bluuebunny/crossref_metadata_2025 huggingface dataset:
CALR frameshift mutations in MPN patient-derived iPS cells accelerate maturation of megakaryocytes
Authors: Olschok Kathrin , Han Lijuan , de Toledo Marcelo A. S. , Böhnke Janik , Graßhoff Martin , Costa Ivan G. , Theocharides Alexandre , Maurer Angela , Schüler Herdit M. , Buhl Eva Miriam , Pannen Kristina , Baumeister Julian , Kalmer Milena , Gupta Siddharth , Boor Peter , Gezer Deniz , Brümmendorf Tim H. , Zenke Martin , Chatain Nicolas , Koschmieder Steffen
Published: July 2021

Calreticulin (CALR) mutations are driver mutations in myeloproliferative neoplasms (MPNs), leading to activation of the thrombopoietin receptor, and causing abnormal megakaryopoiesis. Here, we generated patient-derived CALRins5- or CALRdel52-positive induced pluripotent stem (iPS) cells to establish a MPN disease model for molecular and mechanistic studies. We demonstrated myeloperoxidase deficiency in CD15+ granulocytic cells derived from homozygous CALR-mutant iPS cells, rescued by repairing the mutation using CRISPR/Cas9. iPS cell-derived megakaryocytes showed characteristics of primary megakaryocytes such as formation of demarcation membrane system and cytoplasmic pro-platelets protrusions. Importantly, CALR mutations led to enhanced megakaryopoiesis and accelerated megakaryocytic development in a thrombopoietin-independent manner. Mechanistically, our study identified differentially regulated pathways in mutated vs. unmutated megakaryocytes, such as hypoxia signaling, which represents a potential target for therapeutic intervention. Altogether, we demonstrate key aspects of mutated CALR-driven pathogenesis, dependent on its zygosity and found known and novel therapeutic targets, making our model a valuable tool for clinical drug screening in MPNs.
Polybasic patches in both C2 domains of Synaptotagmin-1 are required for evoked neurotransmitter release
Authors: Wu Zhenyong , Ma Lu , Courtney Nicholas A. , Zhu Jie , Zhang Yongli , Chapman Edwin R. , Karatekin Erdem
Published: July 2021

Synaptotagmin-1 (Syt1) is a vesicular calcium sensor required for synchronous neurotransmitter release. It is composed of a single-pass transmembrane domain linked to two tandem C2 domains (C2A and C2B) that bind calcium, acidic lipids, and SNARE proteins that drive fusion of the synaptic vesicle with the plasma membrane. Despite its essential role, how Syt1 couples calcium entry to synchronous release is not well understood. Calcium binding to C2B, but not to C2A, is critical for synchronous release and C2B additionally binds the SNARE complex. The C2A domain is also required for Syt1 function, but it is not clear why. Here we asked what critical feature of C2A may be responsible for its functional role, and compared this to the analogous feature in C2B. We focused on highly conserved poly-lysine patches located on the sides of C2A (K189-192) and C2B (K324-327). We tested effects of charge-neutralization mutations in either region (Syt1K189-192A and Syt1K326-327A) side-by-side to determine their relative contributions to Syt1 function in cultured cortical mouse neurons and in single-molecule experiments. Combining electrophysiological recordings and optical tweezers measurements to probe dynamic single C2 domain-membrane interactions, we show that both C2A and C2B polybasic patches contribute to membrane binding, and both are required for evoked release. The readily releasable vesicle pool or spontaneous release were not affected, so both patches are specifically required for synchronization of release. We suggest these patches contribute to cooperative binding to membranes, increasing the overall affinity of Syt1 for negatively charged membranes and facilitating evoked release.

