bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of the Tau fibrils with the neuronal membrane†
Authors: Chowdhury Unmesh D. , Paul Arnav , Bhargava B.L.
Published: December 2022

Tau proteins are gaining a lot of interest recently due to their active role in causing a range of tauopathies. Molecular mechanisms underlying the tau interaction with the neuronal membrane are hitherto unknown and difficult to characterize using conventional experimental methods. Starting from the cryo-EM structure of the tau fibrils, we have used atomistic molecular dynamics simulations to model the interaction between the fibril and neuronal membrane, with explicit solvation. The dynamics and structural characteristics of the tau fibril with the neuronal membrane are compared to the tau fibril in the aqueous phase to corroborate the effect of the neuronal membrane on the tau structure. The tau fibrils are in general more compact in the presence of neuronal membrane compared to their structure in the water medium. We find that the number ofβ-sheet residues of the tau fibrils are different in the case of two polymorphs, paired helical filament and straight filaments (PHF and SF) in the two media. PHF is found to approach closer to the neuronal membrane than the SF. The negatively charged lipids in the neuronal membrane are found to mediate the tau-neuronal membrane binding. Our study initiates the understanding of tau conformational ensemble in the presence of neuronal membrane and sheds light on the significant tau – membrane interactions. The simulation times of our report might limit the conformational sampling required to observe membrane permeation, nevertheless it provides significant insights into fibril – neuronal membrane interactions.
Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques
Authors: Larson Erica C. , Ellis Amy L. , Rodgers Mark A. , Gubernat Abigail K. , Gleim Janelle L. , Moriarty Ryan V. , Balgeman Alexis J. , Menezes Yonne K. , Ameel Cassaundra L. , Fillmore Daniel J. , Pergalske Skyler M. , Juno Jennifer A. , Maiello Pauline , White Alexander G. , Borish H. Jacob , Godfrey Dale I. , Kent Stephen J. , Ndhlovu Lishomwa C. , O’Connor Shelby L. , Scanga Charles A.
Published: December 2022

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naïve and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis(Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4-8 year-old children were intravenously infected with SIVmac239M, treated with ART three months later, and coinfected with Mtb three months after initiating ART. SIV-naïve macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naïve macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naïve macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas obtained at necropsy, nor did they differ in the frequency of immune checkpoint and proliferative markers. Thus, ART treatment of juvenile macaques, three months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naïve macaques.
Using in silico perturbational approach to identify critical areas in schizophrenia
Authors: Mana Ludovica , Vila − Vidal Manel , Köckeritz Charlotte , Aquino Kevin , Fornito Alex , Kringelbach Morten L. , Deco Gustavo
Published: December 2022

Schizophrenia is a debilitating neuropsychiatric disorder whose underlying correlates remain unclear despite decades of neuroimaging investigation. One contentious topic concerns the role of global signal fluctuations and how they affect more focal functional changes. Moreover, it has been difficult to pinpoint causal mechanisms of circuit disruption. Here we analysed resting-state fMRI data from 47 schizophrenia patients and 118 age-matched healthy controls and used dynamical analyses to investigate how global fluctuations and other functional metastable states are affected by this disorder. We then used in-silico perturbation of a whole-brain model to identify critical areas involved in the disease. We found that brain dynamics in the schizophrenic group were characterised by an increased probability of globally coherent states and reduced recurrence of a substate dominated by coupled activity in the default mode and limbic networks. Perturbing a set of temporoparietal sensory and associative areas in a model of the healthy brain reproduced global pathological dynamics. Healthy brain dynamics were instead restored by perturbing a set of medial fronto-temporal and cingulate regions in the model of pathology. These results highlight the relevance of global signal alterations in schizophrenia and identify a set of vulnerable areas involved in determining a shift in brain state.
Predictability of the community-function landscape in wine yeast ecosystems
Authors: Ruiz Javier , de Celis Miguel , Diaz-Colunga Juan , Vila Jean CC , Benitez-Dominguez Belen , Vicente Javier , Santos Antonio , Sanchez Alvaro , Belda Ignacio
Published: December 2022

Predictively linking taxonomic composition and quantitative ecosystem functions is a major aspiration in microbial ecology, which must be resolved if we wish to engineer microbial consortia. Here, we have addressed this open question for an ecological function of major biotechnological relevance: alcoholic fermentation in wine yeast communities. By exhaustively phenotyping an extensive collection of naturally occurring wine yeast strains, we find that most enologically-relevant traits exhibit a strong phylogenetic signal, indicating that the most relevant functions in wine yeast communities can be predicted from taxonomy. Further, we demonstrate that the quantitative contributions of individual wine yeast strains to the community function followed simple quantitative rules. These regularities can be integrated to quantitatively predict the function of newly assembled consortia. Besides addressing a fundamental open question in functional ecology, our results and methodologies provide a blueprint for rationally managing microbial processes of biotechnological relevance.
Transcriptomic analyses reveal prenatal stress promotes late-onset neural stem cell proliferation in adult male offspring
Authors: Wang Z. , Zhou L.Q. , Lee C.M. , Shi J.Y. , Liu L. , Yang X.J. , Deng Y.X. , Liu J.P. , Wang J.B. , Zhu W.M. , Sun Y.E. , Lin Q.
Published: December 2022

