insula), while the non-reactive attentional state effect relied on a contribution of (anterior and posterior) cerebellum during meditation. Our results suggest that decreased microstates A and C reflect decreased mental state reactivity, while the increased microstate B relies on attention stability. These findings strongly encourage more research to assess the use of the microstate temporal parameters as a biomarker of the salience network activity, as well as objectify the brain changes induced by non-reactive attention training.

HIGHLIGHT

The present study aimed to characterize microstate dynamics induced by non-reactive attention meditation, by the use of multimodal analysis including EEG microstate clusters decompositions, personality trait questionnaires, phenomenological reports, and source localization analysis.

The occurrence of microstate A, recognized to be related to phonological processing and depressive disorders, was negatively correlated to mindfulness trait and was decreased after non-reactive attention meditation.

The duration of microstate B, generally associated with the visual system, increases after meditation, in particular in meditators with a high non-reactivity trait.

Temporal parameters of microstate C, recognized to be related to default mode, were negatively correlated to the non-reactivity trait of meditators and were decreased after non-reactive attention meditation. Source analysis revealed that these trait and state effects reflect modified activities of the salient network.
Investigating SARS-CoV-2 breakthrough infections per variant and vaccine type
Authors: Dingemans Jozef , van der Veer Brian M.J.W. , Gorgels Koen M.F. , Hackert Volker , Hensels Audrey Y.J. , den Heijer Casper D.J. , Hoebe Christian J.P.A , Savelkoul Paul H.M. , van Alphen Lieke B.
Published: November 2021

Breakthrough SARS-CoV-2 infections have been reported in fully vaccinated individuals, in spite of the high efficacy of the currently available vaccines, proven in trials and real-world studies. Several variants of concern (VOC) have been proffered to be associated with breakthrough infections following immunization. In this study, we investigated 378 breakthrough infections recorded between January and July 2021 and compared the distribution of SARS-CoV-2 genotypes identified in 225 fully vaccinated individuals to the frequency of circulating community lineages in the region of South Limburg (The Netherlands) in a week-by-week comparison. Although the proportion of breakthrough infections was relatively low and stable when the Alpha variant was predominant, the rapid emergence of the Delta variant lead to a strong increase in breakthrough infections, with a higher relative proportion of individuals vaccinated with Oxford-AstraZeneca or J&J/Janssen being infected compared to those immunized with mRNA-based vaccines. A significant difference in median age was observed when comparing fully vaccinated individuals with severe symptoms (83 years) to asymptomatic cases (46.5 years) or individuals with mild-to-moderate symptoms (42 years). There was no association between SARS-CoV-2 genotype or vaccine type and disease symptoms. Interestingly, symptomatic individuals harbored significantly higher SARS-CoV-2 loads than asymptomatic vaccinated individuals and breakthrough infections caused by the Delta variant are associated with increased viral loads compared to those caused by the Alpha variant. Altogether, these results indicate that the emergence of the Delta variant might have lowered the efficiency of particular vaccine types to prevent SARS-CoV-2 infections and that, although rare, the elderly are particularly at risk of becoming severely infected as the consequence of a breakthrough infection.
Final sizes and durations of new COVID-19 pandemic waves in Ukraine and around the world predicted by generalized SIR model
Authors: Nesteruk Igor
Published: November 2021

New waves of the COVID-19 pandemic in Ukraine, which began in the summer of 2021, and after holidays in the middle of October 2021, were characterized by almost exponential growth of smoothed daily numbers of new cases. This is a matter of great concern and the need to immediately predict the epidemic dynamics in order to assess the possible maximum values of new cases, the risk of infection and the number of deaths. The generalized SIR-model and corresponding parameter identification procedure was used to simulate and predict the dynamics of two new epidemic waves in Ukraine and one in the whole world. Results of calculations show that new cases in Ukraine will not stop to appear before November 2022. If the global situation with vaccination, testing and treatment will not change, the pandemic could continue for another ten years.
Oxidative stress and antioxidant defenses in mild cognitive impairment: a systematic review and meta-analysis
Authors: Nantachai Gallayaporn , Vasupanrajit Asara , Tunvirachaisakul Chavit , Solmi Marco , Maes Michael
Published: November 2021

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.
Predictors of Treatment Response, Remission, Relapse and Rehospitalization in First-Episode Psychosis Patients in Medellin, Colombia
Authors: Garcia Jenny , Agudelo Lina M. , Canas Maria A. , Castro-Campos Natalia , Ribero Oscar J. , Gallego Juan A.
Published: November 2021

Background

Most studies with first episode psychosis patients have been conducted in high-income countries. On the other hand, very few first episode studies have been conducted in Latin-America. Therefore, the goal of our study is to determine predictors of treatment response, remission, relapse and rehospitalization in a first episode psychosis population from Medellin, Colombia.