Significance Statement

Synaptotagmin-1 is a vesicular calcium sensor required for synchronous neurotransmitter release. Its tandem cytosolic C2 domains (C2A and C2B) bind calcium, acidic lipids, and SNARE proteins that drive fusion of the synaptic vesicle with the plasma membrane. How calcium-binding to Synaptotagmin-1 leads to release and the relative contributions of the two C2 domains is not clear: unlike C2B, calcium-binding to C2A is not critical for evoked release, yet both domains are needed for Syt1 function. Combining electrophysiological recordings from cultured neurons and optical tweezers measurements that probe single C2 domain-membrane interactions, we show that conserved polybasic regions in both domains contribute to membrane binding cooperatively, and both are required for evoked release, likely by increasing the overall affinity of Synaptotagmin-1 for negatively charged membranes.
Exploring the Inner Workings of Neuron Circuits That Exhibit Persistent Activity To Explain How Working Memory and Executive Function Are Implemented in The Brain
Authors: Gomez Paul , Gomez Jeremy , Gomez Andres
Published: July 2021

In this research we explore in detail how a phenomenon called “sustained persistent activity” is achieved by circuits of interconnected neurons. Persistent activity is a phenomenon that has been extensively studied (Papoutsi et al. 2013; Kaminski et. al. 2017; McCormick et al. 2003; Rahman, and Berger, 2011). Persistent activity consists of neuron circuits whose spiking activity remains even after the initial stimuli are removed. Persistent activity has been found in the prefrontal cortex (PFC) and has been correlated to working memory and decision making (Clayton E. Curtis and Daeyeol Lee, 2010).

We go beyond the explanation of how persistent activity happens and show how arrangements of those basic circuits encode and store data and are used to perform more elaborated tasks and computations.

The purpose of the model we propose here is to describe the minimum number of neurons and their interconnections required to explain persistent activity and how this phenomenon is actually a fast storage mechanism required for implementing working memory, task processing and decision making.
Feeding effects on liver mitochondrial bioenergetics of Boa constrictor (Serpentes: Boidae)
Authors: da Mota Araujo Helena Rachel , Sartori Marina Rincon , Navarro Claudia D. C. , de Carvalho José Eduardo , da Cruz André Luis
Published: July 2021

Snakes are interesting examples of overcoming energy metabolism challenges as many species can endure long periods without feeding, and their eventual meals are of reasonably large sizes, thus exhibiting dual extreme adaptations. Consequently, metabolic rate increases considerably to attend to the energetic demand of digestion, absorption and, protein synthesis. These animals should be adapted to transition from these two opposite states of energy fairly quickly, and therefore we investigated mitochondrial function plasticity in these states. Herein we compared liver mitochondrial bioenergetics of the boid snake Boa constrictor during fasting and after meal intake. We fasted the snakes for 60 days, then we fed a subgroup with 30% of their body size and evaluated their maximum postprandial response. We measured liver respiration rates from permeabilized tissue and isolated mitochondria, and from isolated mitochondria, we also measured Ca2+ retention capacity, the release of H2O2, and NAD(P) redox state. Mitochondrial respiration rates were maximized after feeding, reaching until 60% increase from fasting levels when energized with complex I-linked substrates. Interestingly, fasting and fed snakes exhibited similar respiratory control ratios and citrate synthase activity. Furthermore, we found no differences in Ca2+ retention capacity, indicating no increase in susceptibility to mitochondrial permeability transition pore (PTP), or redox state of NAD(P), although fed animals exhibited increases in the release of H2O2. Thus, we conclude that liver mitochondria from B. constrictor snakes increase the maintenance costs during the postprandial period and quickly improve the mitochondrial bioenergetics capacity without compromising the redox balance.
Individualized prediction of future cognition using baseline developmental changes in cortical anatomy
Authors: Khundrakpam Budhachandra , Booij Linda , Jeon Seun , Tohka Jussi , Evans Alan C.
Published: July 2021

Predictive modeling studies have started to reveal brain measures underlying cognition; however, most studies are based on cross-sectional data (static ‘final’ brain measures acquired at one time point). Since brain development comprises of continuously ongoing events leading to cognitive development, predictive modeling studies need to consider‘dynamic’as opposed tostatic ‘final’brain measures. Using longitudinal neuroimaging and cognitive data (global executive composite score, an index of executive function) from 82 individuals (aged 5-14 years, scanned 3 times), we built highly accurate prediction models (r=0.61,p=1.6e-09) of future cognition (assessed at visit 3) based on baseline developmental changes in cortical anatomy (from visit 1 to 2). More importantly, dynamic brain measures (change in cortical anatomy from visit 1 to 2) and not static brain measures (cortical anatomy at visit 1 and 2) were critical for predicting future cognition, suggesting the need for considering dynamic brain measures in predicting cognitive outcomes.
Exocyst Inactivation in Urothelial Cells Disrupts Autophagy and Activates non-canonical NF-κB
Authors: Ortega Michael A. , Villiger Ross K. , Harrison-Chau Malia , Lieu Suzanna , Tamashiro Kadee-Kalia , Lee Amanda J. , Fujimoto Brent A. , Patwardhan Geetika Y. , Kepler Joshua , Fogelgren Ben
Published: July 2021

Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have reported that ureteric bud-specific ablation of the exocyst Exoc5 subunit in late-murine gestation results in failure of urothelial stratification, cell death, and complete ureter obstruction. However, the mechanistic connection between disrupted exocyst activity, urothelial cell death, and subsequent ureter obstruction was unclear. Here, we report that inhibited urothelial stratification does not drive cell death during ureter development. Instead, we demonstrate that the exocyst plays a critical role in autophagy in urothelial cells, and that disruption of autophagy activates a urothelial NF-κB stress response. Impaired autophagy first provokes canonical NF-κB activity which is progressively followed by increasing non-canonical NF-κB activity and cell death if the stress remains unresolved. Furthermore, we demonstrate that ureter obstructions can be completely rescued in Exoc5 conditional knockout mice by administering a single dose of pan-caspase inhibitor z-VAD-FMK at E16.5 prior to urothelial cell death. Taken together, ablation of Exoc5 disrupts autophagic stress response and activates progressive NF-κB signaling which promotes obstructive uropathy.
Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel
Authors: Patel Vishal R. , Salinas Arturo M. , Qi Darong , Gupta Shipra , Sidote David J. , Goldschen-Ohm Marcel P.
Published: July 2021

Ligand binding to membrane proteins is critical for many biological signaling processes. However, individual binding events are rarely directly observed, and their asynchronous dynamics are occluded in ensemble-averaged measures. For membrane proteins, single-molecule approaches that resolve these dynamics are challenged by dysfunction in nonnative lipid environments, lack of access to intracellular sites, and costly sample preparation. Here, we introduce an approach combining cell-derived nanovesicles, microfluidics, and single-molecule fluorescence colocalization microscopy to track individual binding events at a cyclic nucleotide-gated TAX-4 ion channel critical for sensory transduction. Our observations reveal dynamics of both nucleotide binding and a subsequent conformational change likely preceding pore opening. We further show that binding of the second ligand in the tetrameric channel is less cooperative than previously estimated from ensemble-averaged binding measures. This approach is broadly applicable to studies of binding dynamics for proteins with extracellular or intracellular domains in native cell membrane.
An advanced automated patch clamp protocol design to investigate drug – ion channel binding dynamics
Authors: Lukacs Peter , Pesti Krisztina , Földi Mátyás C. , Zboray Katalin , Toth Adam V. , Papp Gábor , Mike Arpad
Published: July 2021

Standard high throughput screening projects using automated patch-clamp instruments often fail to grasp essential details of the mechanism of action, such as binding/unbinding dynamics and modulation of gating. In this study, we aim to demonstrate that depth of analysis can be combined with acceptable throughput on such instruments. Using the microfluidics-based automated patch clamp, IonFlux Mercury, we developed a method for a rapid assessment of the mechanism of action of sodium channel inhibitors, including their state-dependent association and dissociation kinetics. The method is based on a complex voltage protocol, which is repeated at 1 Hz. Using this time resolution we could monitor the onset and offset of both channel block and modulation of gating upon drug perfusion and washout. Our results show that the onset and the offset of drug effects are complex processes, involving several steps, which may occur on different time scales. We could identify distinct sub-processes on the millisecond time scale, as well as on the second time scale. Automated analysis of the results allows collection of detailed information regarding the mechanism of action of individual compounds, which may help the assessment of therapeutic potential for hyperexcitability-related disorders, such as epilepsies, pain syndromes, neuromuscular disorders, or neurodegenerative diseases.
Brain-like functional specialization emerges spontaneously in deep neural networks
Authors: Dobs Katharina , Martinez Julio , Kell Alexander J.E. , Kanwisher Nancy
Published: July 2021