Perturbations during critical time windows during embryonic development can lead to adverse functional consequences that manifest later in life. Here, we report that prenatal maternal stress (PNS) during the peak of embryonic neurogenesis (E14-delivery) dramatically increased numbers of proliferating neural stem/progenitor cells (NSC/NPCs) in the ependymal-subventricular zone (E-SVZ) and neuroblasts (NBs) in the rostral migratory stream and newborn neurons in the olfactory bulb (OB) of male mouse offspring without causing significant cell death or a deficit in cell migration to the OB. Mechanistically, bulk and single-nucleus transcriptomic analyses showed that PNS affected gene regulatory networks controlling cell cycle progression and stem cell maintenance, maturation of neural circuits, and gliogenesis in prenatally stressed (STR) offspring. More specifically, we found that prenatal exposure to mild maternal restraint-stress sustained MAPK (ERK) activity in the E-SVZ and thus prolonged NSC/NPC/NB proliferation in stressed brains. Moreover, we found PNS disorganized the cytoarchitecture of the glomerular layer of the OB, which may directly relate to the deficit in discriminating different social orders in stressed offspring. Compared to STR males, their female littermates showed less change in the number of proliferating cells in the E-SVZ.
A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin
Authors: Gu Wei , Huang Xiaofeng , Singh Pratik N. P. , Lan Ying , Gomez-Salinero Jesus M , Rafii Shahin , Verzi Mike , Shivdasani Ramesh , Zhou Qiao
Published: December 2022

Plasticity between cell lineages is a fundamental but poorly understood property of regenerative tissues. In the gut tube, small intestine absorbs nutrients whereas colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screen, we identified MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrain colonic plasticity. MTA2 loss in adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-binds with HNF4A, an activating pan-intestine transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic and gain on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through a HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages; their release unleashes plasticity.
Mapping Typical and Altered Neurodevelopment with Sleep Macro- and Micro-Architecture
Authors: Kozhemiako N , Buckley AW , Chervin RD , Redline S , Purcell SM
Published: December 2022

Profiles of sleep duration and timing and corresponding electroencephalographic activity reflect brain changes that support cognitive and behavioral maturation and may provide practical markers for tracking typical and atypical neurodevelopment. To build and evaluate a sleep-based, quantitative metric of brain maturation, we used whole-night polysomnography data, initially from two large National Sleep Research Resource samples, spanning childhood and adolescence (totalN= 4,013, aged 2.5 to 17.5 years): the Childhood Adenotonsillectomy Trial (CHAT), a research study of children with snoring without neurodevelopmental delay, and NCH, a pediatric sleep clinic cohort. Among children without developmental disorders, sleep metrics derived from the electroencephalogram (EEG) displayed robust age-related changes consistently across datasets. Prominent stage-, band- and channel-specific developmental trajectories in spectral power were found. During non-rapid eye movement (NR) sleep, spindles and slow oscillations further exhibited characteristic developmental patterns, with respect to their rate of occurrence, temporal coupling and morphology. Based on these metrics in NCH, we constructed a model to predict an individual’s chronological age. The model performed with high accuracy (r= 0.95 in the held-out NCH testing sample andr= 0.88 in a second independent replication sample (PATS) with a broadly comparable age range). EEG-based age predictions reflected clinically meaningful neurodevelopmental differences; for example, compared to typically developing children, those with neurodevelopmental diagnoses (NDD) showed greater variability in predicted age, and children with Down syndrome or intellectual disability had significantly younger brain age predictions (respectively, 2.2 and 0.59 years less than their chronological age) compared to age-matched non-NDD children. Overall, our results indicate that sleep architecture offers a sensitive window for characterizing brain maturation, suggesting the potential for scalable, objective sleep-based biomarkers to measure typical and atypical neurodevelopment.
Circadian clock factors regulate seed oil accumulation by promoting fatty acid synthesis in Arabidopsis
Authors: Kim Sang-Chul , Edgeworth Kristen N. , Nusinow Dmitri A. , Wang Xuemin
Published: December 2022