Methods

Data was obtained from electronic health records from first episode patients with a diagnosis of schizophrenia-spectrum disorder diagnoses who were evaluated between January 2014 and December 2016 at two psychiatric institutions in Medellin, Colombia. Survival and Cox proportional hazard models were used for the analysis.

Results

Duration of untreated psychosis and hospitalization at the time of presentation was associated with both response and remission. Response was also predicted by less first-order symptoms and more years of education. Remission was predicted by older age of onset. Relapse and rehospitalization were predicted by use of substances and poor adherence to pharmacologic treatment. Less years of education and hospitalization at the time of presentation were also associated with rehospitalization.

Conclusion

Predictors of treatment response, remission, relapse and rehospitalization in first-episode patients are similar in Colombia compared to other high-income regions such as the United States and Europe.
Bibliometric Analysis of Academic Journal Articles Reporting Results of Psychedelic Clinical Studies
Authors: Weleff Jeremy , Akiki Teddy J. , Barnett Brian S.
Published: November 2021

After a decades long period of investigational dormancy, there is renewed interest in employing psychedelics as treatments for mental illness and addiction. The academic journals, journal articles, academic institutions, and countries that have helped sustain clinical psychedelic research and the evolution of the literature on clinical studies of psychedelic compounds have only been minimally investigated. Therefore, in we conducted a bibliometric analysis of clinical studies of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), ayahuasca, dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), ibogaine, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin published from 1965-2018. Our search revealed 320 articles published across 106 journals. After a nearly quarter century lull between the 1970s and 1990s, publications in this area have resurged over the last two decades and continue on an upward trajectory, with most clinical studies now focusing on LSD, MDMA, and psilocybin. A subanalysis of the ten most cited articles in psychedelic research prior to 2010 and afterwards demonstrated a shift from research on risks of psychedelics, primarily those of MDMA, to research on therapeutic applications, predominantly those of psilocybin. We also conducted network analyses of inter-country collaborations in psychedelic research, which suggested that psychedelic researchers in the United Kingdom have more diverse international collaborations.
Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5
Authors: Buscham Tobias J. , Eichel-Vogel Maria A. , Steyer Anna M. , Jahn Olaf , Strenzke Nicola , Dardawal Rakshit , Memhave Tor R. , Siems Sophie B. , Müller Christina , Meschkat Martin , Sun Ting , Ruhwedel Torben , Möbius Wiebke , Krämer-Albers Eva-Maria , Boretius Susann , Nave Klaus-Armin , Werner Hauke B.
Published: November 2021

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here we find that expression of the tetraspan-transmembrane protein CMTM5 (Chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and CNS myelin. Genetic disruption of the Cmtm5-gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial Cmtm5-deficiency causes an early-onset progressive axonopathy, which we also observe in global and in tamoxifen-induced oligodendroglial Cmtm5-mutants. Presence of the Wlds mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis.
Genetic diversity assessment of neem (Azadirachta indica A. Juss) in northern Nigeria
Authors: Mshelmbula Barka P. , Anoliefo Geoffrey O. , Ikhajiagbe Beckley , Edegbai Boniface O.
Published: November 2021

Neem is a tropical tree that can adapt to a wide range of places and particularly to semi-arid conditions. As at present, it is grown in many Asian countries and also in the tropical regions of the western hemisphere. Genetic variability and diversity are a major requirement needed for both immediate results and the one ones thereafter adaptation of plant types in their original domain. The evaluation of genetic diversity of any species is extremely crucial for their sustainability, continuity, survival and gene manipulation. Major breakthroughs in the field of molecular biology was able to develop several tools for the investigation of genetic diversity at the genome level to determine phylogenetic relationships among inter or intra-species. The advent of molecular markers for the detection and exploitation of DNA polymorphism is one of the major breakthroughs in the world of molecular genetics.