The last quarter century of cognitive neuroscience has revealed numerous cortical regions in humans with distinct, often highly specialized functions, from recognizing faces to understanding language to thinking about what other people are thinking. But it remains unclear why the cortex exhibits this high degree of functional specialization in the first place. Here, we consider the case of face perception, using artificial neural networks to test the hypothesis that functional segregation of face recognition in the brain reflects the computational requirements of the task. We find that networks trained on generic object recognition perform poorly on face recognition and vice versa, and further that networks optimized for both tasks spontaneously segregate themselves into separate systems for faces and objects. Thus, generic visual features that suffice for object recognition are apparently suboptimal for face recognition and vice versa. We then show functional segregation to varying degrees for other visual categories, revealing a widespread tendency for optimization (without built-in task-specific inductive biases) to lead to functional specialization in machines and, we conjecture, also brains.
Differential impact of Kv8.2 loss on rod and cone signaling and degeneration
Authors: Inamdar Shivangi M , Lankford Colten K , Poria Deepak , Laird Joseph G , Solessio Eduardo , Kefalov Vladimir J. , Baker Sheila A
Published: July 2021

Heteromeric Kv2.1/Kv8.2 channels are voltage-gated potassium channels localized to the photoreceptor inner segment. They carry IKx, which is largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset Cone Dystrophy with Supernormal Rod Response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms we show that there were delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels were controlled by the perfusion buffer, so we propose the in vivo alteration is influenced by genotype-associated ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone-driven ERG b wave amplitudes and underwent degeneration. Altogether, we provide insight into how a deficit in the dark current affects the health and function of photoreceptors.
D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain
Authors: Semenza Evan R. , Harraz Maged M. , Abramson Efrat , Malla Adarsha P. , Vasavda Chirag , Gadalla Moataz M. , Kornberg Michael D. , Snyder Solomon H. , Roychaudhuri Robin
Published: July 2021

D-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the D-stereoisomer of the amino acid with the fastest in vitro spontaneous racemization rate, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and an stereospecific luciferase assay, we identify endogenous D-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the NMDA glutamate receptor co-agonist D-serine, as a candidate biosynthetic enzyme for D-cysteine. Levels of D-cysteine are enriched over twentyfold in the embryonic mouse brain compared to the adult. D-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by approximately 50%, effects not shared with D-serine or L-cysteine. The antiproliferative effect of D-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of D-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for D-cysteine-binding proteins in NPCs by immunoprecipitation with a D-cysteine-specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative D-cysteine-binding protein. Together, these results establish endogenous mammalian D-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.
Disentangling niche theory and beta diversity change
Authors: Godsoe William , Bellingham Peter J. , Moltchanova Elena
Published: July 2021

Beta diversity describes the differences in species composition among communities. Changes in beta diversity over time are thought to be due to selection based on species’ niche characteristics. For example, theory predicts that selection that favours habitat specialists will increase beta diversity. In practice, ecologists struggle to predict how beta diversity changes. To remedy this problem, we propose a novel solution that formally measures selection’s effects on beta diversity. Using the Price equation, we show how change in beta diversity over time can be partitioned into fundamental mechanisms including selection among species, variable selection among communities, drift, and immigration. A key finding of our approach is that a species’ short-term impact on beta diversity cannot be predicted using information on its long-term environmental requirements (i.e. its niche). We illustrate how our approach can be used to partition causes of diversity change in a montane tropical forest before and after an intense hurricane. Previous work in this system highlighted the resistance of habitat specialists and the recruitment of light-demanding species but was unable to quantify the importance of these effects on beta diversity. Using our approach, we show that changes in beta diversity were consistent with ecological drift. We use these results to highlight the opportunities presented by a synthesis of beta diversity and formal models of selection.
Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques
Authors: He Wan-ting , Yuan Meng , Callaghan Sean , Musharrafieh Rami , Song Ge , Silva Murillo , Beutler Nathan , Lee Wilma , Yong Peter , Torres Jonathan , Melo Mariane , Zhou Panpan , Zhao Fangzhu , Zhu Xueyong , Peng Linghang , Huang Deli , Anzanello Fabio , Ricketts James , Parren Mara , Garcia Elijah , Ferguson Melissa , Rinaldi William , Rawlings Stephen A. , Nemazee David , Smith Davey M. , Briney Bryan , Safonova Yana , Rogers Thomas F. , Crotty Shane , Irvine Darrell J. , Ward Andrew B. , Wilson Ian A. , Burton Dennis R. , Andrabi Raiees
Published: July 2021