The circadian clock regulates temporal metabolic activities, enabling organisms to adapt to cyclic environmental changes, but how it affects lipid metabolism in plants is poorly understood. Our previous finding showed that the central clock transcription factors LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) increased seed oil contents in Arabidopsis. Here we investigated the molecular and metabolic mechanism underlying the LHY and CCA1 regulated oil accumulation. Triacylglycerol (TAG) accumulation in Arabidopsis developing seeds was increased inLHY-overexpressing (LHY-OE) and decreased inlhycca1plants compared to wild-type (WT). Metabolic tracking of lipids in developing seeds indicated that fatty acids (FAs) of major lipid precursors for TAG production increased more rapidly in LHY-OE and slowly inlhycca1than in WT, suggesting that LHY enhanced FA synthesis. Transcript analysis revealed that the expression of genes involved in FA synthesis, including the one encoding β-ketoacyl-ACP synthase III (KASIII), was oppositely changed in developing seeds of LHY/CCA1-OEs and those oflhycca1. Chromatin immunoprecipitation, electrophoretic mobility shift, and transactivation assays indicated that LHY directly bound and activated the promoter ofKASIII. Furthermore, phosphatidic acid, a metabolic precursor to TAG, inhibited LHY binding toKASIIIpromoter elements. Our data reveal a new regulatory mechanism by the core clock regulators for storage lipid production during plant seed development.
Cellular integration with a subretinal honeycomb-shaped prosthesis
Authors: Bhuckory Mohajeet B. , Chen Zhijie , Wang Bing-Yi , Shin Andrew , Huang Tiffany , Galambos Ludwig , Vounotrypidis Efstathios , Mathieson Keith , Kamins Theodore , Palanker Daniel
Published: December 2022

In patients blinded by geographic atrophy, subretinal photovoltaic implant with 100µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional electrodes. In particular, elevating the return electrode on top of honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that the majority of the inner retinal neurons migrate into 25µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This is important for selective stimulation of the second-order neurons to preserve the retinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability.
The protooncogene Ski regulates the neuron-glia switch during development of the mammalian cerebral cortex
Authors: Grison Alice , Karimaddini Zahra , Breda Jeremie , Mukhtar Tanzila , Boareto Marcelo , Eschbach Katja , Beisel Christian , Iber Dagmar , van Nimwegen Erik , Taylor Verdon , Atanasoski Suzana
Published: December 2022

The brain is the most complex organ in mammals and understanding the origin of this complexity is a major challenge for developmental biologists. Crucial to the size and morphology of the cortex is the timing and transition of neural stem cell (NSC) fate. An interesting candidate for modulating and fine tuning these processes is the transcriptional regulator Ski, a protooncogene expressed in cortical cells. Ski is involved in diverse cellular processes and epigenetic programs, and mice deficient in Ski exhibit complex central nervous system defects that resemble some of the features observed in patients with 1p36 deletion syndrome and Shprintzen–Goldberg syndrome. Here, we took advantage ofin vivotransgenic labeling and next-generation sequencing to analyze the gene expression profiles of NSCs, basal progenitor (BP) cells, and newborn neurons (NBNs) from wildtype and Ski-deficient embryos throughout cortical development. We created a unique database that allowed us to identify and compare signaling pathways and transcriptional networks within each progenitor population in the presence and absence of Ski. We find that NSCs are the most affected cell population and uncover that mutant NSCs fail to switch to a gliogenic fate in time. We show that Ski functions in concert with the Bone Morphogenetic Protein (BMP) signaling pathway to alter the cell differentiation fate of NSCs from neurons to glia, which is key to generating adequate numbers of specific cell types during corticogenesis. Thus, by combining genetic tools and bioinformatic analysis, our work not only deepens the knowledge of how Ski functions in the brain, but also provides an immense resource for studying neurodevelopmental disorders.
Cholesterol and ceramide facilitate SARS-CoV-2 Spike protein-mediated membrane fusion
Authors: Niort Kristina , Dancourt Julia , Boedec Erwan , Amir Dache Zahra Al , Lavieu Grégory , Tareste David
Published: December 2022

SARS-CoV-2 entry into host cells is mediated by the Spike (S) protein of the viral envelope. The S protein is composed of two subunits: S1 that induces binding to the host cellviaits interaction with the ACE2 receptor of the cell surface and S2 that triggers fusion between viral and cellular membranes. Fusion by S2 depends on its heptad repeat domains that bring membranes close together, and its fusion peptide (FP) that interacts with and perturb the membrane structure to trigger fusion. Recent studies suggest that cholesterol and ceramide lipids from the cell surface may facilitate SARS-CoV-2 entry into host cells, but their exact mode of action remains unknown. We have used a combination ofin vitroliposome-liposome andin situcell-cell fusion assays to study the lipid determinants of S-mediated membrane fusion. We found that cholesterol and ceramide both facilitated fusion, suggesting that targeting lipids could be effective against SARS-CoV-2. As proof of concept, we examined the effect of chlorpromazine (CPZ), an antipsychotic drug known to perturb membrane structure. We found that CPZ inhibited S-mediated membrane fusion and thus potentially SARS-CoV-2 entry.
Cortical Reactivation of Non-Spatial and Spatial Memory Representations Coordinate with Hippocampus to Form a Memory Dialogue
Authors: Chang HaoRan , Esteves Ingrid M. , Neumann Adam R. , Mohajerani Majid H. , McNaughton Bruce L.
Published: December 2022

