bluuebunny/crossref_metadata_2025 huggingface dataset:
LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
Authors: Singleton S. Parker , Luppi Andrea I. , Carhart-Harris Robin L. , Cruzat Josephine , Roseman Leor , Nutt David J. , Deco Gustavo , Kringelbach Morten L. , Stamatakis Emmanuel A. , Kuceyeski Amy
Published: May 2021

Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics.

Significance Statement

We present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide evidence that psychedelics flatten the brain’s control energy landscape, allowing for more facile state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD and psilocybin - is optimized for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain activity dynamics.
Distinct features of brain perivascular fibroblasts and mural cells revealed by in vivo two-photon imaging
Authors: Bonney Stephanie K. , Sullivan Liam T. , Cherry Timothy J. , Daneman Richard , Shih Andy Y.
Published: May 2021

Perivascular fibroblasts (PVFs) are recognized for their pro-fibrotic role in many central nervous system disorders. Like mural cells, PVFs surround blood vessels and express Pdgfrβ. However, these shared attributes hinder the ability to distinguish PVFs from mural cells. We used in vivo two-photon imaging and transgenic mice with PVF-targeting promoters (Col1a1 or Col1a2) to compare the structure and distribution of PVFs and mural cells in cerebral cortex of healthy, adult mice. We show that PVFs localize to all cortical penetrating arterioles and their pre-capillary offshoots, as well as the main trunk of only larger ascending venules. However, the capillary zone is devoid of PVF coverage. PVFs display short-range mobility along the vessel wall and exhibit distinct structural features (flattened somata and thin ruffled processes) not seen with smooth muscle cells or pericytes. These findings clarify that PVFs and mural cells are distinct cell types coexisting in a similar perivascular niche.
Signal Inhibitory Receptor on Leukocytes-1 recognizes S100 proteins
Authors: Rumpret Matevž , von Richthofen Helen J. , van der Linden Maarten , Westerlaken Geertje H. A. , Ormeño Cami Talavera , Low Teck Y. , Ovaa Huib , Meyaard Linde
Published: May 2021

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. We here identify S100 proteins as SIRL-1 ligands. S100 proteins are composed of two calcium-binding domains. Various S100 proteins are damage-associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL-1 recognizes individual calcium-binding domains of all tested S100 proteins. Blocking SIRL-1 on human neutrophils enhanced S100 protein S100A6-induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL-1. We conclude that SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs.
An epigenomic shift in amygdala marks the transition to maternal behaviors in alloparenting virgin female mice
Authors: Seward Christopher H. , Saul Michael C. , Troy Joseph M. , Dibaeinia Payam , Zhang Huimin , Sinha Saurabh , Stubbs Lisa J.
Published: May 2021

In many species, adults care for young offspring that are not their own, a phenomenon called alloparenting. However, most nonparental adults must be sensitized by repeated or extended exposures to newborns before they will robustly display parental-like behaviors. To capture neurogenomic events underlying the transition to active parental caring behaviors, we analyzed brain gene expression and chromatin profiles of virgin female mice co-housed with mothers during pregnancy and after birth. After an initial display of antagonistic behaviors and a surge of defense-related gene expression, we observed a dramatic shift in the chromatin landscape specifically in amygdala of the pup-exposed virgin females, accompanied by a dampening of anxiety-related gene expression. This epigenetic shift coincided with hypothalamic expression of the oxytocin gene and the emergence of behaviors and gene expression patterns classically associated with maternal care. The results outline a neurogenomic program associated with dramatic behavioral changes and suggest molecular networks relevant to human postpartum mental health.
Interplay between cell proliferation and recruitment controls the duration of growth and final size of the Drosophila wing
Authors: Diaz-Torres Elizabeth , Muñoz-Nava Luis Manuel , Nahmad Marcos
Published: May 2021

How organs robustly attain a final size despite perturbations in cell growth and proliferation rates is a fundamental question in developmental biology. Since organ growth is an exponential process driven mainly by cell proliferation, even small variations in cell proliferation rates, when integrated over a relatively long time, will lead to large differences in size, unless intrinsic control mechanisms compensate for these variations. Here we use a mathematical model to consider the hypothesis that in the developing wing of Drosophila, cell recruitment, a process in which undifferentiated neighboring cells are incorporated into the wing primordium, determines the time in which growth is arrested in this system. Under this assumption, our model shows that perturbations in proliferation rates of wing-committed cells are compensated by an inversely proportional duration of growth. This mechanism ensures that the final size of the wing is robust in a range of cell proliferation rates. Furthermore, we predict that growth control is lost when fluctuations in cell proliferation affects both wing-committed and recruitable cells. Our model suggests that cell recruitment may act as a temporal controller of growth to buffer fluctuations in cell proliferation rates, offering a solution to a long-standing problem in the field.

