bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal Arsenite Exposure Alters Maternal Cardiac Remodeling During Late Pregnancy
Authors: Taube Nicole , Kabir Raihan , Ebenebe Obialunanma V. , Garbus Haley , Din Sarah-Marie Alam El , Illingworth Emily , Fitch Michael , Wang Nadan , Kohr Mark J.
Published: September 2023

Exposure to inorganic arsenic through drinking water is widespread and has been linked to many chronic diseases, including cardiovascular disease. Arsenic exposure has been shown to alter hypertrophic signaling in the adult heart, as well as in-utero offspring development. However, the effect of arsenic on maternal cardiac remodeling during pregnancy has not been studied. As such, there is a need to understand how environmental exposure contributes to adverse pregnancy-related cardiovascular events. This study seeks to understand the impact of trivalent inorganic arsenic exposure during gestation on maternal cardiac remodeling in late pregnancy, as well as offspring outcomes. C57BL/6J mice were exposed to 0 (control), 100 or 1000 µg/L sodium arsenite (NaAsO2) beginning at embryonic day (E) 2.5 and continuing through E17.5. Maternal heart function and size were assessed via transthoracic echocardiography, gravimetric measurement, and histology. Transcript levels of hypertrophic markers were probed via qRT-PCR and confirmed by western blot. Offspring outcomes were assessed through echocardiography and gravimetric measurement. We found that exposure to 1000 µg/L iAs abrogated normal physiologic growth of the maternal heart during late pregnancy and reduced transcript levels of estrogen receptor alpha (ERα), progesterone receptor membrane component 1 (Pgrmc1) and progesterone receptor membrane component 2 (Pgrmc2). Both 100 and 1000 µg/L iAs also reduced transcription of protein kinase B (Akt) and atrial natriuretic peptide (ANP). Akt protein expression was also significantly reduced after 1000 µg/L iAs exposure in the maternal heart with no change in activating phosphorylation. This significant abrogation of maternal cardiac hypertrophy suggests that arsenic exposure during pregnancy can potentially contribute to cardiovascular disease. Taken together, our findings further underscore the importance of reducing arsenic exposure during pregnancy and indicate that more research is needed to assess the impact of arsenic and other environmental exposures on the maternal heart and adverse pregnancy events.
Differential Reorganization of Episodic and Semantic Memory Systems in Epilepsy-Related Mesiotemporal Pathology
Authors: Cabalo Donna Gift , DeKraker Jordan , Royer Jessica , Xie Ke , Tavakol Shahin , Rodríguez-Cruces Raúl , Bernasconi Andrea , Bernasconi Neda , Weil Alexander , Pana Raluca , Frauscher Birgit , Caciagli Lorenzo , Jefferies Elizabeth , Smallwood Jonathan , Bernhardt Boris C.
Published: September 2023

Abstract

Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, while semantic memory houses context-independent knowledge. Behavioral and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions and distributed neocortices. Here, we studied a population of patients with unilateral temporal lobe epilepsy (TLE) and variable degrees of MTL pathology as a human disease model to explore declarative memory system reorganization, and to examine neurocognitive associations. Our cohort included 20 patients with TLE as well as 60 age and sex-matched healthy controls, who underwent episodic and semantic retrieval tasks during a functional MRI session. Tasks were closely matched in terms of stimuli and trial design. Capitalizing on connectome gradient mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, both in the MTL and in neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed topographic reorganization during episodic but not semantic memory states, characterized by marked gradient compression in lateral temporal and midline parietal cortices in both hemispheres, cooccurring with an expansion of anterior-posterior hippocampal differentiation ipsilateral to the MTL pathology. These findings suggest that episodic processes are supported by a distributed network, implicating both hippocampus and neocortex, and such alterations can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage such as TLE. Leveraging microstructural and morphological MRI proxies of MTL pathology, we furthermore observed that pathological markers selective to the hippocampus are associated with TLE-related functional reorganization. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioral deficits in episodic memory in patients. Altogether, our findings point to a selective mesiotemporal and neocortical functional reorganization of episodic memory systems in patients with TLE, which consistently affects behavioral memory deficits. These findings point to consistent structure-function relationships in declarative memory and reaffirm the critical role of the MTL in episodic memory systems.
REM disruption and REM Vagal Activity Predict Extinction Recall in Trauma-Exposed Individuals
Authors: Yuksel Cagri , Watford Lauren , Muranaka Monami , McCoy Emma , Lax Hannah , Mendelsohn Augustus Kram , Oliver Katelyn I. , Daffre Carolina , Acosta Alexis , Vidrin Abegail , Martinez Uriel , Lasko Natasha , Orr Scott , Pace-Schott Edward F.
Published: September 2023