Episodic memory depends on the association of diverse attribute representations that are distributed across the neocortex, and evidence suggests that these attributes are linked, at least initially, by the hippocampus, which orchestrates retrieval and the offline replay of experience during memory consolidation. The dynamics that characterize this hippocampal-cortical dialogue, however, are only partly understood. Although it was originally proposed that replay is initiated in CA3, with the spontaneous emission of sharp-wave ripple (SWR) bursts, increasing evidence suggests that cortex may seed the process with partial information, leading to pattern completion in CA3 and subsequent global reactivation of the episode. A recent study has shown that the secondary motor cortex (M2), among other areas, carries two distinct types of representations: place cell-like activity, which relies on an intact hippocampus for its development, and responses tied to visuo-tactile cues — the ‘attributes’ of the experience, which do not require the hippocampus. Using two-photon Ca2+imaging, while simultaneously acquiring LFP from the ipsilateral CA1, we assessed the interactions among cortical retrieval of visuo-tactile attributes of previous experiences in a virtual environment, hippocampal SWR, and the cortical reinstatement of the spatial aspects of the same experiences. During rest after the experience, two types of reactivation events occurred, which separately conveyed information about spatial trajectories and visuo-tactile attributes. Reactivation of attribute information preceded that of trajectories in relation to hippocampal SWRs. Furthermore, paired reactivations of cue and trajectory information supported similar features of previous experiences. These results are consistent with the hypothesis that cortical retrieval of non-spatial attributes of recent experience seeds hippocampal reactivation of associated spatial sequences, which is followed by retrieval of episodic memory traces.
Chelerythrine as an anti-Zika virus agent: therapeutic potential and mode of action
Authors: Españo Erica , Kim Jiyeon , Lee Chong-Kil , Webster Robert G. , Webby Richard J. , Kim Jeong-Ki
Published: December 2022

Zika virus (ZIKV) is a mosquito-borne virus that has been associated with adult and neonatal neurological conditions. So far, there is no approved drug or vaccine against ZIKV infection; thus, ZIKV remains a global health threat. Here, we explored the effects of chelerythrine (CTC), a known protein kinase C (PKC) inhibitor, against ZIKV infection in cell culture models to determine its potential as a therapeutic agent for ZIKV infection. We found that CTC protected Vero cells from ZIKV-induced cytopathic effects in a dose-dependent manner. It also reduced the production of ZIKV in Vero and A549 cells. In contrast, other PKC inhibitors failed to protect Vero cells from ZIKV-induced cytopathic effects, indicating PKC-independent mechanisms underlying the effects of CTC on ZIKV. Further investigation suggested that CTC inhibited ZIKV attachment/binding rather than internalization in the host cells. Pretreatment of cell-free ZIKV particles rather than pretreatment of cells with CTC resulted in reduced ZIKV infectivityin vitro, indicating that CTC blocked the attachment/binding of the ZIKV particles to host factors.In silicoanalyses suggested that these effects are potentially due to the binding of CTC to the ZIKV E protein, which may occlude the interaction of the E protein with attachment factors or receptors on the host cell surface. Overall, our findings suggest that CTC reduces the infectivity of ZIKV particles through PKC- and cell-independent mechanisms. Our findings also support further exploration of CTC as an anti-ZIKV agent.
Parallel motion vision pathways in the brain of a tropical bee
Authors: Honkanen Anna , Hensgen Ronja , Kannan Kavitha , Adden Andrea , Warrant Eric , Wcislo William , Heinze Stanley
Published: December 2022