The importance of genetic diversity in plant germplasm conservation, especially in economically important species such as Azadirachtaindica, is enormous, particularly in Nigeria. The question is whether A. indica from different Agro-ecological zones have genetic variations or similarities. This was the bane of the current study, which used RAPD to look atgenetic diversity of 27 randomly selected neem trees within the agro-ecological zones in Northern Nigeria. A total of 9 primers were employed out of which only 5 were responsive (OPA-02, OPA-03, OPA-15 and OPA-19). These primers showed dissimilarities in the visible DNA bands among the various tree samples. There was evidence of genetic dissimilarities among the trees sampled. Differences in percentage polymorphism was reported, where it was reportedly highest among the Borno State tree samples (97.44%), compared to those in Yobe State with no polymorphism.
Vocal markers of autism: assessing the generalizability of machine learning models
Authors: Rybner Astrid , Jessen Emil Trenckner , Mortensen Marie Damsgaard , Larsen Stine Nyhus , Grossman Ruth , Bilenberg Niels , Cantio Cathriona , Møllegaard Jepsen Jens Richardt , Weed Ethan , Simonsen Arndis , Fusaroli Riccardo
Published: November 2021

Machine learning (ML) approaches show increasing promise in their ability to identify vocal markers of autism. Nonetheless, it is unclear to what extent such markers generalize to new speech samples collected e.g., using a different speech task or in a different language. In this paper, we systematically assess the generalizability of ML findings across a variety of contexts.

We train promising published ML models of vocal markers of autism on novel cross-linguistic datasets following a rigorous pipeline to minimize overfitting, including cross-validated training and ensemble models. We test the generalizability of the models by testing them on i) different participants from the same study, performing the same task; ii) the same participants, performing a different (but similar) task; iii) a different study with participants speaking a different language, performing the same type of task.

While model performance is similar to previously published findings when trained and tested on data from the same study (out-of-sample performance), there is considerable variance between studies. Crucially, the models do not generalize well to different, though similar, tasks and not at all to new languages. The ML pipeline is openly shared.

Generalizability of ML models of vocal markers of autism is an issue. We outline three recommendations for strategies researchers could take to be more explicit about generalizability and improve it in future studies.

LAY SUMMARY

Machine learning approaches promise to be able to identify autism from voice only. These models underestimate how diverse the contexts in which we speak are, how diverse the languages used are and how diverse autistic voices are. Machine learning approaches need to be more careful in defining their limits and generalizability.
Identifying high-risk comorbidities of short and long-term opioid prescription use
Authors: Jennings Mariela V , Lee Hyunjoon , Rocha Daniel B , Bianchi Sevim B , Coombes Brandon J , Crist Richard C , Faucon Annika , Hu Yirui , Kember Rachel L , Mallard Travis T , Niarchou Maria , Poulsen Melissa N , Straub Peter , Urman Richard D , Walsh Colin G ,   PsycheMERGE Substance Use Disorder Workgroup, Davis Lea K , Smoller Jordan W , Troiani Vanessa , Sanchez-Roige Sandra
Published: November 2021

Background

Electronic health records (EHR) are useful tools for understanding complex medical phenotypes, but they have been underutilized for opioid use disorders (OUD). Patterns of prescription opioid use might provide an objective measure of OUD risk.

Methods

We extracted data for over 2.6 million patients across three health registries (Vanderbilt University Medical Center, Mass General Brigham, Geisinger) between 2005 and 2018. We defined three groups based on levels of opioid exposure: No Prescription, Minimal Exposure (2 prescriptions within 90 days at least once, but never 3 prescriptions <90 days apart), and Chronic Exposure (≥10 opioid prescriptions in a year), and compared them to the full registries and to patients with OUD diagnostic codes. We extracted demographic and clinical characteristics known to co-occur with OUD, including psychiatric and substance use disorders, pain-related diagnoses, HIV, and hepatitis C.

Results

The prevalence of substance (alcohol, tobacco, cannabis) use disorders was higher in patients with OUD and Chronic Exposure than those with No Prescription or Minimal Exposure. Patients in the OUD and Chronic Exposure groups had more psychiatric (anxiety, depression, schizophrenia, bipolar disorder) and medical comorbidities (pain, hepatitis C, HIV) than those in the Minimal Exposure group. Notably, patients in the Minimal Exposure group had different comorbidity profiles (higher rates of substance use and psychiatric disorders, more pain conditions) than those in the Unscreened or No Prescription groups, highlighting the value of including opioid exposure in studies of OUD.