Graphical abstract
Mammary lineage dictates homologous recombination repair and PARP inhibitor vulnerability
Authors: Kim Hyeyeon , Casey Alison E. , Palomero Luis , Aliar Kazeera , Mahendralingam Mathepan , Parsons Michael , Narala Swami , Mateo Francesca , Hofer Stefan , Waterhouse Paul D. , Kislinger Thomas , Pujana Miquel A. , Berman Hal K. , Khokha Rama
Published: May 2021

It has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show that mammary epithelial lineage dictates the DSB repair pathway choice. Primary mammary proteomes and DSB repair enumeration by γ-H2AX, Rad51 and DNA-PKc foci reveal that NHEJ operates in all epithelial cells, but high-fidelity HR is restricted to the luminal lineage. This translates to divergent poly (ADP-ribose) polymerase inhibitor (PARPi) vulnerability of mammary epithelial progenitor activity in both mouse and human, irrespective of the BRCA1/2 status. Proteome-defined lineage-specific signatures correlate to breast cancer subtypes and predict PARPi response of triple-negative human breast cancer xenografts. These intrinsically divergent HR characteristics of mammary cell types underpin a new strategy for identifying PARPi responders.
EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities
Authors: Yedier-Bayram Ozlem , Gokbayrak Bengul , Aksu Ali Cenk , Cavga Ayse Derya , Kayabolen Alisan , Kala Ezgi Yagmur , Karabiyik Goktug , Günsay Rauf , Morova Tunc , Uyulur Fırat , Lack Nathan A. , Önder Tamer T. , Bagci-Onder Tugba
Published: May 2021

Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To discover new drug targets for more targeted and personalized therapies, functional interrogation of epigenetic modifiers is essential. We therefore generated an epigenome-wide CRISPR-Cas9 knock-out library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution, depletion of essential genes and steady behaviors of non-targeting sgRNAs. From this, we discovered novel epigenetic modifiers besides previously known ones that regulate triple-negative breast cancer and prostate cancer cell fitness. With further validation assays, we confirmed the growth-regulatory function of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in triple negative breast cancer cells. Overall, we show that EPIKOL, a focused sgRNA library targeting approximately 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness and serve as a tool to offer novel anti-cancer targets. With its thoroughly generated epigenome-wide gene list, and the relatively high number of sgRNAs per gene, EPIKOL offers a great advantage to study functional roles of epigenetic modifiers in a wide variety of research applications, such as screens on primary cells, patient-derived xenografts as well asin vivomodels.
Neurogrid simulates cortical cell-types, active dendrites, and top-down attention
Authors: Benjamin Ben Varkey , Steinmetz Nicholas A , Oza Nick N , Aguayo Jose J , Boahen Kwabena
Published: May 2021

A central challenge for systems neuroscience and artificial intelligence is to understand how cognitive behaviors arise from large, highly interconnected networks of neurons. Digital simulation is linking cognitive behavior to neural activity to bridge this gap in our understanding at great expense in time and electricity. A hybrid analog-digital approach, whereby slow analog circuits, operating in parallel, emulate graded integration of synaptic currents by dendrites while a fast digital bus, operating serially, emulates all-or-none transmission of action potentials by axons, may improve simulation efficacy. Due to the latter’s serial operation, this approach has not scaled beyond millions of synaptic connections (per bus). This limit was broken by following design principles the neocortex uses to minimize its wiring. The resulting hybrid analog-digital platform, Neurogrid, scales to billions of synaptic connections, between up to a million neurons, and simulates cortical models in real-time using a few watts of electricity. Here, we demonstrate that Neurogrid simulates cortical models spanning five levels of experimental investigation: biophysical, dendritic, neuronal, columnar, and area. Bridging these five levels with Neurogrid revealed a novel way active dendrites could mediate top-down attention.
Evidence of wiring development processes from the connectome of adult Drosophila
Authors: Scheffer Louis K.
Published: May 2021