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody responses against multiple CoVs. Because of the phylogenetic similarity to humans, rhesus macaques are an animal model of choice for many virus-challenge and vaccine-evaluation studies, including SARS-CoV-2. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein generates potent receptor binding domain cross- neutralizing antibody (nAb) responses to both SARS-CoV-2 and SARS-CoV-1, in contrast to human infection or vaccination where responses are typically SARS-CoV-2-specific. Furthermore, the macaque nAbs are equally effective against SARS-CoV-2 variants of concern. Structural studies show that different immunodominant sites are targeted by the two primate species. Human antibodies generally target epitopes strongly overlapping the ACE2 receptor binding site (RBS), whereas the macaque antibodies recognize a relatively conserved region proximal to the RBS that represents another potential pan-SARS-related virus site rarely targeted by human antibodies. B cell repertoire differences between the two primates appear to significantly influence the vaccine response and suggest care in the use of rhesus macaques in evaluation of vaccines to SARS-related viruses intended for human use.

ONE SENTENCE SUMMARY

Broadly neutralizing antibodies to an unappreciated site of conservation in the RBD in SARS- related viruses can be readily induced in rhesus macaques because of distinct properties of the naïve macaque B cell repertoire that suggest prudence in the use of the macaque model in SARS vaccine evaluation and design.
Discovery of putative Golgi S-Adenosyl methionine transporters reveals the importance of plant cell wall polysaccharide methylation
Authors: Temple Henry , Phyo Pyae , Yang Weibing , Lyczakowski Jan J. , Echevarría-Poza Alberto , Yakunin Igor , Parra-Rojas Juan Pablo , Terrett Oliver M. , Saez-Aguayo Susana , Dupree Ray , Orellana Ariel , Hong Mei , Dupree Paul
Published: July 2021

Polysaccharide methylation, especially that of pectin, is a common and important feature of land plant cell walls. Polysaccharide methylation takes place in the Golgi apparatus and therefore relies on the import of S-adenosyl methionine (SAM) from the cytosol into the Golgi. However, to date, no Golgi SAM transporter has been identified in plants. In this work, we studied major facilitator superfamily members in Arabidopsis that we identified as putative Golgi SAM transporters (GoSAMTs). Knock-out of the two most highly expressed GoSAMTs led to a strong reduction in Golgi-synthesised polysaccharide methylation. Furthermore, solid-state NMR experiments revealed that reduced methylation changed cell wall polysaccharide conformations, interactions and mobilities. Notably, the NMR revealed the existence of pectin ‘egg-box’ structures in intact cell walls, and showed that their formation is enhanced by reduced methyl-esterification. These changes in wall architecture were linked to substantial growth and developmental phenotypes. In particular, anisotropic growth was strongly impaired in the double mutant. The identification of putative transporters that import SAM into the Golgi lumen in plants provides new insights into the paramount importance of polysaccharide methylation for plant cell wall structure and function.
Tumour Suppressor Parafibromin/Hyrax Governs Cell Polarity and Centrosome Assembly in Neural Stem Cells
Authors: Deng Qiannan , Wang Cheng , Koe Chwee Tat , Heinen Jan Peter , Tan Ye Sing , Li Song , Gonzalez Cayetano , Sung Wing-Kin , Wang Hongyan
Published: July 2021

Neural stem cells (NSCs) divide asymmetrically to balance their self-renewal and differentiation, an imbalance in which can lead to NSC overgrowth and tumour formation. The functions of Parafibromin, a conserved tumour suppressor, in the nervous system are not established. Here, we demonstrate that Drosophila Parafibromin/Hyrax (Hyx) inhibits NSC overgrowth by governing cell polarity. Hyx is essential for the apicobasal polarization of NSCs, through its role in the asymmetric distribution of polarity proteins. hyx depletion results in the symmetric division of NSCs, leading to the formation of supernumerary NSCs in the larval brain. Importantly, we show that human Parafibromin can fully rescue NSC overgrowth and cell polarity defects in Drosophila hyx mutant brains. We have also discovered a novel role for Hyx in regulating the formation of interphase microtubule-organizing center and mitotic spindles in NSCs. Moreover, Hyx is required for the proper localization of a key centrosomal protein, Polo, and the microtubule-binding proteins Msps and D-TACC in dividing NSCs. Furthermore, Hyx directly regulates the polo expression in vitro. Altogether, our study provides the first evidence that the brain tumour suppressor-like role and polarity establishing functions of Hyx are mediated by its role in regulating microtubule growth and centrosomal assembly. The new paradigm that Parafibromin orchestrates cell polarization by regulating centrosomal assembly may be relevant to future studies on Parafibromin/HRPT2-associated cancers.
UVC inactivation of pathogenic samples suitable for cryoEM analysis
Authors: Depelteau JS , Renault L , Althof N , Cassidy CK , Mendonça LM , Jensen GJ , Resch GP , Briegel A
Published: July 2021