Conclusions

Long-term opioid prescription use may serve as an additional tool to characterize OUD risk.
BrainPalmSeq: A curated RNA-seq database of palmitoylating and de-palmitoylating enzyme expression in the mouse brain
Authors: Wild AR , Hogg PW , Flibotte S , Nasseri G , Hollman R , Haas K , Bamji SX
Published: November 2021

Protein S-palmitoylation is a reversible post-translational lipid modification that plays a critical role in neuronal development and plasticity, while dysregulated S-palmitoylation underlies a number of severe neurological disorders. Dynamic S-palmitoylation is regulated by a large family of ZDHHC palmitoylating enzymes, their accessory proteins, and a small number of known de-palmitoylating enzymes. Here, we curated and analyzed expression data for the proteins that mediate S-palmitoylation from publicly available RNAseq datasets, providing a comprehensive overview of their distribution in the mouse nervous system. We developed a web-tool that enables interactive visualization of the expression patterns for these proteins in the nervous system (http://brainpalmseq.med.ubc.ca/), and explored this resource to find region and cell-type specific expression patterns that give insight into the function of palmitoylating and de-palmitoylating enzymes in the brain and neurological disorders. We found coordinated expression of ZDHHC enzymes with their accessory proteins, de-palmitoylating enzymes and other brain-expressed genes that included an enrichment of S-palmitoylation substrates. Finally, we utilized ZDHHC expression patterns to predict and validate palmitoylating enzyme-substrate interactions.
An allelic series of spontaneous mutations in Rorb cause a gait phenotype, retinal abnormalities, and transcriptomic changes relevant to human neurodevelopmental conditions
Authors: Murray George C , Bubier Jason , Zinder Oraya J , Harris Belinda , Clark James , Christopher Mia-Cara , Hanley Courtany , Tjong Harianto , Li Meihong , Ngan Chew Yee , Reinholdt Laura , Burgess Robert W , Tadenev Abby LD
Published: November 2021

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic high-stepper or duck-like gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent(TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD.
Fuzzy set intersection based paired-end short-read alignment
Authors: Bolosky William J. , Subramaniyan Arun , Zaharia Matei , Pandya Ravi , Sittler Taylor , Patterson David
Published: November 2021

Much genomic data comes in the form of paired-end reads: two reads that represent genetic material with a small gap between. We present a new algorithm for aligning both reads in a pair simultaneously by fuzzily intersecting the sets of candidate alignment locations for each read. This algorithm is often much faster and produces alignments that result in variant calls having roughly the same concordance as the best competing aligners.
Directing iPSC Differentiation into iTenocytes using Combined Scleraxis Overexpression and Cyclic Loading
Authors: Papalamprou Angela , Yu Victoria , Chen Angel , Stefanovic Tina , Kaneda Giselle , Salehi Khosrowdad , Castaneda Chloe , Gertych Arkadiusz , Glaeser Juliane D , Sheyn Dmitriy
Published: November 2021

Regenerative therapies for tendon are falling behind other tissues due to the lack of an appropriate and potent cell therapeutic candidate. This study aimed to induce cell tenogenesis using stable Scleraxis (Scx) overexpression in combination with uniaxial mechanical stretch of mesenchymal stromal cells (MSCs) of different origins. Scleraxis (Scx) is the single direct molecular regulator of tendon differentiation known to date. Mechanoregulation is known to be a central element guiding tendon development and healing. Cells explored were bone marrow-derived (BM-)MSCs as well as MSCs differentiated from induced pluripotent stem cells (iMSCs). Mechanical stimulation combined with Scx overexpression resulted in morphometric and cytoskeleton-related changes, upregulation of early and late tendon markers, increased ECM deposition and alignment, and tenomodulin perinuclear localization in iMSCs, which was greater compared to BM-MSCs and controls. Our findings suggest that these cells can be differentiated into tenocytes and may be a better candidate for tendon cell therapy applications than BM-MSCs.
Interferometric imaging of thermal expansion for temperature control in retinal laser therapy
Authors: Veysset David , Ling Tong , Zhuo Yueming , Palanker Daniel
Published: November 2021