Spatial orientation is a prerequisite for most behaviors. In insects, the underlying neural computations take place in the central complex (CX), the brain’s navigational center. In this region different streams of sensory information converge to enable context-dependent navigational decisions. Accordingly, a variety of CX input neurons deliver information about different navigation-relevant cues. In bees, direction encoding polarized light signals converge with translational optic flow signals that are suited to encode the flight speed of the animals. The continuous integration of speed and directions in the CX can be used to generate a vector memory of the bee’s current position in space in relation to its nest, i.e. perform path integration. This process depends on specific, complex features of the optic flow encoding CX input neurons, but it is unknown how this information is derived from the visual periphery. Here, we thus aimed at gaining insight into how simple motion signals are reshaped upstream of the speed encoding CX input neurons to generate their complex features. Using electrophysiology and anatomical analyses of the halictic beesMegalopta genalisandMegalopta centralis, we identified a wide range of motion-sensitive neurons connecting the optic lobes with the central brain. While most neurons formed pathways with characteristics incompatible with CX speed neurons, we showed that one group of lobula projection neurons possess some physiological and anatomical features required to generate the visual responses of CX optic-flow encoding neurons. However, as these neurons cannot explain all features of CX speed cells, local interneurons of the central brain or alternative input cells from the optic lobe are additionally required to construct inputs with sufficient complexity to deliver speed signals suited for path integration in bees.
Quantifying the deformability of malaria-infected red blood cells using deep learning trained on synthetic cells
Authors: Rademaker Daniel T. , Koopmans Joshua J. , Thyen Gwendolyn M.S.M. , Piruska Aigars , Huck Wilhelm T.S. , Vriend Gert , ‘t Hoen Peter A.C. , Kooij Taco W.A. , Huynen Martijn A. , Proellochs Nicholas I.
Published: December 2022

Several haematologic diseases, including malaria, diabetes, and sickle cell anaemia, result in a reduced red blood cell deformability. This deformability can be measured using a microfluidic device with channels of varying width. Nevertheless, it is challenging to algorithmically recognise large numbers of red blood cells and quantify their deformability from image data. Deep learning has become the method of choice to handle noisy and complex image data. However, it requires a significant amount of labelled data to train the neural networks. By creating images of cells and mimicking noise and plasticity in those images, we generate synthetic data to train a network to detect and segment red blood cells from video-recordings, without the need for manually annotated labels. Using this new method, we uncover significant differences between the deformability of RBCs infected with different strains ofPlasmodium falciparum, providing clues to the variation in virulence of these strains.
Transposable elements as tissue-specific enhancers in cancers of endodermal lineage
Authors: Karttunen Konsta , Patel Divyesh , Xia Jihan , Fei Liangru , Palin Kimmo , Aaltonen Lauri , Sahu Biswajyoti
Published: December 2022

Transposable elements (TE) are repetitive genomic elements that harbor binding sites for human transcription factors (TF). A regulatory role for TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions has been limited by their widespread silencing in the genome. Here, we have utilized unbiased massively parallel reporter assay data using whole human genome library to identify TEs with functional enhancer activity in two human cancer types of endodermal lineage, colorectal and liver cancers. We show that the identified TE enhancers are characterized by genomic features associated with active enhancers, such as epigenetic marks and TF binding. Importantly, we identified distinct TE subfamilies that function as tissue-specific enhancers, namely MER11- and LTR12-elements in colon and liver cancers, respectively. These elements are bound by distinct TFs in each cell type, and they have predicted associations to differentially expressed genes. In conclusion, these data demonstrate how different cancer types can utilize distinct TEs as tissue-specific enhancers, paving the way for comprehensive understanding of the role of TEs as bona fide enhancers in the cancer genomes.
AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1
Authors: Bancet Alexandre , Frem Rita , Jeanneret Florian , Mularoni Angélique , Bazelle Pauline , Roelants Caroline , Delcros Jean-Guy , Guichou Jean-François , Pillet Catherine , Coste Isabelle , Renno Toufic , Battail Christophe , Cochet Claude , Lomberget Thierry , Filhol Odile , Krimm Isabelle
Published: December 2022

Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric αD pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 αD pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.
Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice
Authors: Harrison Mark A.A. , Morris Sara L. , Rudman Grace A. , Rittenhouse Daniel J. , Monk Chandler H. , Sakamuri Siva SVP , Jones MaryJane J. , Hasan Md Mehedi , Khatun Mst Shamima , Wang Hanyun , Garfinkel Lucas P. , Norton Elizabeth B. , Steele Chad , Kim Sangku , Kolls Jay K. , Jazwinski S. Michal , Mostany Ricardo , Katakam Prasad VG , Engler-Chiurazzi Elizabeth B. , Zwezdaryk Kevin J.
Published: December 2022

Risk factors contributing to dementia are multifactorial. Pathogens as risk factors for dementia is largely correlative with few causal relationships. Here, we demonstrate that intermittent cytomegalovirus (CMV) infection in mice, mimicking human chronic infection and reactivation/reinfection events, alters blood brain barrier (BBB) metabolic pathways. An increase in basal mitochondrial function is observed in brain microvasculature endothelial cells (BMEC) at 12 months post infection but not at earlier time points and is accompanied by elevated levels of superoxide, indicative of oxidative stress. Further, these mice score lower in cognitive assays as compared to age-matched controls. Our data show that repeated systemic infection with CMV, alters BBB metabolic function and impacts cognition. These observations provide mechanistic insights through which pathogens contribute to the progression of pathologies associated with dementia.