Accumulating evidence suggests that rapid eye movement sleep (REM) supports the consolidation of extinction memory. REM is disrupted in PTSD, and REM abnormalities after traumatic events increase the risk of developing PTSD. Therefore, it was hypothesized that abnormal REM in trauma-exposed individuals may pave the way for PTSD by interfering with the processing of extinction memory. In addition, PTSD patients display reduced vagal activity. Vagal activity contributes to the strengthening of memories, including fear extinction memory, and recent studies show that the role of vagus in memory processing extends to memory consolidation during sleep. Therefore, it is plausible that reduced vagal activity during sleep in trauma-exposed individuals may be an additional mechanism that impairs extinction memory consolidation. However, to date, the contribution of sleep vagal activity to the consolidation of extinction memory or any emotional memory has not been investigated. To test these hypotheses, we examined the association of extinction memory with REM characteristics and REM vagal activity (indexed as heart rate variability) in a large sample of trauma-exposed individuals (n=113). Consistent with our hypotheses, REM disruption was associated with poorer physiological and explicit extinction memory. Furthermore, higher vagal activity during REM was associated with better explicit extinction memory, and physiological extinction memory in males. These findings support the notion that abnormal REM may contribute to PTSD by impairing the consolidation of extinction memory and indicate the potential utility of interventions that target REM sleep characteristics and REM vagal activity in fear-related disorders.
Cannabidiol prevents the locomotor sensitization induced by cocaine and caffeine and upregulates genes of extracellular matrix and anti-inflammatory pathways in the nucleus accumbens: a transcriptome-wide analysis
Authors: Prieto José Pedro , Fort Rafael , Eastman Guillermo , Kaminski Oliver , Ferreiro-Vera Carlos , de Medina Verónica Sanchez , Scorza Cecilia , Sotelo-Silveira José Roberto
Published: September 2023

Cannabidiol (CBD), a non-psychotomimetic phytocannabinoid found in theCannabisplant, has emerged as a potential therapeutic agent for psychostimulant use disorders. In recent work, we demonstrated that CBD is able to attenuate the expression of locomotor sensitization and the enhanced metabolic activity in the nucleus accumbens (NAc) generated by the combination of cocaine and caffeine. CDB interacts directly or indirectly with several molecular targets, so the underlying mechanisms of its beneficial effects are hard to determine. Here we used high-throughput RNA-sequencing in mice’s NAc after a sensitization protocol with combined cocaine plus caffeine and a CBD pre-treatment, to identify the major pathways and genes involved in CBD attenuating behavioral effects. Results indicated that CBD pretreatment consistently reduced both the acquisition and expression of cocaine and caffeine locomotor sensitization. The transcriptome analysis revealed that CBD pre-treatment enriched genes and functional association between proteins mainly related to extracellular matrix (ECM) organization and cell interactions in the NAc. Moreover, the neuroinflammation and BDNF signaling pathways were also influenced by CBD. Some specially enriched genes such as Tnc were identified as interesting specific candidates for follow-up studies. These findings provide valuable and novel insights into molecular mechanisms of CBD putatively associated with a protective effect on psychostimulant actions. A better understanding of the therapeutic targets of CBD can open new avenues for psychostimulant use disorder treatment strategies.
SoxB1 transcription factors are essential for initiating and maintaining the neural plate border gene expression
Authors: Schock Elizabeth N. , York Joshua R. , Li Austin P. , Tu Ashlyn Y. , LaBonne Carole
Published: September 2023

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). UsingXenopus laevis, we set out to determine if SoxB1 transcription factors have a regulatory function in NPB formation. Herein, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq we demonstrate that Sox3 is enriched upstream of NPB genes in early NPB cells and, surprisingly, in blastula stem cells. Depletion of SoxB1 factors in blastula stem cells results in downregulation of NPB genes. Finally, we identify Pou5f3 factors as a potential SoxB1 partners in regulating the formation of the NPB and show their combined activity is needed to maintain NPB gene expression. Together, these data identify a novel role for SoxB1 factors in the establishment and maintenance of the NPB, in part through partnership with Pou5f3 factors.
Activity-dependent synapse clustering underlies eye-specific competition in the developing retinogeniculate system
Authors: Zhang Chenghang , Vatan Tarlan , Speer Colenso M.
Published: September 2023