How is the brain wired during development? Here we look at some of the characteristics of the adult Drosophila brain, a result of this development process. From this we can speculate on at least some aspects of how the wiring was done. A common hypothesis is that surface proteins direct synapse formation among touching neurons. Assuming that surface proteins are specific to cell types, we find support for this hypothesis. The brain in general supports a wide variety of connections of different degrees of reciprocity, with ratios up to a thousand to one in the two directions of synapses between types. However, contacts between cells of the same type are always bi-directional and nearly equal strength. Furthermore, among similar cell types, at least in the mushroom body, the closer the cell type by morphology, the closer the inter-type contacts are to symmetrical. These findings are all consistent with the hypothesis that surface proteins specific to cell types determine the directivity of connections. Next we look at synapses per area, and find this varies widely and is roughly log-normally distributed. In most cases, the number of synapses saturates at higher areas, though other forms are seen - linear, flat, or decreasing with increasing area. Evidence suggests that at least some of this distinction is post-synaptic.
Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides
Authors: Sung Min Woo , Yang Zhongying , Patton Bruce L. , Mostofian Barmak , Russo John , Zuckerman Daniel M. , Shyng Show-Ling
Published: May 2021

Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined the first cryoEM structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational “propeller” and “quatrefoil” geometries surrounding their Kir6.1 core. The previously unseen ED-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. MD simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated and MgADP-bound activated conformations wherein the ED-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.
Preparation of cationized albumin nanoparticles loaded indirubin by high pressure hemogenizer
Authors: Nekounam Houra , Dinarvand Rassoul , Khademi Rahele , Karimi Roya , Arzani Hossein , Mahmoodi Narges , Hasanzadeh Elham , Kamali Morteza , Khosravani Masood
Published: May 2021

Indirubin can be applied as an anti-cancer drug for inhibition of brain tumors. However, its performance is reduced due to hydrophobicity. In this study, we synthesized cationic human serum albumin (CHSA) nanoparticle by a new hybrid approach for improvement the surface chemistry of albumin and investigate the amount of indirubin loaded CHSA nanoparticle. In this study, the generated mechanical force from a high-pressure homogenizer (HPH) was used to make nanoparticles with a certain size with narrow polydispersity. The results indicated that the size of indirubin loaded CHSA nanoparticles were 130 nm and their zeta potential were +9. Besides, the encapsulation efficiency and drug loading capacity were found to be 85% and 5.8 %, respectively. To the best to our knowledge, this is the first time that indirubin has been used in albumin nanoparticles. In this study, indirubin loaded CHSA nanoparticles was shown can be a potential candidate for drug delivery in the treatment of glioblastoma. Moreover, the cationized form allows the chemical agent to be transmitted to the brain.
Reduced cortico-muscular beta coupling in Parkinson’s disease predicts motor impairment
Authors: Zokaei Nahid , Quinn Andrew J , Hu Michele T , Husain Masud , van Ede Freek , Nobre Anna Christina
Published: May 2021

Long-range communication through the motor system is thought to be facilitated by phase coupling between neural activity in the 15-30 Hz beta range. During periods of sustained muscle contraction (grip), such coupling is manifest between motor cortex and the contralateral forearm muscles – measured as the cortico-muscular coherence (CMC). We examined alterations in CMC in individuals with Parkinson’s disease (PD), while equating grip strength between individuals with PD (off their medication) and healthy control participants. We show a marked reduction in beta CMC in the PD group, even though the grip strength was comparable between the two groups. Moreover, the reduced CMC was related to motor symptoms, so that individuals with lower CMC also displayed worse motor symptoms. These findings highlight the CMC as a simple, effective, and clinically relevant neural marker of PD pathology, with the potential to aid monitoring of disease progression and the efficacy of novel treatments for PD.
Compositional data analysis of microbiome and any-omics datasets: a revalidation of the additive logratio transformation
Authors: Greenacre Michael , Martínez-Álvaro Marina , Blasco Agustín
Published: May 2021

Background

Microbiome and omics datasets are, by their intrinsic biological nature, of high dimensionality, characterized by counts of large numbers of components (microbial genes, operational taxonomic units, RNA transcripts, etc…). These data are generally regarded as compositional since the total number of counts identified within a sample are irrelevant. The central concept in compositional data analysis is the logratio transformation, the simplest being the additive logratios with respect to a fixed reference component. A full set of additive logratios is not isometric in the sense of reproducing the geometry of all pairwise logratios exactly, but their lack of isometry can be measured by the Procrustes correlation. The reference component can be chosen to maximize the Procrustes correlation between the additive logratio geometry and the exact logratio geometry, and for high-dimensional data there are many potential references. As a secondary criterion, minimizing the variance of the reference component’s log-transformed relative abundance values makes the subsequent interpretation of the logratios even easier. Finally, it is preferable that the reference component not be a rare component but well populated, and substantive biological reasons might also guide the choice if several reference candidates are identified. Results: On each of three high-dimensional datasets the additive logratio transformation was performed, using references that were identified according to the abovementioned criteria. For each dataset the compositional data structure was successfully reproduced, that is the additive logratios were very close to being isometric. The Procrustes correlations achieved for these datasets were 0.9991, 0.9977 and 0.9997, respectively. In the third case, where the objective was to distinguish between three groups of samples, the approximation was made to the restricted logratio space of the between-group variance. Conclusions: We show that for high-dimensional compositional data additive logratios can provide a valid choice as transformed variables that are (1) subcompositionally coherent, (2) explaining 100% of the total logratio variance and (3) coming measurably very close to being isometric, that is approximating almost perfectly the exact logratio geometry. The interpretation of additive logratios is simple and, when the variance of the log-transformed reference is very low, it is made even simpler since each additive logratio can be identified with a corresponding compositional component.
The autophagy initiating kinase ULK1 is required for pancreatic cancer cell growth and survival
Authors: Brun Sonja N. , Sancar Gencer , Lumibao Jan , Limpert Allison S. , Ren Huiyu , Ianniciello Angela , Tiriac Herve , Downes Michael , Engle Danielle D. , Evans Ronald M. , Cosford Nicholas D.P. , Shaw Reuben J.
Published: May 2021