Precise control of the temperature rise is a prerequisite for proper photothermal therapy. In retinal laser therapy, the heat deposition is primarily governed by the melanin concentration, which can significantly vary across the retina and from patient to patient. In this work, we present a method for determining the optical and thermal properties of layered materials, directly applicable to the retina, using low-energy laser heating and phase-resolved optical coherence tomography (pOCT). The method is demonstrated on a polymer-based tissue phantom heated with a laser pulse focused onto an absorbing layer buried below the phantom’s surface. Using a line-scan spectral-domain pOCT, optical path length changes induced by the thermal expansion were extracted from sequential B-scans. The material properties were then determined by matching the optical path length changes to a thermo-mechanical model developed for fast computation. This method determined the absorption coefficient with a precision of 2.5% and the temperature rise with a precision of about 0.2°C from a single laser exposure, while the peak did not exceed 8°C during 1 ms pulse, which is well within the tissue safety range and significantly more precise than other methods.
Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii
Authors: Islam Nowrosh , Kazi Misha I. , Kang Katie N. , Biboy Jacob , Gray Joe , Ahmed Feroz , Schargel Richard D. , Boutte Cara C. , Dörr Tobias , Vollmer Waldemar , Boll Joseph M.
Published: November 2021

The Gram-negative cell envelope is an essential structure that not only protects the cell against lysis from the internal turgor, but also forms a barrier to limit entry of antibiotics. Some of our most potent bactericidal antibiotics, the β-lactams, exploit the essentiality of the cell envelope by inhibiting its biosynthesis, typically inducing lysis and rapid death. However, many Gram-negative bacteria exhibit “antibiotic tolerance”, the ability to sustain viability in the presence of β-lactams for extended time periods. Despite several studies showing that antibiotic tolerance contributes directly to treatment failure, and is a steppingstone in acquisition of true resistance, the molecular factors that promote intrinsic tolerance are not well-understood.Acinetobacter baumanniiis a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. While typically reserved to combat multidrug resistant infections, carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treatA. baumanniiinfections. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptibleA. baumanniiclinical isolates demonstrate high intrinsic tolerance to meropenem, form spheroplasts with the antibiotic and revert to normal growth after antibiotic removal. Using transcriptomics and genetics screens, we characterized novel tolerance factors and found that outer membrane integrity maintenance, drug efflux and peptidoglycan homeostasis collectively contribute to meropenem tolerance inA. baumannii. Furthermore, outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to meropenem tolerance inA. baumannii.

Importance

Carbapenem treatment failure associated with “superbug” infections has rapidly increased in prevalence, highlighting an urgent need to develop new therapeutic strategies. Antibiotic tolerance can directly lead to treatment failure but has also been shown to promote acquisition of true resistance within a population. While some studies have addressed mechanisms that promote tolerance, factors that underlie Gram-negative bacterial survival during carbapenem treatment are not well-understood. Here, we characterized a role for peptidoglycan recycling in outer membrane integrity maintenance and carbapenem tolerance inA. baumannii. These studies suggest that the pathogen limits antibiotic concentrations in the periplasm and highlights physiological processes that could be targeted to improve antimicrobial treatment.
Age Differences in Diffusivity in the Locus Coeruleus and its Ascending Noradrenergic Tract
Authors: Porat Shai , Sibilia Francesca , Yoon Josephine , Shi Yonggang , Dahl Martin J. , Werkle-Bergner Markus , Düzel Sandra , Bodammer Nils , Lindenberger Ulman , Kühn Simone , Mather Mara
Published: November 2021

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used three datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220, and Stockholm Sleepy Brain, N = 49), to replicate published findings and expand them by investigating diffusivity in the LC’s ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC’s ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to microstructural changes in aging that have opposing effects on fractional anisotropy.