Co-active synaptic connections are often spatially clustered to facilitate local dendritic computations underlying learning, memory, and basic sensory processing. In the mammalian visual system, retinal ganglion cell (RGC) axons converge to form clustered synaptic inputs that enable local signal integration in the dorsal lateral geniculate nucleus (dLGN) of the thalamus. While visual experience promotes retinogeniculate synapse clustering after eye-opening, the earliest events in cluster formation prior to visual experience are unknown. Here, using volumetric super-resolution single-molecule localization microscopy and eye-specific labeling of developing retinogeniculate synapses in mice, we show that synaptic clustering is eye-specific and activity-dependent during retinogeniculate refinement in the first postnatal week. We identified a subset of retinogeniculate synapses with multiple active zones that are surrounded by like-eye synapses and depleted of synapse clustering from the opposite eye. In mutant mice with disrupted spontaneous retinal wave activity, synapses with multiple active zones still form, but do not exhibit the synaptic clustering seen in controls. These results highlight a role for spontaneous retinal activity in regulating eye-specific synaptic clustering in circuits essential for visual perception and behavior.
Cyclic nucleotide-induced bidirectional long-term synaptic plasticity inDrosophilamushroom body
Authors: Yamada Daichi , Davidson Andrew M. , Hige Toshihide
Published: September 2023

Activation of the cAMP pathway is one of the common mechanisms underlying long-term potentiation (LTP). In theDrosophilamushroom body, simultaneous activation of odor-coding Kenyon cells (KCs) and reinforcement-coding dopaminergic neurons activates adenylyl cyclase in KC presynaptic terminals, which is believed to trigger synaptic plasticity underlying olfactory associative learning. However, learning induces long-term depression (LTD) at these synapses, contradicting the universal role of cAMP as a facilitator of transmission. Here, we develop a system to electrophysiologically monitor both short-term and long-term synaptic plasticity at KC output synapses and demonstrate that they are indeed an exception where activation of the cAMP/protein kinase A pathway induces LTD. Contrary to the prevailing model, our cAMP imaging finds no evidence for synergistic action of dopamine and KC activity on cAMP synthesis. Furthermore, we find that forskolin-induced cAMP increase alone is insufficient for plasticity induction; it additionally requires simultaneous KC activation to replicate the presynaptic LTD induced by pairing with dopamine. On the other hand, activation of the cGMP pathway paired with KC activation induces slowly developing LTP, proving antagonistic actions of the two second-messenger pathways predicted by behavioral study. Finally, KC subtype-specific interrogation of synapses reveals that different KC subtypes exhibit distinct plasticity duration even among synapses on the same postsynaptic neuron. Thus, our work not only revises the role of cAMP in synaptic plasticity by uncovering the unexpected convergence point of the cAMP pathway and neuronal activity, but also establishes the methods to address physiological mechanisms of synaptic plasticity in this important model.

Abstract Figure

Mushroom body (MB) is the olfactory learning center of theDrosophilabrain (left). Dopamine input activates the cAMP/Protein kinase A pathway in Kenyon cells (KCs), the principal neurons of the MB. When it coincides with KC activity, it induces presynaptic long-term depression at the synapses on the MB output neuron (Top right). A subset of dopaminergic neurons is also known to release nitric oxide, which activates the cGMP pathway. When it coincides with KC activity, it induces long-term potentiation (Bottom right). Created withBioRender.com.
Curcumin and turmeric extract inhibit SARS-CoV-2 pseudovirus cell entry and spike-mediated cell fusion
Authors: Septisetyani Endah Puji , Lestari Dinda , Paramitasari Komang Alit , Prasetyaningrum Pekik Wiji , Kastian Ria Fajarwati , Anam Khairul , Santoso Adi , Eriani Kartini
Published: September 2023

Turmeric extract (TE) with curcumin as its main active ingredient has been studied as a potential COVID-19 therapeutic. Curcumin has been studied in silico and in vitro against a naive SARS-CoV-2 virus, yet little is known about TE’s impact on SARS-CoV-2 infection. Moreover, no study reveals the potential of both curcumin and TE on the inhibition of SARS-CoV-2 cell-to-cell transmission. Here, we investigated the effects of both curcumin and TE on inhibiting SARS-CoV-2 entry and cell-to-cell transmission using pseudovirus (PSV) and syncytia models. We performed a PSV entry assay in 293T or 293 cells expressing hACE2. The cells were pretreated with curcumin or TE and then treated with PSV with or without the test samples. Next, we carried out syncytia assay by co-transfecting 293T cells with plasmids encoding spike, hACE2, and TMPRSS2 to be treated with the test samples. The results showed that in PSV entry assay on 293T/hACE/TMPRSS2 cells, both curcumin and TE inhibited PSV entry at concentrations of 1 µM and 10 µM for curcumin and 1 µg/ml and 10 µg/ml for TE. Moreover, both curcumin and TE reduced syncytia formation compared to control cells. Our study shows that TE and curcumin are potential inhibitors of SARS-CoV-2 infection at entry points, either by direct or indirect infection models.