Amongst cancer subtypes, pancreatic ductal adenocarcinoma (PDA) has been demonstrated to be most sensitive to autophagy inhibition, which may be due to unique metabolic rewiring in these cells. The serine/threonine kinase ULK1 forms the catalytic center of a complex mediating the first biochemical step of autophagy. ULK1 directly recieves signals from mTORC1 and AMPK to trigger autophagy under stress and nutrient poor conditions. Studies in genetic engineered mouse models of cancer have revealed that deletion of core downstream autophagy genes (ATG5, ATG7) at the time of tumor iniation leads to a profound block in tumor progression leading to the development of autophagy inhibitors as cancer therapeutics. However, most preclinical studies and all clinical studies have relied on non-specific lysomotropic agents such as chloroquine and its derivatives, whose toxicity and off-target issues preclude further clinical development and which do not represent the impact of solely biochemically disrupting the autophagy pathway. Furthermore, druggable targets in the core autophagy pathway are quite limited, with ULK1 and ULK2 representing the only protein kinases in the pathway. Here we explore the genetic requirement for ULK1 and ULK2 in human PDA cancer cell lines and xenografts, and take advantage of new small molecule ULK1 inhibitors to demonstrate that ULK inhibition can overcome autophagy induction triggered by PDA therapeutics including chemotherapy and MEK inhibition. Finally we show that ULK inhibitors increase MHC Class I in PDA cells, suggestion a potential therapeutic avenue for such agents in combination with checkpoint immunotherapy.
The Unconventional Self-Cleavage of Selenoprotein K
Authors: Cheng Rujin , Liu Jun , Forstner Martin B. , Woodward George , Heppard Elmer , Hoffmann Peter R. , Rozovsky Sharon
Published: May 2021

Through known association with other proteins, human selenoprotein K (selenok) is currently implicated in the palmitoylation of proteins, degradation of misfolded proteins, innate immune response, and the life cycle of SARS-CoV-2 virus. However, neither the catalytic function of selenok’s selenocysteine (Sec), which, curiously, resides in an intrinsically disordered protein segment nor selenok’s specific role in these pathways are known to date. This report casts these questions in a new light as it describes that selenok is able -both in vitro and in vivo- to cleave some of its own peptide bonds. The cleavages not only release selenok segments that contain its reactive Sec, but as the specific cleavage sites were identified, they proved to cluster tightly near sites through which selenok interacts with protein partners. Furthermore, it is shown that selenok’s cleavage activity is neither restricted to itself nor promiscuous but selectively extends to at least one of its protein partners. Together, selenok’s cleavage ability and its features have all hallmarks of a regulatory mechanism that could play a central role in selenok’s associations with other proteins and its cellular functions overall.
Beyond BOLD: Evidence for diffusion fMRI contrast in the human brain distinct from neurovascular response
Authors: Olszowy Wiktor , Diao Yujian , Jelescu Ileana O.
Published: May 2021