In Brief

Mechanistic evidence supporting an infectious etiology of dementia (e.g. Alzheimer’s Disease) are poorly defined. Harrison et al., show that intermittent infection with cytomegalovirus metabolically rewires the blood brain barrier and neighboring glial cells altering their function, resulting in decreased cognitive function.
A pathogen effector FOLD diversified in symbiotic fungi
Authors: Teulet Albin , Quan Clement , Evangelisti Edouard , Wanke Alan , Yang Weibing , Schornack Sebastian
Published: December 2022

Pathogenic fungi use secreted effector proteins to suppress immunity and support their infection, but effectors have also been reported from fungi that engage in nutritional symbioses with plants. Sequence based effector comparisons between pathogens and symbiotic arbuscular mycorrhizal (AM) fungi are hampered by the huge diversity of effector sequences even within closely related microbes.

Here we used a systematic protein structure modelling approach to classify the secretome of the AM fungusRhizophagus irregularis. We identified secreted proteins with high structural similarity toFusarium oxysporumf. sp.lycopersicidual domain (FOLD) effectors, which occur in low numbers in fungal pathogen genomes. Contrastingly, genes encoding FOLD proteins from AM fungi (MycFOLDs) are found in enlarged and diversified gene families.

Our structure-model comparison suggests that MycFOLDs are similar to carbohydrate binding motifs. Different MycFOLD genes are expressed during colonisation of different hosts andMycFOLD-17transcripts accumulate in plant intracellular arbuscules.

The exclusive presence of MycFOLDs across unrelated plant-colonising fungi, their inducible expression, lineage specific sequence diversification, and transcripts in arbuscules support the hypothesis that FOLD proteins act as effectors during plant colonisation by symbiotic and pathogenic fungi.
Wings of Change: aPKC/FoxP-dependent plasticity in steering motor neurons underlies operant selflearning inDrosophila
Authors: Ehweiner Andreas , Duch Carsten , Brembs Björn
Published: December 2022

Background

Motor learning is central to human existence, such as learning to speak or walk, sports moves, or rehabilitation after injury. Evidence suggests that all forms of motor learning share an evolutionarily conserved molecular plasticity pathway. Here, we present novel insights into the neural processes underlying operant self-learning, a form of motor learning in the fruit flyDrosophila.

Methods

We operantly trained wild type and transgenicDrosophilafruit flies, tethered at the torque meter, in a motor learning task that required them to initiate and maintain turning maneuvers around their vertical body axis (yaw torque). We combined this behavioral experiment with transgenic peptide expression, CRISPR/Cas9-mediated, spatio-temporally controlled gene knock-out and confocal microscopy.

Results

We find that expression of atypical protein kinase C (aPKC) in direct wing steering motoneurons co-expressing the transcription factorFoxPis necessary for this type of motor learning and that aPKC likely acts via non-canonical pathways. We also found that it takes more than a week for CRISPR/Cas9-mediated knockout ofFoxPin adult animals to impair motor learning, suggesting that adultFoxPexpression is required for operant self-learning.

Conclusions

Our experiments suggest that, for operant self-learning, a type of motor learning inDrosophila, co-expression of atypical protein kinase C (aPKC) and the transcription factorFoxPis necessary in direct wing steering motoneurons. Some of these neurons control the wing beat amplitude when generating optomotor responses, and we have discovered modulation of optomotor behavior after operant self-learning. We also discovered that aPKC likely acts via non-canonical pathways and thatFoxPexpression is also required in adult flies.
Direct neural perturbations reveal a dynamical mechanism for robust computation
Authors: O’Shea Daniel J. , Duncker Lea , Goo Werapong , Sun Xulu , Vyas Saurabh , Trautmann Eric M. , Diester Ilka , Ramakrishnan Charu , Deisseroth Karl , Sahani Maneesh , Shenoy Krishna V.
Published: December 2022

The rich repertoire of skilled mammalian behavior is the product of neural circuits that generate robust and flexible patterns of activity distributed across populations of neurons. Decades of associative studies have linked many behaviors to specific patterns of population activity, but association alone cannot reveal the dynamical mechanisms that shape those patterns. Are local neural circuits high-dimensional dynamical reservoirs able to generate arbitrary superpositions of patterns with appropriate excitation? Or might circuit dynamics be shaped in response to behavioral context so as to generate only the low-dimensional patterns needed for the task at hand? Here, we address these questions within primate motor cortex by delivering optogenetic and electrical microstimulation perturbations during reaching behavior. We develop a novel analytic approach that relates measured activity to theoretically tractable, dynamical models of excitatory and inhibitory neurons. This computational model captures the dynamical effects of these perturbations and demonstrates that motor cortical activity during reaching is shaped by a self-contained, low-dimensional dynamical system. The subspace containing task-relevant dynamics proves to be oriented so as to be robust to strong non-normal amplification within cortical circuits. This task dynamics space exhibits a privileged causal relationship with behavior, in that stimulation in motor cortex perturb reach kinematics only to the extent that it alters neural states within this subspace. Our results resolve long-standing questions about the dynamical structure of cortical activity associated with movement, and illuminate the dynamical perturbation experiments needed to understand how neural circuits throughout the brain generate complex behavior.
Pediatric health system impact of an early respiratory viral season in Eastern Ontario, Canada: A descriptive analysis
Authors: Thampi Nisha , Meng Lynn , Bruce Liam , McLean Connor , Buba Melanie , Bisnaire Lise , Farion Ken J. , Samson Lindy M.
Published: December 2022