GRAPHICAL ABSTRACT
Acute and chronic psychosocial stress by the brain-derived neurotrophic factor in male humans: a highly standardized and controlled study
Authors: Herhaus Benedict , Heni Martin , Bloch Wilhelm , Petrowski Katja
Published: September 2023

Objective

The neurotrophic protein brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain function and is affected by acute and chronic stress. We here investigate the patterns of BDNF and cortisol stress reactivity and recovery under the standardized stress protocol of the TSST and the effect of perceived chronic stress on the basal BDNF levels in healthy young men.

Methods

Twenty-nine lean young men underwent the Trier Social Stress Test (TSST) and a resting condition. Serum BDNF and cortisol were measured before and repeatedly after both conditions. The perception of chronic stress was assessed by the Trier Inventory for Chronic Stress (TICS).

Results

After the TSST, there was a significant increase over time for BDNF and cortisol. Stronger increase in cortisol in response to stress was linked to an accelerated BDNF decline after stress. Basal resting levels of BDNF was significantly predicted by chronic stress perception.

Conclusions

The increased BDNF level following psychosocial stress suggest a stress-induced neuroprotective mechanism. The presumed interplay between BDNF and the HPA-axis indicates an antagonistic relationship of cortisol on BDNF recovery post-stress. Chronically elevated high cortisol levels, as present in chronic stress, could thereby contribute to reduced neurogenesis, and an increased risk of neurodegenerative conditions in persons suffering from chronic stress.

Highlights

Acute psychosocial stress increases serum BDNF and cortisol

Stress-induced cortisol secretion may accelerate the decline of BDNF after stress.

Chronic stress is linked to lower basal serum BDNF levels
AsymptomaticPlasmodium falciparumCarriage at the End of the Dry Season is Associated with Subsequent Infection and Clinical Malaria in Eastern Gambia
Authors: Fogang Balotin , Lellouche Lionel , Ceesay Sukai , Drammeh Sainabou , Jaiteh Fatou K. , Guery Marc-Antoine , Landier Jordi , Haanappel Cynthia , Froberg Janeri , Conway David , D’Alessandro Umberto , Bousema Teun , Claessens Antoine
Published: September 2023

Background

Chronic carriage of asymptomatic low-densityPlasmodium falciparumparasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear.

Methods

In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria.

Results

Among the 5,256 samples collected, 444 (8.4%) were positive forP. falciparum. A multivariate model identified village of residence, male sex, age ≥5 years old, anaemia, and fever as independent factors associated withP. falciparumparasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR= 3.0, p< 0.0001) and clinical malaria (HR= 1.561, p= 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season.

Conclusion

Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.
Goal-Oriented Attentional Self-Regulation Training in Chronic Mild Traumatic Brain Injury Leads to Microstructural Plasticity in Prefrontal White Matter
Authors: Karbasforoushan Haleh , Wren-Jarvis Jamie , Hwang Anna , Santiago Rachel , Raptentsetsang Sky , Cai Lanya T. , Xiao Jaclyn , Maruyama Brian A. , Abrams Gary M. , Novakovic-Agopian Tatjana , Mukherjee Pratik
Published: September 2023

Impaired attention is one of the most common, debilitating, and persistent consequence of traumatic brain injury (TBI), which impacts overall cognitive and executive functions in these patients. Previous neuroimaging studies, trying to understand the neural mechanism underlying attention impairment post TBI, have highlighted the role of prefrontal white matter tracts in attentional functioning in mild TBI. Goal-Oriented Attentional Self-Regulation (GOALS) is a cognitive rehabilitation training program that targets executive control functions in participants by applying mindfulness-based attention regulation and goal management strategies. GOALS training has been demonstrated to improve attention and executive functioning in patients with chronic TBI. However, its impact on microstructural integrity of attention-associated prefrontal white matter tracts is still unclear. Here, using diffusion MRI in a pilot randomized controlled trial, we investigated the effect of GOALS training on prefrontal white matter microstructure in US military veterans with chronic mild TBI (mTBI), compared to a matched control group of veterans with chronic mTBI who received standard of care brain health education. We also tested for an association between microstructural white matter changes and sustained attention ability in these patients pre- and post-GOALS training. Our results show significantly better white matter microstructural integrity in left and right anterior corona radiata in the GOALS group compared to the control group post-training. Moreover, we found a significant correlation between sustained attention ability of GOALS training participants and white matter integrity of their right anterior corona radiata pre- and post-training. Finally, our findings indicated that the improved white matter integrity of the anterior corona radiata in GOALS training participants was the result of increased neurite density and decreased fiber orientation dispersion within this tract.
Influenza virus circulation and vaccine effectiveness during June 2021–May 2023 in Thailand
Authors: Prasert Kriengkrai , Praphasiri Prabda , Nakphook Sutthichai , Ditsungnoen Darunee , Sapchookul Patranuch , Sornwong Kanlaya , Naosri Suriya , Okada Pilailuk Akkapaiboon , Suntarattiwong Piyarat , Chotpitayasunondh Tawee , Montgomery Martha P. , Davis William W. , Pittayawonganon Chakrarat
Published: September 2023