Functional Magnetic Resonance Imaging (fMRI) is an essential method to measure brain activity non-invasively. While fMRI almost systematically relies on the blood oxygenation level-dependent (BOLD) contrast, there is an increasing interest in alternative methods that would not rely on neurovascular coupling. A promising but controversial such alternative is diffusion fMRI (dfMRI), which relies instead on dynamic fluctuations in apparent diffusion coefficient (ADC) due to microstructural changes underlying neuronal activity, i.e. neuromorphological coupling. However, it is unclear whether genuine dfMRI contrast, distinct from BOLD contamination, can be detected in the human brain in physiological conditions. Here, we present the first dfMRI study in humans attempting to minimize BOLD contamination sources and comparing functional responses at two field strengths (3T and 7T). Our study benefits from unprecedented high spatio-temporal resolution, harnesses novel denoising strategies and examines characteristics of not only task but also resting-state dfMRI. We report task-induced decrease in ADC with temporal and spatial features distinct from the BOLD response and yielding more specific activation maps. Furthermore, we report dfMRI resting-state functional connectivity which, compared to its BOLD counterpart, is essentially free from physiological artifacts and preserves positive correlations but preferentially suppresses anti-correlations, which are likely of vascular origin. A careful acquisition and processing design thus enable the detection of genuine dfMRI contrast on clinical MRI systems. As opposed to BOLD, diffusion functional contrast could be particularly well suited for low-field MRI.
A Novel Non-Invasive Epithelial Ovarian Cancer Mouse Model Of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Authors: Alali Zahraa , Horowitz Max P. , Chau Danielle , Trestan Lexie , Hao Jing , Qi Peng , Esakov Emily L. , DeBernardo Robert L. , Yu Jennifer S. , Reizes Ofer
Published: May 2021

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) in combination with interval cytoreductive surgery increases the overall survival of epithelial ovarian cancer (EOC) patients with advanced disease. Despite its proven benefits, the mechanism by which HIPEC extends overall survival remains unknown and current strategies to optimize HIPEC are therefore limited. A major challenge is the lack of a robust and streamlined model to investigate the mechanisms underlying HIPEC efficacy.

Objective

To introduce a novel murine model that can be used to enhance our understanding of HIPEC therapy.

Method

ID8-luc, an EOC mouse cell line, is inoculated into immunocompetent C57BL/6J mice intraperitoneally. Once tumor is detected by In Vivo Imaging System (IVIS), cisplatin (5 mg/kg) is injected intraperitoneally and superficial hyperthermia of 40°C is applied to the animal’s abdomen and pelvis using an FDA-approved hyperthermia unit (BSD500) for 20 minutes. To validate the model, four treatment conditions were tested: cisplatin and hyperthermia, cisplatin and normothermia, vehicle and hyperthermia, and vehicle and normothermia. Tumor growth was assessed over the course of treatment using IVIS optical spectrum.

Results

Tumor growth in mice treated with hyperthermic cisplatin was significantly suppressed compared to mice treated with normothermic cisplatin (p < 0.05). No significant differences in tumor growth were observed in the hyperthermic vehicle and normothermic vehicle groups.

Conclusions

We developed an innovative noninvasive mouse model of HIPEC. Similar to patients with advanced ovarian cancer who are treated with HIPEC at the time of interval cytoreductive surgery, our model demonstrates that hyperthermia enhances the inhibitory effect of cisplatin on intraperitoneal tumor growth. Development of this murine model provides an opportunity to elucidate the mechanisms underlying HIPEC and offer an opportunity to test adjunct treatments in a pre-clinical setting to enhance the utility of HIPEC.
Distance-guided protein folding based on generalized descent direction
Authors: Wang Liujing , Liu Jun , Xia Yuhao , Xu Jiakang , Zhou Xiaogen , Zhang Guijun
Published: May 2021

Advances in the prediction of the inter-residue distance for a protein sequence have increased the accuracy to predict the correct folds of proteins with distance information. Here, we propose a distance-guided protein folding algorithm based on generalized descent direction, named GDDfold, which achieves effective structural perturbation and potential minimization in two stages. In the global stage, random-based direction is designed using evolutionary knowledge, which guides conformation population to cross potential barriers and explore conformational space rapidly in a large range. In the local stage, locally rugged potential landscape can be explored with the aid of conjugate-based direction integrated into a specific search strategy, which can improve exploitation ability. GDDfold is tested on 347 proteins of a benchmark set, 24 FM targets of CASP13 and 20 FM targets of CASP14. Results show that GDDfold correctly folds (TM-score ≥ 0.5) 316 out of 347 proteins, where 65 proteins have TM-scores that are greater than 0.8, and significantly outperforms Rosetta-dist (distance-assisted fragment assembly method) and L-BFGSfold (distance geometry optimization method). On CASP FM targets, GDDfold is comparable with five state-of-the-art methods, namely, Quark, RaptorX, Rosetta, MULTICOM and trRosetta in the CASP 13 and 14 server groups.
Differentiation of cortical brain organoids and optic nerve-like structures from retinal confluent cultures of pluripotent stem cells
Authors: Fernando Milan , Lee Scott , Wark Jesse R. , Xiao Di , Kim Hani J. , Smith Grady C. , Wong Ted , Teber Erdahl T. , Ali Robin R. , Yang Pengyi , Graham Mark E. , Gonzalez-Cordero Anai
Published: May 2021