Highlights

Fractional anisotropy in the locus coeruleus was lower in younger adults

Fractional anisotropy in the noradrenergic bundle was higher in younger adults

Sleep deprivation may affect diffusivity in younger adults more than older adults
Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Authors: Edgar Rebecca C.S. , Siddiqui Ghizal , Hjerrild Kathryn , Malcolm Tess R. , Vinh Natalie B. , Webb Chaille T. , MacRaild Christopher A. , Counihan Natalie A. , Creek Darren J. , Scammells Peter J , McGowan Sheena , de Koning-Ward Tania F.
Published: November 2021

Plasmodium falciparum, a causative agent of malaria, continues to remain a global health threat since these parasites have developed increasing resistance to all anti-malaria drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the hosts main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here we utilize both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that our inhibitor is on-target for PfA-M17 and has the ability to kill parasites at nanomolar concentrations. Thus, in contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target.
Astrocytic expression of ALS-causative mutant FUS leads to TNFα-dependent neurodegeneration in vivo
Authors: Jensen Brigid K. , McAvoy Kevin J. , Heinsinger Nicolette M. , Lepore Angelo C. , Ilieva Hristelina , Haeusler Aaron R. , Trotti Davide , Pasinelli Piera
Published: November 2021

Genetic mutations that cause Amyotrophic Lateral Sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non-neuronal cells is also an important driver of disease. Previously, we demonstrated that mutations in DNA/RNA binding protein Fused in Sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro, via activation of the NF-κB pathway and release of pro-inflammatory cytokine TNFα. Here, we developed an intraspinal cord injection model to test whether astrocyte-specific expression of ALS-causative FUSR521G variant (mtFUS) causes neuronal damage in vivo. We show that mtFUS expression causes TNFα upregulation, motor function deficits, and spinal motor neuron loss. We further demonstrate a lack of phenotype in TNFα knockout animals expressing mtFUS, and prevention of neurodegeneration in mtFUS-transduced animals through administration of TNFα neutralizing antibodies. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS, establish that FUS-ALS astrocytes induce pathogenic changes to motor neurons in vivo, and provide insights identifying FUS-ALS specific potential therapeutic targets.
Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations
Authors: Damianou Andreas , Liang Zhu , Lassen Frederik , Vere George , Hester Svenja , Charles Philip D , Pinto-Fernandez Adan , Santos-Delgado Alberto , Fischer Roman , Kessler Benedikt M
Published: November 2021

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute up to 30% of human solid tumours including lung adenocarcinoma, pancreatic and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. Here, APEX-2 proximity labelling was used to profile the molecular environment of wild type and G12D, G13D and Q61H activating mutants of KRAS under both, starvation and stimulation conditions. We demonstrate by quantitative proteomics the presence of known interactors of KRAS including a-RAF and LZTR1, which varied in abundance with wildtype and KRAS mutants. Notably, the KRAS mutations G12D, G13D and Q61H abrogate association with LZTR1. Wildtype KRAS and LZTR1, as part of the CUL3 ubiquitin E3 ligase complex, affect each other’s protein stability, revealing a direct feedback loop mechanism. KRAS mutations disconnect this regulatory circuit, thereby contributing to oncogenesis.
A newly-evolved chimeric lysin motif receptor-like kinase in Medicago truncatula spp. tricycla R108 extends its Rhizobia symbiotic partnership
Authors: Luu Thi-Bich , Ourth Anna , Pouzet Cécile , Pauly Nicolas , Cullimore Julie
Published: November 2021

Rhizobial lipochitooligosaccharidic Nod factors (NFs), specified by nod genes, are the primary determinants of host specificity in the legume-Rhizobia symbiosis.

We examined the nodulation ability of Medicago truncatula cv Jemalong A17 and M. truncatula ssp. tricycla R108 with the Sinorhizobium meliloti nodF/nodL mutant, which produces modified NFs. We then applied genetic and functional approaches to study the genetic basis and mechanism of nodulation of R108 by this mutant.

We show that the nodF/nodL mutant can nodulate R108 but not A17. Using genomics and reverse genetics, we identified a newly-evolved, chimeric LysM receptor-like kinase gene in R108, LYK2bis, which is responsible for the phenotype and can allow A17 to gain nodulation with the nodF/nodL mutant. We found that LYK2bis is involved in nodulation by mutants producing non-O-acetylated NFs and interacts with the key receptor protein NFP. Many, but not all natural S. meliloti and S. medicae strains tested require LYK2bis for efficient nodulation of R108.