We evaluated 2023 Southern Hemisphere influenza vaccine effectiveness against medically attended illness using surveillance data from nine Thai hospitals and a test-negative design. During June 2022–May 2023, influenza vaccine provided protection against seeking care for influenza illness (adjusted vaccine effectiveness 43%; 95% confidence interval 15–61).
Single-cell multimodal profiling of atherosclerosis identifies CD200 as a cell surface lineage marker of vascular smooth muscle cells and their derived cells
Authors: Bashore Alexander C. , Chung Allen , Ibikunle Chinyere , Yan Hanying , Xue Chenyi , Li Mingyao , Bauer Robert C. , Reilly Muredach P.
Published: September 2023

Vascular smooth muscle cells (VSMCs) play a central role in the development of atherosclerosis due in part to their capability to phenotypically transition into either a protective or harmful state. However, the ability to identify and trace VSMCs and their progeny in vivo is limited due to the lack of well-defined VSMC cell surface markers. Therefore, investigations into VSMC fate must utilize lineage-tracing mouse models, which are time-consuming and challenging to generate and not feasible in humans. Here, we employed CITE-seq to characterize the phenotypic expression of 119 cell surface proteins in mouse atherosclerosis. We found that CD200 is a highly expressed and specific marker of VSMCs, which persists even with phenotypic modulation. We validated our findings using a combination of flow cytometry, qPCR, and immunohistochemistry, all confirming that CD200 can identify and mark VSMCs and their derived cells in early to advanced mouse atherosclerotic lesions. Additionally, we describe a similar expression pattern of CD200 in human coronary and carotid atherosclerosis. Thus, our data support the use of CD200 as a lineage marker for VSMCs and VSMC-derived cells in mouse and human atherosclerosis.
Folate depletion alters mouse trophoblast stem cell regulationin vitro
Authors: Rakoczy Joanna , Watson Erica D.
Published: September 2023

Maternal folate deficiency increases risk of congenital malformations, yet its effect on placenta development is unclear. Here, we investigated how folate-depleted culture medium affects the developmental potential of mouse trophoblast stem cells (TSCs). When cultured in stem cell conditions, TSC viability was unaffected by folate depletion, but ectopic differentiation of several trophoblast cell subtypes occurred. When cultured in conditions that promote differentiation, folate-depleted TSCs were driven towards a syncytiotrophoblast cell fate potentially at the expense of other lineages. Additionally, trophoblast giant cell nuclei were small implicating folate in the regulation of endoreduplication. Therefore, dietary folate intake likely promotes placenta development.
Sex- and caste-specific developmental responses to juvenile hormone in an ant with maternal caste determination
Authors: Brülhart J. , Süß A. , Oettler J. , Heinze J. , Schultner E.
Published: September 2023

Queen-worker caste polyphenism in social insects is a prime example for developmental plasticity. Most of what we know about caste development comes from studies of the honeybee, in which female caste is determined during larval development and workers retain functional ovaries. The ant genusCardiocondylais one of only few genera in which complete worker sterility has evolved, so that adult workers completely lack reproductive organs. InC. obscurior, queen- and worker-destined individuals are distinct in their development by late-embryogenesis, and castes can be distinguished in a non-invasive manner from this stage onwards. This provides the opportunity to investigate the degree of flexibility in caste development in a species with early caste determination. Using topical juvenile hormone treatment, a method known to influence caste determination and differentiation in some species, we investigated whether hormone manipulation affects the development and growth of queen and worker-destined late-stage embryos and larvae, as well as of early-stage embryos which cannot yet be distinguished by caste. We found no effect of hormone treatment on female caste ratios or body sizes in any of the treated stages, even though individuals reacted to heightened hormone availability with increases in the expression ofkrüppel-homolog 1, a conserved JH first-response gene. In contrast, hormone treatment resulted in the emergence of significantly larger males. These results show that inC. obscurior, early, presumably maternal caste determination leads to irreversible and highly-canalized caste-specific development and growth.
A conserved class of viral RNA structures regulate translation reinitiation through dynamic ribosome interactions
Authors: Sherlock Madeline E. , Langeberg Conner J. , Segar Katherine E. , Kieft Jeffrey S.
Published: September 2023