Advances in the study of neurological conditions have been possible due to induced pluripotent stem cell technologies and the generation of neural cell types and organoids. Numerous studies have described the generation of neural ectoderm-derived retinal and brain structures from pluripotent stem cells. However, the field is still troubled by technical challenges, including high culture costs and organoid-to-organoid variability. Here, we describe a simple and economical protocol that reproducibly gives rise to the neural retina and cortical brain regions from confluent cultures of stem cells. The spontaneously generated cortical organoids were isolated and cultured in suspension conditions for maturation and are transcriptionally comparable to organoids generated by other methods and to human foetal cortex. Furthermore, these organoids show spontaneous functional network activity with proteomic analysis and electron microscopy demonstrating the presence of synaptic components and maturity. The generation of retinal and brain organoids in close proximity also enabled their mutual isolation. Further culture of this complex organoid system demonstrated the formation of optic nerve-like structures connecting retinal and brain organoids, which might facilitate the investigation of the mechanisms of neurological diseases of the eye and brain.
Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing
Authors: Lasrado Ninaad , Borcherding Nicholas , Arumugam Rajkumar , Starr Timothy K. , Reddy Jay
Published: May 2021

Myocarditis induced with Coxsackievirus B3 (CVB3) is commonly employed to study viral pathogenesis in mice. Although infectious virus is cleared after the acute phase, affected animals chronically develop the features of dilated cardiomyopathy, which may involve the mediation of immune and non-immune cells. To dissect this complexity, we performed single-cell RNA sequencing on heart cells obtained from healthy and myocarditic mice, leading us to note that myocarditic mice had significantly higher proportions of myeloid cells, CD4 and CD8 T cells, and fibroblasts, whereas NK cells, ILCs and B cells were low. While the transcriptome profiles of myeloid cells revealed detection of monocytes and macrophages of M2 phenotype with pathways important in immune metabolism and inflammation, T cells consisted of Th17 cells, CTLs, and Treg cells with transcriptome signatures critical for cytotoxic functions. Although fibroblasts detected in myocarditic mice were phenotypically heterogeneous, their transcriptomes played roles in fibrosis and regulation of inflammation and immune responses. Additionally, analysis of intercellular communication networks revealed unique interactions and signaling pathways in the cardiac cellulome, whereas myeloid cells and T cells in myocarditic mice revealed uniquely upregulated transcription factors modulating cardiac remodeling functions. Taken together, our data suggest that M2 cells, T cells, and fibroblasts may cooperatively or independently participate in the pathogenesis of viral myocarditis.
Assessment of exposure to ionizing radiation in Chernobyl tree frogs (Hyla orientalis)
Authors: Burraco Pablo , Car Clément , Bonzom Jean-Marc , Orizaola Germán
Published: May 2021

Ionizing radiation can damage organic molecules, causing detrimental effects on human and wildlife health. The accident at the Chernobyl nuclear power plant (1986) represents the largest release of radioactive material to the environment. An accurate estimation of the current exposure to radiation in wildlife, often reduced to ambient dose rate assessments, is crucial to understand the long-term impact of radiation on living organisms. Here, we present an evaluation of the sources and variation of current exposure to radiation in breeding Eastern tree frogs (Hyla orientalis) males living in the Chernobyl Exclusion Zone. Total dose rates inH. orientaliswere highly variable, although generally below widely used thresholds considered harmful for animal health. Internal exposure was the main source of absorbed dose rate (81% on average), with90Sr being the main contributor (78% of total dose rate, on average). These results highlight the importance of assessing both internal and external exposure levels in order to perform a robust evaluation of the exposure to radiation in wildlife. Further studies incorporating life-history, ecological, and evolutionary traits are needed to fully evaluate the effects that these exposure levels can have in amphibians and other taxa inhabiting radio-contaminated environments.
A close-to-native structure of the synaptonemal complex
Authors: Ortiz Rosario , Echeverría Olga M. , Masich Sergej , Höög Christer , Hernández-Hernández Abrahan
Published: May 2021

Genetic variability in sexually reproducing organisms results from an exchange of genetic material between homologous chromosomes. The genetic exchange mechanism is dependent on the synaptonemal complex (SC), a protein structure localized between the homologous chromosomes. Current structural models of the SC are based on electron microscopy, super resolution, and expansion microscopy studies using chemical fixatives and sample dehydration of gonads, which are methodologies known to produce structural artifacts. We have developed a novel electron microscopy sample-preparation approach where pachytene cells are isolated from mouse testis by FACS, followed by cryo-fixation and cryo-substitution to achieve visualization of a close-to-native structure of the SC. We found that the central region of the SC was wider than previously recognized, and the transverse filaments more densely packed in the central region. Furthermore, we identified a structure nucleating the central element of the SC.
Firms’ performance during the COVID-19 outbreak: international evidence from 13 countries
Authors: Golubeva Olga
Published: May 2021

Purpose

The purpose of this paper is to explore the impact of firm-, finance- and country-specific indicators to the performance of companies under the COVID-19 outbreak.