Background

The current respiratory viral season in Ontario started early with an intensity experienced throughout the pediatric health system. We sought to examine trends in patient volumes and level of care intensity among children admitted with laboratory-confirmed respiratory viral infection over the last five years in Ottawa.

Methods

This was a retrospective cohort study of patients at CHEO, a pediatric health centre in Ottawa, who were diagnosed with a laboratory-confirmed respiratory viral infection in the first 72 hours of admission between October 22, 2017 and December 10, 2022. Their admissions were stratified by age groups and levels of care intensity and evaluated for trends over six surveillance periods that begin in Week 35 and end in Week 34 of the following calendar year.

Results

During this current surveillance period, there was an early, rapid, two-fold increase in admissions due to respiratory viral infections compared to previous periods, driven largely by RSV and influenza. While there were similar age distributions, there was a larger volume of Level 2 and 3 admissions, and higher proportion of patients requiring Level 2 intensity of care (20.8% versus 2.2% to 12.0% in pre-pandemic years; p<0.001). Lengths of stay were comparable to pre-pandemic surveillance years.

Interpretation

The current viral season has been associated with elevated volumes and higher inpatient acuity compared to previous years and underscores the need for additional operational and human health resources to support pediatric health systems.
CT-based imaging metrics for identification of radiation-induced lung damage
Authors: Lee Joonsang , Benveniste Marcelo , Odisio Erika G. , Court Laurence E. , Lin Steven H.
Published: December 2022

Purpose

This study investigates the feasibility of radiomics for identifying textural changes of radiation-induced lung damage (RILD) after chemoradiotherapy.

Methods

The severity of RILD on each CT scan was graded on a scale from 0 (similar to the baseline CT scan) to 5 (lung fibrosis). The delineation of abnormal areas inside the lung on CT images was performed semi-automatically using a median filter. We extracted a total of 138 quantitative image features from this delineated region of interest and ran a random forest algorithm as a classifier for identifying the severity of RILD. After training and testing the model, we validated the model using a separate dataset.

Results

The classification accuracies for identifying grade 0 from grades 1 ∼ 5 were 70% for the test dataset and 85% for the validation dataset; for identifying grade 1 from grades 2∼5, 90% for the test dataset and 95% for the validation dataset; and for identifying grade 5 from grades 2∼4, 80% for the test dataset and 85% for the validation dataset.

Conclusions

Our preliminary study shows that the classification accuracy was robust, the model was most useful for distinguishing grade 1 from other grades, and the results demonstrated the feasibility of radiomics for identifying the severity of lung damage after chemoradiotherapy. This approach could be a potential tool for helping diagnostic radiologists identify RILD and its severity on CT images.
Maturity models in SSCM: a systematic review aimed at consolidating models and outlining possibilities for future research
Authors: Pavan Raquel Ottoboni , Ferreira Marco Antonio , Stefanelli Nelson Oliveira , Leal Gislaine Camila Lapasini
Published: December 2022

Purpose

This research analyzes the current knowledge regarding the use of maturity models (MMs) in SSCM, aiming to identify the main characteristics, trends and research gaps on the subject. Facing the growing interest in carrying out studies directed at sustainability, to the detriment of more prescient environmental and social impacts and the need to consolidate the concepts present in the literature regarding the SSCM, an absence of similar studies in the current literature was found. The authors have selected articles to compose a database that allows users to analyze and classify publications on MMs in SSCM, being those subdivided into 7 categories: focus, methodology, analyzed sector, sustainable practices, dimensions of sustainable development, type of MM and model/framework validation method.

Design/methodology/approach

To achieve this purpose, a literature systematization was conducted by searching publications using defined keywords in two databases and following a process of classification. The systematic process has five steps, from the selection of databases to the filtering of publications, review of information and analysis of the sample.

Findings

The topic under study is promising, with a few publications dealing with it, mainly in Brazil, and there is a trend to exploit more of the area in future research.