Certain viral RNAs encode proteins downstream of the main protein coding region, expressed through “termination-reinitiation” events, dependent on RNA structure. RNA elements located upstream of the first stop codon within these viral mRNAs bind the ribosome, preventing ribosome recycling and inducing reinitiation. We used bioinformatic methods to identify new examples of viral reinitiation-stimulating RNAs and experimentally verified their secondary structure and function. We determined the structure of a representative viral RNA-ribosome complex using cryoEM. 3D classification and variability analyses reveal that the viral RNA structure can sample a range of conformations while remaining tethered to the ribosome, which enabling the ribosome to find a reinitiation start site within a limited range of mRNA sequence. Evaluating the conserved features and constraints of this entire RNA class in the context of the cryoEM reconstruction provides insight into mechanisms enabling reinitiation, a translation regulation strategy employed by many other viral and eukaryotic systems.
Location, Location, Location: Protein kinase nanoclustering for optimized signalling output
Authors: Gormal Rachel S. , Martínez-Mármol Ramón , Brooks Andrew J. , Meunier Frédéric A.
Published: September 2023

Protein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most of the cellular physiological processes and their regulations. As for all cellular proteins, they are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PKs localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein-protein and protein-lipid interactions as well as liquid-liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will mainly focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.
Protective non-neutralizing mAbs Ab94 and Ab81 retain high-affinity and potent Fc-mediated function against SARS-CoV-2 variants from Omicron to XBB1.5
Authors: Izadi Arman , Godzwon Magdalena , Ohlin Mats , Nordenfelt Pontus
Published: September 2023

Antibodies play a central role in the immune defense against SARS-CoV-2. There is substantial evidence supporting that Fc-mediated effector functions of anti-spike antibodies contribute to anti-SARS-Cov-2 immunity. We have previously shown that two non-neutralizing but opsonic mAbs, Ab81 and Ab94, are protective against lethal Wuhan SARS-CoV-2 infection in mice. The protective effect was comparable to a potent neutralizing antibody, Ab59. Here, we hypothesized that, unlike the neutralizing antibodies, non-neutralizing opsonic antibodies would have a higher likelihood of retaining their function to the mutated variants, potentially functioning as broadly protective mAbs. Most of the mutations on the SARS-CoV-2 variants cluster on neutralizing epitopes, leaving other epitopes unaltered. We observed that neutralizing antibodies lost binding to Omicron. In contrast, seven non-neutralizing opsonic antibodies retained nanomolar affinity towards Omicron, BA.2, BA.4, and BA.5. Focusing on the two protective non-neutralizing antibodies Ab81 and Ab94, we showed that they maintain their strong reactivity even to XBB, XBB1.5, and BQ1.1. In the case of Ab94, interestingly, it even has increased affinity towards all variants except for XBB, which is comparable to WT. Finally, we show that Ab94 and Ab81 have potent Fc-mediated functions in vitro against the XBB and BQ1.1 and that combining the mAbs in a cocktail further enhances the effect. These results show that protective non-neutralizing mAbs such as Ab94 and Ab81 can be a viable strategy for anti-SARS-CoV-2 mAb therapies against current and possibly future SARS-CoV-2 variants and that opsonic epitopes could have implications for vaccine design.
Evolutionary Adaptation of an HP1-protein Chromodomain Integrates Chromatin and DNA Sequence Signals
Authors: Baumgartner Lisa , Ipsaro Jonathan J. , Hohmann Ulrich , Handler Dominik , Schleiffer Alexander , Duchek Peter , Brennecke Julius
Published: September 2023

Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin binding patterns, likely due to interactions with various specificity factors. Here, we elucidate the molecular basis of the interaction between the HP1 protein Rhino, a crucial factor of theDrosophilapiRNA pathway, and Kipferl, a DNA sequence-specific C2H2zinc finger protein and Rhino guidance factor. Through phylogenetic analyses, structure prediction, andin vivogenetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying therhinoG31Dmutation phenocopykipferlmutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile ofrhinoG31Dflies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.
Functional opsin patterning forDrosophilacolor vision is established through signaling pathways in adjacent object-detection neurons
Authors: Kitamata Manabu , Otake Yoshiaki , Kitagori Hideaki , Zhang Xuanshuo , Maki Yusuke , Boku Rika , Takeuchi Masato , Nakagoshi Hideki
Published: September 2023

Vision is mainly based on two different tasks, object detection and color discrimination through activities of photoreceptor (PR) cells.Drosophilacompound eye consists of ∼800 ommatidia. Every ommatidium contains eight PR cells; six outer cells (R1-R6) and two inner cells (R7 and R8) by which object detection and color vision are achieved, respectively. Expression of opsin genes in R7 and R8 is highly coordinated through the instructive signal from R7 to R8, and two major ommatidial subtypes are distributed stochastically; pale type expresses Rh3/Rh5, while yellow type expresses Rh4/Rh6 in R7/R8. The homeodomain protein Defective proventriculus (Dve) is expressed in yellow-type R7 and in six outer PRs, and it is involved in Rh3 repression to specify the yellow-type R7.dvemutant eyes exhibited atypical coupling, Rh3/Rh6 and Rh4/Rh5, indicating that the Dve activity is required for proper opsin coupling. Surprisingly, Dve activity in R1 is required for instructive signal, whereas those in R6 and R7 block the signal. Our results indicate that functional coupling of two different neurons is established through signaling pathways from adjacent neurons that are functionally different.