Our findings reveal that a newly-evolved gene in R108, LYK2bis, extends nodulation specificity to mutants producing non-O-acetylated NFs and is important for nodulation by many natural Sinorhizobia. Evolution of this gene may present an adaptive advantage to allow nodulation by a greater variety of strains.
Single virus assay reveals membrane determinants and mechanistic features of Sendai virus binding
Authors: Lam Amy , Kirkland Orville O. , Anderson Papa Freduah , Seetharaman Nandini , Vujovic Dragan , Thibault Patricia A. , Azarm Kristopher D. , Lee Benhur , Rawle Robert J.
Published: November 2021

Sendai virus (SeV, formally murine respirovirus) is a membrane-enveloped, negative sense RNA virus in the Paramyxoviridae family, and is closely related to human parainfluenza viruses. SeV has long been utilized as a model paramyxovirus and has recently gained attention as a viral vector candidate for both laboratory and clinical applications. To infect host cells, SeV must first bind to sialic-acid glycolipid or glycoprotein receptors on the host cell surface via its hemagglutinin-neuraminidase (HN) protein. Receptor binding induces a conformational change in HN, which allosterically triggers the viral fusion (F) protein to catalyze membrane fusion. While it is known that SeV binds to α2,3-linked sialic acid receptors, and there has been some study into the chemical requirements of those receptors, key mechanistic features of SeV binding remain unknown, in part because traditional approaches often convolve binding and fusion. Here, we develop and employ a fluorescence microscopy-based assay to observe SeV binding to supported lipid bilayers (SLBs) at the single particle level, which easily disentangles binding from fusion. Using this assay, we investigate mechanistic questions of SeV binding. We identify chemical structural features of ganglioside receptors that influence viral binding and demonstrate that binding is cooperative with respect to receptor density. We measure the characteristic decay time of unbinding and provide evidence supporting a “rolling” mechanism of viral mobility following receptor binding. We also study the dependence of binding on target cholesterol concentration. Interestingly, we find that while SeV binding shows striking parallels in cooperative binding with a prior report of Influenza A virus, it does not demonstrate a similar sensitivity to cholesterol concentration and receptor nano-cluster formation.

STATEMENT OF SIGNIFICANCE

Paramyxoviruses are a family of membrane-enveloped viruses with many notable human and animal pathogens. In this study, we develop and use an assay to observe the initial step of infection – virus binding to the host membrane – for Sendai virus, the prototypical paramyxovirus, at the single virus level. This assay uses cell membrane mimics – supported lipid bilayers – as targets for virus binding to enable easy control of the membrane components with which the virus interacts. Using our assay, we gain insight into basic biophysical questions about Sendai virus binding, including the chemical characteristics of the receptor, the cooperative nature of binding, the influence of cholesterol, and the mechanism of viral mobility following binding.
START domain mediates Arabidopsis GLABRA2 transcription factor dimerization and turnover independently of homeodomain DNA binding
Authors: Mukherjee Thiya , Subedi Bibek , Khosla Aashima , Begler Erika M. , Stephens Preston M. , Warner Adara L. , Lerma-Reyes Ruben , Thompson Kyle A. , Gunewardena Sumedha , Schrick Kathrin
Published: November 2021

Class IV homeodomain leucine-zipper transcription factors (HD-Zip IV TFs) are key regulators of epidermal differentiation that are characterized by a DNA-binding homeodomain (HD) in conjunction with a lipid-binding domain termed START (Steroidogenic Acute Regulatory (StAR)-related lipid Transfer). Previous work established that the START domain of GLABRA2 (GL2), a HD-Zip IV member from Arabidopsis, is required for transcription factor activity. Here, we address the functions and possible interactions of START and the HD in DNA binding, dimerization, and protein turnover. Deletion analysis of the HD and missense mutations of a conserved lysine (K146) result in phenotypic defects in leaf trichomes, root hairs and seed mucilage, similar to those observed for START domain mutants, despite nuclear localization of the respective proteins. In vitro and in vivo experiments demonstrate that while HD mutations impair binding to target DNA, the START domain is dispensable for DNA binding. Vice versa, protein interaction assays reveal impaired GL2 dimerization for multiple alleles of START mutants, but not HD mutants. Using in vivo cycloheximide chase experiments, we provide evidence for the role of START, but not HD, in maintaining protein stability. This work advances our mechanistic understanding of HD-Zip TFs as multidomain regulators of epidermal development in plants.
Influence of selected plant growth stimulators in enhancing germinability and germination parameters of Zea mays L. under microgravity conditions simulated by a two-dimensional clinostat
Authors: Ikhajiagbe Beckley , Anoliefo Geoffrey O. , Orukpe Alexander O. , Musa Saheed I.
Published: November 2021