Cryo-electron microscopy has become an essential tool to understand structure and function of biological samples, from individual proteins to whole cells. Especially for pathogens, such as disease-causing bacteria and viruses, insights gained by cryo-EM can aid in developing cures. However, due to the biosafety restrictions of human pathogens, samples are often treated by chemical fixation to render the pathogen inert, affecting the delicate ultrastructure of the sample. Alternatively, researchers use in vitro or ex vivo models, which are non-pathogenic but lack the complexity of the pathogen of interest. Here we show that ultraviolet-C (UVC) radiation at cryogenic temperatures can be used to eliminate or dramatically reduce the infectivity of two model organisms, a pathogenic bacterium (Vibrio cholerae) and a virus-like particle (the ICP1 bacteriophage). We show no discernable structural impact of this treatment of either sample using two cryo-EM methods: cryo-electron tomography (cryo-ET) followed by sub-tomogram averaging (STA), and single particle analysis (SPA). Additionally, we applied the UVC irradiation to the protein apoferritin (ApoF), which is a widely used test sample for high resolution SPA studies. The UVC-treated ApoF sample resulted in a 2.1 Å structure that did not reveal any discernable structural damage. Together, these results show that the UVC irradiation dose that effectively inactivates cryo-EM samples does not negatively impact their structure. This research demonstrates that UVC treatment is an effective and inexpensive addition to the cryo-EM sample preparation toolbox.
PLK1 controls centriole distal appendage formation and centrobin removal via independent pathways
Authors: Roux-Bourdieu Morgan Le , Harry Daniela , Meraldi Patrick
Published: July 2021

Centrioles are central structural elements of centrosomes and cilia. They originate as daughter centrioles from existing centrioles in S-phase and reach their full functionality with the formation of distal and subdistal appendages two mitoses later. Current models postulate that the centriolar protein centrobin acts as placeholder for distal appendage proteins that must be removed to complete distal appendage formation. Here, we investigated in non-transformed human epithelial cells the mechanisms controlling centrobin removal and its effect on distal appendage formation. We demonstrate that centrobin is removed from older centrioles due to a higher affinity for the newly born daughter centrioles, under the control of the centrosomal kinase Plk1. Centrobin removal also depends on the presence of subdistal appendage proteins on the oldest centriole. It is, however, not required for distal appendage formation even though this process is equally dependent on Plk1. We conclude that during centriole maturation, Plk1 kinase regulates centrobin removal and distal appendage formation via separate pathways.
Multidimensional MRI for characterization of subtle axonal injury accelerated using an adaptive nonlocal multispectral filter
Authors: Benjamini Dan , Bouhrara Mustapha , Komlosh Michal E. , Iacono Diego , Perl Daniel P. , Brody David L. , Basser Peter J.
Published: July 2021

Multidimensional MRI is an emerging approach that simultaneously encodes water relaxation (T1 and T2) and mobility (diffusion) and replaces voxel-averaged values with subvoxel distributions of those MR properties. While conventional (i.e., voxel-averaged) MRI methods cannot adequately quantify the microscopic heterogeneity of biological tissue, using subvoxel information allows to selectively map a specific T1-T2-diffusion spectral range that corresponds to a group of tissue elements. The major obstacle to the adoption of rich, multidimensional MRI protocols for diagnostic or monitoring purposes is the prolonged scan time. Our main goal in the present study is to evaluate the performance of a nonlocal estimation of multispectral magnitudes (NESMA) filter on reduced datasets to limit the total acquisition time required for reliable multidimensional MRI characterization of the brain. Here we focused and reprocessed results from a recent study that identified potential imaging biomarkers of axonal injury pathology from the joint analysis of multidimensional MRI, in particular voxelwise T1-T2 and diffusion-T2 spectra in human Corpus Callosum, and histopathological data. We tested the performance of NESMA and its effect on the accuracy of the injury biomarker maps, relative to the co-registered histological reference. Noise reduction improved the accuracy of the resulting injury biomarker maps, while permitting data reduction of 35.7% and 59.6% from the full dataset for T1-T2 and diffusion-T2 cases, respectively. As successful clinical proof-of-concept applications of multidimensional MRI are continuously being introduced, reliable and robust noise removal and consequent acquisition acceleration would advance the field towards clinically-feasible diagnostic multidimensional MRI protocols.
Small molecules enhance the potency of natural antimicrobial peptides
Authors: Losasso Valeria , Agarwal Khushbu , Waskar Morris , Majumdar Amitabha , Crain Jason , Winn Martyn , Hoptroff Michael
Published: July 2021