Summary Statement

Dve activity is required for proper opsin coupling of two neurons that is established through signaling pathways from adjacent neurons that are functionally different.
Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB
Authors: Munir Moiz , Embry Aaron , Doench John G. , Heaton Nicholas S. , Wilen Craig B. , Orchard Robert C.
Published: September 2023

The innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape we conducted a gain of function, genome-wide CRISPR activation screen with influenza A virus. We identified both appreciated and novel antiviral genes, including JADE3 a protein involved in directing the histone acetyltransferase HBO1 complex to modify chromatin and regulate transcription. JADE3 is both necessary and sufficient to restrict influenza A virus infection. Interestingly, expression of the closely related paralogues JADE1 and JADE2 are unable to restrict influenza A virus infection, suggesting a distinct function of JADE3. We identify both shared and unique transcriptional signatures between uninfected cells expressing JADE3 and JADE2. These data provide a framework for understanding the overlapping and distinct functions of the JADE family of paralogues. Specifically, we find that JADE3 expression activates the NF-kB signaling pathway, consistent with an antiviral function. Therefore, we propose JADE3, but not JADE1 or JADE2, activates an antiviral genetic program involving the NF-kB pathway to restrict influenza A virus infection.
Upc2-mediated mechanisms of azole resistance inCandida auris
Authors: Li Jizhou , Aubry Lola , Brandalise Danielle , Coste Alix T. , Sanglard Dominique , Lamoth Frederic
Published: September 2023

Candida aurisis an emerging yeast pathogen of major concern because of its ability to cause hospital outbreaks of invasive candidiasis and to develop resistance to antifungal drugs. A majority ofC. aurisisolates are resistant to fluconazole, a first-line treatment of invasive candidiasis. Mechanisms of azole resistance are multiple, including mutations in the target geneERG11and activation of the transcription factors Tac1b and Mrr1, which control the drug transporters Cdr1 and Mdr1, respectively. In this study, we investigated the role the transcription factor Upc2, which is known to regulate the ergosterol biosynthesis pathway and azole resistance in otherCandidaspp.

Genetic deletion and hyperactivation of Upc2 by epitope tagging inC. aurisresulted in drastic increased and decreased susceptibility to azoles, respectively. This effect was conserved in strains with genetic hyperactivation of Tac1b or Mrr1. Reverse transcription PCR analyses showed that Upc2 regulatesERG11expression and also activates the Mrr1/Mdr1 pathway. We showed that upregulation ofMDR1by Upc2 could occur independently from Mrr1. The impact ofUPC2deletion onMDR1expression and azole susceptibility in a hyperactive Mrr1 background was stronger than that ofMRR1deletion in a hyperactive Upc2 background. While Upc2 hyperactivation resulted in a significant increase of expression ofTAC1b,CDR1expression remained unchanged.

Taken together, our results showed that Upc2 is crucial for azole resistance inC. auris, via regulation of the ergosterol biosynthesis pathway and activation of the Mrr1/Mdr1 pathway. Notably, Upc2 is a very potent and direct activator of Mdr1.
Emergence of bluetongue virus serotype 3 in the Netherlands in September 2023
Authors: Holwerda Melle , Santman-Berends Inge M.G.A. , Harders Frank , Engelsma Marc , Vloet Rianka P.M. , Dijkstra Eveline , van Gennip Rene G.P. , Mars Maria H. , Spierenburg Marcel , Roos Lotte , van den Brom René , van Rijn Piet A.
Published: September 2023

Since 1998, WOAH-notifiable bluetongue virus (BTV) serotype 1, 2, 3, 4, 6, 8, 9, 11, and 16 have been reported in Europe. In mid-August, 2006, a BTV-8 outbreak started in Northwestern Europe. The Netherlands was declared BT-free again in February 2012 and annual monitoring demonstrated BT-freedom up to 2023. On September 3rd2023, clinical manifestations in sheep typical for BT were notified to the Dutch Food and Product Safety Consumer Authority. Laboratory diagnosis confirmed BTV-infection on September 6 and the first notifications of clinical signs in cattle were also reported. Two days later, the virus was identified as serotype 3 by whole genome sequencing. Clinical signs were like these of BTV-8 outbreak and were most serious in sheep. Retrospective analysis revealed no earlier circulation of BTV. It was concluded that the BTV-3 outbreak was detected shortly after introduction, while the virus source and route of introduction remains unknown.