The earth has become increasingly overcrowded as a result of rapid urbanization and population growth, predicting that its carrying capacity could be overstretched. As a result, it is important to test the possibilities of growing plants under space exploration conditions, especially gravitational balance. Since microgravity impedes plant development, to what extent can plant growth stimulators reverse or enhance this trend? A total of 12 maize seeds were weighed and placed sideways in petri dish and inoculated with plant growth stimulators such as indole acetic acid (IAA), gibberellic acid (GA), and ascorbate (AA) and the clinorotated at different rates (0.5, 1.0 and 2.0 rpm), while control seeds were just placed on a table. Results showed that at 72 hrs, the maize seeds under microgravity showed reduced germination percentage with increasing clinorotation rates as against the control. But when stimulated with IAA, GA and AA, improved germination percentage was observed as against the control even under microgravity condition. The seedling dry weight, germination time and other germination parameters also showed similar improvements. Comparatively, the three growth stimulators showed no major variations in their ability to improve germination percentage under microgravitational impact. However, IAA showed more improvement on seedling vigor as against others, while GA showed more effect on the peak time and rate of germination. This research confirmed the possibilities of improving germinability of maize seeds under space exploration condition.
Genetic mapping of a bioethanol yeast strain reveals new targets for aldehyde- and thermotolerance
Authors: de Mello Fellipe da Silveira Bezerra , Coradini Alessandro Luis Venega , Carazzolle Marcelo Falsarella , Maneira da Silva Carla , Furlan Monique , Pereira Gonçalo Amarante Guimarães , Teixeira Gleidson Silva
Published: November 2021

Current technology that enables bioethanol production from agricultural biomass imposes harsh conditions for Saccharomyces cerevisiae’s metabolism. In this work, the genetic architecture of industrial bioethanol yeast strain SA-1 was evaluated. SA-1 segregant FMY097 was previously described as highly aldehyde resistant and here also as thermotolerant: two important traits for the second-generation industry. A Quantitative Trait Loci (QTL) mapping of 5-hydroxymethylfurfural (HMF) -resistant segregants of hybrid FMY097/BY4742 disclosed a region in chromosome II bearing alleles with uncommon non-synonymous (NS) single nucleotide polymorphisms (SNPs) in FMY097: MIX23, PKC1, SEA4, and SRO77. Allele swap to susceptible laboratory strain BY4742 revealed that SEA4FMY097 enhances robustness towards HMF, but the industrial fitness could not be fully recovered. The genetic network arising from the causative genes in the QTL window suggests that intracellular signaling TOR (Target of Rapamycin) and CWI (Cell Wall Integrity) pathways are regulators of this phenotype in FMY097. Because the QTL mapping did not result in one major allelic contribution to the evaluated trait, a background effect in FMY097’s HMF resistance is expected. Quantification of NADPH - cofactor implied in endogenous aldehyde detoxification reactions - supports the former hypothesis, given its high availability in FMY097. Regarding thermotolerance, SEA4FMY097 grants BY4742 ability to grow in temperatures as high as 38 °C in liquid, while allele PKC1FMY097 allows growth up to 40 °C in solid medium. Both SEA4FMY097 and PKC1FMY097 encode rare NS SNPs, not found in other >1,013 S. cerevisiae. Altogether, these findings point towards crucial membrane and stress mediators for yeast robustness.

KEY POINTS

QTL mapping of the HMF-resistant strain FMY097 reveals a region enriched with SNPs in Chr II

SEA4FMY097 has rare non-synonymous mutations and improves cell growth at 10 mM HMF and 38°C

PKC1FMY097 has rare non-synonymous mutations and improves cell growth at 40 °C in solid media
Evaluation of the Efficacy of Omega-3 Fatty Acids Formulations in the Lipopolysaccharide-Induced Acute Lung Inflammation Rat Model
Authors: Kocherlakota Chandrashekhar , Banda Nagaraju , Narala Arjun , Akula Srinath , Kothapalli Kumar S.D. , Brenna J.T.
Published: November 2021

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. The O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour later, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3 groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress like COVID-19.