Originality/value

This research provides a detailed analysis of an emerging theme, divided into seven thematic categories. Results demonstrate that the topic is still underexplored, indicating an important research gap to be filled.
Understanding the fundamental economics of AI
Authors: Leavy Brian
Published: December 2022

Purpose

Despite the hype about transformative technology, the authors of “Power and Prediction: The Disruptive Economics of Artificial Intelligence” see the recent AI advances as all basically ‘better statistical techniques’ that allow us to take really big data sets and come up with more refined predictions.

Design/Methodology/Approach

University of Toronto experts, Ajay Agrawal, Joshua Gans and Avi Goldfarb explain why transformation of business model by AI will be some time in the future when we move beyond simply substituting the new technology into existing systems and start to leverage its potential to enable the reimagining of old system solutions and innovate radically new value propositions.

Findings

What economic history tells us is that technology-driven transformation does not come easy and real adoption only occurs when new systems are created.

Practical Implications

As there are likely many decisions in your organization that have been codified into rules, AI offers the potential to turn them to dynamic decisions.

Originality/Value

To realize the full potential of AI, companies need to adopt a “system mind-set,” in contrast to the “task-level thinking” that still predominates in most companies.
Behavioural responses of a large, heat‐sensitive mammal to climatic variation at multiple spatial scales
Authors: Verzuh Tana L. , Rogers Savannah A. , Mathewson Paul D. , May Alex , Porter Warren P. , Class Corey , Knox Lee , Cufaude Teal , Hall L. Embere , Long Ryan A. , Monteith Kevin L.
Published: December 2022

Climate warming creates energetic challenges for endothermic species by increasing metabolic and hydric costs of thermoregulation. Although endotherms can invoke an array of behavioural and physiological strategies for maintaining homeostasis, the relative effectiveness of those strategies in a climate that is becoming both warmer and drier is not well understood.

In accordance with the heat dissipation limit theory which suggests that allocation of energy to growth and reproduction by endotherms is constrained by the ability to dissipate heat, we expected that patterns of habitat use by large, heat‐sensitive mammals across multiple scales are critical for behavioural thermoregulation during periods of potential heat stress and that they must invest a large portion of time to maintain heat balance.

To test our predictions, we evaluated mechanisms underpinning the effectiveness of bed sites for ameliorating daytime heat loads and potential heat stress across the landscape while accounting for other factors known to affect behaviour. We integrated detailed data on microclimate and animal attributes of moose Alces alces, into a biophysical model to quantify costs of thermoregulation at fine and coarse spatial scales.

During summer, moose spent an average of 67.8% of daylight hours bedded, and selected bed sites and home ranges that reduced risk of experiencing heat stress. For most of the day, shade could effectively mitigate the risk of experiencing heat stress up to 10°C, but at warmer temperatures (up to 20°C) wet soil was necessary to maintain homeostasis via conductive heat loss. Consistent selection across spatial scales for locations that reduced heat load underscores the importance of the thermal environment as a driver of behaviour in this heat‐sensitive mammal.

Moose in North America have long been characterized as riparian‐obligate species because of their dependence on woody plant species for food. Nevertheless, the importance of dissipating endogenous heat loads conductively through wet soil suggests riparian habitats also are critical thermal refuges for moose. Such refuges may be especially important in the face of a warming climate in which both high environmental temperatures and drier conditions will likely exacerbate limits to heat dissipation, especially for large, heat‐sensitive animals.
Abundance and diversity of eukaryotic rather than bacterial community relate closely to the trophic level of urban lakes
Authors: Wan Wenjie , Gadd Geoffrey Michael , He Donglan , Liu Wenzhi , Xiong Xiang , Ye Luping , Cheng Yarui , Yang Yuyi
Published: December 2022

Scientific understanding of biotic effects on the water trophic level is lacking for urban lakes during algal bloom development stage. Based on the Illumina MiSeq sequencing, quantitative polymerase chain reaction (PCR), and multiple statistical analyses, we estimated distribution patterns and ecological roles of planktonic bacteria and eukaryotes in urban lakes during algal bloom development stage (i.e., April, May, and June). Cyanobacteria and Chlorophyta mainly dominated algal blooms. Bacteria exhibited significantly higher absolute abundance and community diversity than eukaryotes, whereas abundance and diversity of eukaryotic rather than bacterial community relate closely to the water trophic level. Multinutrient cycling (MNC) index was significantly correlated with eukaryotic diversity rather than bacterial diversity. Stronger species replacement, broader environmental breadth, and stronger phylogenetic signal were found for eukaryotic community than for bacterial community. In contrast, bacterial community displayed stronger community stability and environmental constraint than eukaryotic community. Stochastic and differentiating processes contributed more to community assemblies of bacteria and eukaryotes. Our results emphasized that a strong linkage between planktonic diversity and MNC ensured a close relationship between planktonic diversity and the water trophic level of urban lakes. Our findings could be useful to guide the formulation and implementation of environmental lake protection measures.