Design/methodology/approach

The study uses a regression performance model for enterprises during the COVID-19 crisis. The investigation is based upon a data set of 5,730 firms from 13 countries collected by the World Bank through enterprise surveys. The author combined the analysis of traditional performance measurements with the testing of relatively novel variables.

Findings

This study confirms the significance of multiple factors for company performance: sector, size, participation in exports and market demand for firms’ products. Robust financing solutions during the coronavirus pandemic period include equity contributions, followed by firms’ cash balances and debt. Support by a government, however, has not yet been confirmed as a significant source of finance. This paper also suggests the importance of country-specific factors for the performance of enterprises, including the level of economic development and the corporate governance infrastructure.

Practical implications

The research outcomes might assist regulatory bodies, policymakers and companies in their formulation of public and corporate governance strategies concerning future emergency preparedness and responses.

Originality/value

This paper is among the first empirical studies in the management realm that addresses the impact of COVID-19 on company performance, with cross-national empirical data.
A multi-objective approach to determining the usefulness of papers in academic search
Authors: Khalid Shah , Wu Shengli , Zhang Fang
Published: May 2021

Purpose

How to provide the most useful papers for searchers is a key issue for academic search engines. A lot of research has been carried out to address this problem. However, when evaluating the effectiveness of an academic search engine, most of the previous investigations assume that the only concern of the user is the relevancy of the paper to the query. The authors believe that the usefulness of a paper is determined not only by its relevance to the query but also by other aspects including its publication age and impact in the research community. This is vital, especially when a large number of papers are relevant to the query.

Design/methodology/approach

This paper proposes a group of metrics to measure the usefulness of a ranked list of papers. When defining these metrics, three factors, including relevance, publication age and impact, are considered at the same time. To accommodate this, the authors propose a framework to rank papers by a combination of their relevance, publication age and impact scores.

Findings

The framework is evaluated with the ACL (Association for Computational Linguistics Anthology Network) dataset. It demonstrates that the proposed ranking algorithm is effective for improving usefulness when two or three aspects of academic papers are considered at the same time, while the relevance of the retrieved papers is slightly down compared with the relevance-only retrieval.

Originality/value

To the best of the authors’ knowledge, the proposed multi-objective academic search framework is the first of its kind that is proposed and evaluated with a group of new evaluation metrics.
Who could have seen this coming? The Kenya red cross society and the drought appeal of 2019
Authors: Ngoye Ben Otieno , Saado Halima , Gachari Caroline Wambui
Published: May 2021

Learning outcomes

The case will be useful in helping learners: to appreciate concepts in and develop the necessary understanding to apply relevant theories in crisis communications; to identify communications issues along with the evolution of a crisis; to understand the importance and role of a crisis communications team; and to develop skills in writing a crisis communications plan.

Case overview/synopsis

The case is a narration of the experiences of the Kenya Red Cross Society (KRCS) as it launched the Kenya drought appeal in March 2019, and the unexpected media and public backlash that ensued. The background is that of an unusual-yet-previously-predicted dry spell, consequent drought and famine, alleged famine-related deaths, mixed signals from the national and county government and a hitherto well-regarded institution (the KRCS) coming in to launch an appeal aimed at raising funds to help alleviate the effects of the prolonged drought and consequent famine in the northern parts of the country. Unfortunately, a major media and public backlash that was not foreseen by KRCS ensued, and it threatened the reputation and very existence of the organization. Drawing on interviews and secondary material in the public domain, the case focuses on how the KRCS navigates the media and public backlash that ensued following the funding appeal. The case is interesting because of the type of organization involved (a not-for-profit institution set up as auxiliary to the government and of good repute), the nature of the problem (reputational crisis and attendant risk management), the setting (a LMIC in sub-Saharan Africa) and the level of analysis (organizational rather than individual decision-making).[AQ1]

Complexity academic level

Masters level – MBA, Executive MBA, Master’s in Public Management, Master’s in Communication and/or similar courses.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
InterGlobe Aviation Ltd.: need for strategy
Authors: Malhotra Mohak , Ghura Amarpreet Singh , Thakur Barun
Published: May 2021

Learning outcomes

Discussion of the case will enable the students to: ● use “Strengths, Weaknesses, Opportunities, and Threats” analysis. ● Use “pros and cons” analysis. ● Explain what constitutes an effective strategy. ● Analyze the quality of the strategy for IndiGo Airlines (IA). ● Explain sustained competitive advantage through value, rareness, imitability and organization framework.