Article summary line

During September 2023, a novel serotype 3 Bluetongue virus (BTV) emerged in the Netherlands which affected sheep and cattle.
Non-coding 886 (nc886/vtRNA2-1), the epigenetic odd duck – implications for future studies
Authors: Raitoharju Emma , Rajić Sonja , Marttila Saara
Published: September 2023

Non-coding 886 (nc886,VTRNA2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability, and consequences of the methylation pattern, as well as the nature and function of the nc886 RNAs transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 RNAs has been redefined multiple times and are still under debate and in carcinogenesis, these RNAs have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of thenc886locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets.

Here, we aim to summarise the existing literature regardingnc886, discuss how the characteristics ofnc886give rise to contradictory results, and reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how thenc886methylation pattern distribution is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and RNA, we aim to highlight issues in the analysis of DNA methylation and non-coding RNAs in general and offer our suggestions for what should be taken into consideration in future analyses.
Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation
Authors: Feng Lijuan , Barrows Douglas , Zhong Liangwen , Mätlik Kärt , Porter Elizabeth G. , Djomo Annaelle M. , Yau Iris , Soshnev Alexey A. , Carroll Thomas S. , Wen Duancheng , Hatten Mary E. , Garcia Benjamin A. , Allis C. David
Published: September 2023

Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain sizein vivo, reminiscent of the microcephaly phenotypes of patients. Together, our studies unveil a distinct molecular pathogenic mechanism from other known histone mutants, where H4K91 mutants misregulate cell fate during development through abnormal genomic localization.
Investigating the effects of contextual information, visual working memory, and inhibitory control in hybrid visual search
Authors: Barbosa Alessandra , Ries Anthony J. , Kamienkowski Juan E. , Ison Matias J.
Published: September 2023

In real-life scenarios, individuals frequently engage in tasks that involve searching for one of various items stored in memory. This combined process of visual search and memory search is known as hybrid search. To date, most hybrid search studies have been restricted to average observers looking for previously well-memorized targets in blank backgrounds. Here we investigated the effects of context and the role of memory in hybrid search by modifying the task’s memorization phase to occur in all-new single trials. Additionally, we aimed to assess how individual differences in visual working memory capacity and inhibitory control influence performance during hybrid search. In an online experiment, 110 participants searched for potential targets in images with and without context. A change detection and go/no-go task were also performed to measure working memory capacity and inhibitory control, respectively. We show that, in target present trials, the main hallmarks of hybrid search remain present, with a linear relationship between reaction time and visual set size, and a logarithmic relationship between reaction time and memory set size. Context affected search efficiency in different ways. In target-absent trials we found large differences between context-present and absent conditions, suggesting participants’ adoption of adaptive strategies. Finally, working memory capacity did not predict most search performance measures. Inhibitory control, when relationships were significant, could account for only a small portion of the variability in the data. This study provides insights into the effects of context and individual differences on search efficiency and termination.
A genome-wide CRISPR/Cas9 screen identifies genes that regulate the cellular uptake of α-synuclein fibrils by modulating heparan sulfate proteoglycans
Authors: Vanderperre B. , Muraleedharan A. , Dorion M.-F. , Larroquette F. , Del Cid Pellitero E. , Rajakulendran N. , Chen C. X.-Q. , Larivière R. , Michaud-Tardif C. , Chidiac R. , Lipuma D. , MacLeod G. , Thomas R. , Wang Z. , Reintsch W.E. , Luo W. , Shlaifer I. , Fuming Z. , Xia K. , Yan L. , Steinhart Z. , Linhardt R.J. , Trempe J.-F. , Liu J. , Durcan T.M. , Angers S. , Fon E.A.
Published: September 2023

Synucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. Understanding how these aggregates propagate from cell to cell in a prion-like fashion thus holds great therapeutic promises. Here, we focused on understanding the cellular processes involved in the entry and accumulation of pathological α-syn aggregates. We used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout (KO) screening to identify genes that regulate the accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. We show that all confirmed hits affect heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including of α-syn and tau. Intriguingly, KO ofSLC39A9andC3orf58genes, encoding respectively a Golgi-localized exporter of Zn2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs uptake but not of tau oligomers, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains indicated major defects in HS maturation inSLC39A9andC3orf58KO cells, explaining the cell surface binding deficit. Our findings now clearly establish these two genes as HSPG-modulating factors. Interestingly,C3orf58KO human iPSC-derived microglia exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data establish HSPGs as major receptors for α-syn PFFs binding on the cell surface and identifies new players in α-syn PFFs cell surface binding and uptake.