Case overview/synopsis

This case describes a situation in which InterGlobe Aviation Ltd. (IGAL) has been experiencing multiple engine snags because of the faulty Pratt and Whitney engines. In a span of two years between June 2018 and January 2020, IGAL faced around 22 snags. IGAL is known to be one of the safest airlines in the world, the engine issue has tainted its reputation. In October 2019, in just one week IA faced four-engine snags, forcing the Directorate General of Civil Aviation (DGCA) to come out with a guideline in November 2019. The faulty engines were to be replaced by January 31, 2020. If IA failed to complete the task by the given deadline then IA would have to ground around 70–80 aircraft. IA was way behind the deadline when on January 13, 2020, they received an email from DGCA mentioning an extension of the deadline to May 31, 2020. The purpose of this case is to provide an opportunity for the participants to take into consideration the data given for IA and make assumptions and resolve the dilemma through which Ronojoy Dutta (Dutta), the Chief executive officer if IA is going through.

Complexity academic level

The case engages the participants in deciding a suitable course of action for IA to develop a strategy and is ideal to teach elements of strategy. The case can be used in the following courses/programs: ● A strategy formulation module in strategic management program or post-graduate program in management.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 11: Strategy.

Supplementary materials

Teaching Notes are available for educators only.
The evolution of the pathways of innovation strategies in the automotive industry. The case of Fiat Chrysler Automobiles
Authors: Candelo Elena , Troise Ciro , Matricano Diego , Lepore Amedeo , Sorrentino Mario
Published: May 2021

Purpose

Fundamental management innovations have been ideated and developed in the automotive industry. Over the years, carmakers have radically modified their innovation strategies. Currently, carmakers are increasingly adopting open innovation approaches, moving from a closed to open innovation paradigm. The aim of this paper is to reconstruct the evolution of the innovation activities performed by carmakers and to propose an original periodisation of innovation strategies in the automotive industry since its origins.

Design/methodology/approach

This paper analyses the relevant literature and proposes a theoretical framework that defines how innovation strategies have changed from the birth of the automotive industry to current times. A detailed in-depth case study of Fiat Chrysler Automobiles (FCA), one of the top ten global carmakers, is used to corroborate the theoretical framework. The case study reconstructs the entire evolution of the innovation strategies of the company from its origins to the present day.

Findings

The paper proposes an original periodisation by identifying three evolutionary phases of innovation strategies pursued by carmakers: “internal innovation”, “collaborative innovation” and “towards open innovation”. Each phase embraces a historical period, and for each period, the most relevant managerial aspects, as well as the types and direction of knowledge flows for fostering innovation, are analysed. The case study provides clear evidence that FCA has undergone the three above-cited phases in fostering its innovation strategies.

Originality/value

The study reconstructs the evolution of the innovation strategies performed by global carmakers, proposing an original periodisation of the transitions that occurred in practice in the automotive industry. This paper is among the first to explore the evolution of innovation strategies in the automotive industry since its origins to date and to highlight the salient differences that have occurred over time.
Forecasting daily attraction demand using big data from search engines and social media
Authors: Tian Fengjun , Yang Yang , Mao Zhenxing , Tang Wenyue
Published: May 2021

Purpose

This paper aims to compare the forecasting performance of different models with and without big data predictors from search engines and social media.

Design/methodology/approach

Using daily tourist arrival data to Mount Longhu, China in 2018 and 2019, the authors estimated ARMA, ARMAX, Markov-switching auto-regression (MSAR), lasso model, elastic net model and post-lasso and post-elastic net models to conduct one- to seven-days-ahead forecasting. Search engine data and social media data from WeChat, Douyin and Weibo were incorporated to improve forecasting accuracy.

Findings

Results show that search engine data can substantially reduce forecasting error, whereas social media data has very limited value. Compared to the ARMAX/MSAR model without big data predictors, the corresponding post-lasso model reduced forecasting error by 39.29% based on mean square percentage error, 33.95% based on root mean square percentage error, 46.96% based on root mean squared error and 45.67% based on mean absolute scaled error.

Practical implications

Results highlight the importance of incorporating big data predictors into daily demand forecasting for tourism attractions.

Originality/value

This study represents a pioneering attempt to apply the regularized regression (e.g. lasso model and elastic net) in tourism forecasting and to explore various daily big data indicators across platforms as predictors.