The skin-associated microbiome plays an important role in general well-being and in a variety of treatable conditions. In this regard, endogenous antimicrobial peptides have a role in controlling the microbial population. We demonstrate here that certain small molecular species can amplify the potency of naturally-occurring antimicrobial peptides. For example, Niacinamide is a vitamin B3 analogue naturally found in foods and widely used in topical skin care products, and here we have investigated its cooperativity with the human antimicrobial peptide LL37 on the bacterium Staphylococcus aureus. We have also studied two other structurally related B3 analogs. We observed a clear synergistic effect of niacinamide and, to some extent, methyl niacinamide, whereas isonicotinamide showed no significant cooperativity with LL37. Adaptively-biased molecular dynamics simulations revealed that the analogs partition into the head group region of an anionic bilayer used to mimic the bacterial membrane. The observed effects on the physical properties of the membrane are well correlated with experimental activity. In contrast, the analogs have little effect on zwitterionic bilayers which mimic a mammalian membrane. We conclude that these vitamin B3 analogues can potentiate the activity of host peptides by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide. The level of cooperativity is strongly dependent on the detailed chemistry of the additive, suggesting an opportunity to fine-tune the behaviour of host peptides.
C2CD6 is required for assembly of the CatSper calcium channel complex and fertilization
Authors: Yang Fang , Gervasi Maria Gracia , Leu N. Adrian , Tourzani Darya A. , Ruthel Gordon , Visconti Pablo E. , Wang P. Jeremy
Published: July 2021

The CatSper cation channel is essential for sperm capacitation and male fertility. The multi-subunit CatSper complexes form highly organized calcium signaling nanodomains on flagellar membranes. Here we report identification of an uncharacterized protein C2CD6 as a novel subunit of the CatSper ion channel complex. C2CD6 contains a calcium-dependent membrane targeting C2 domain. C2CD6 interacts with the CatSper calcium-selective core forming subunits. Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility. C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo. Interestingly, transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore the fertilization capacity of C2CD6-deficient sperm in vitro. C2CD6 interacts with EFCAB9, a pH-dependent calcium sensor in the CatSper complex. We postulate that C2CD6 may regulate CatSper assembly, target the CatSper complex to flagellar plasma membrane, and function as a calcium sensor. The identification of C2CD6 as an essential subunit may facilitate the long-sought reconstitution of the CatSper ion channel complex in a heterologous system for male contraceptive development.
Grow or successfully disengage? Navigating the revolution of South African tower companies
Authors: Prim Sebastian , Samuelsson Mikael
Published: July 2021

Subject area of the teaching case:

The case is suitable for strategy or entrepreneurship modules. It is designed to teach students about the importance of implementing formal processes when entering a growth phase as well as the complexities, unexpected costs, and benefits that growing a business can bring.

Student level:

The case is aimed at MBA or Master-level students or executive education programmes as part of a strategy or entrepreneurship module.

Brief overview of the teaching case:

Lattice Towers is a South African company in the telecommunications infrastructure sector. They are struggling to generate sufficient cash flow to sustain operations as a result of poor strategic decision-making regarding tower-build site acquisition. To compound matters, the owner has been struggling with health issues related to the stress caused by the crises that Lattice Towers is going through. Recently, however, a multinational publicly listed behemoth in the telecommunications industry, Helios Towers, offered to acquire the company. The acquisition offer seems like a saving grace to the owner; however, Lattice Towers is deeply personal to the him and he would not like to lose the brand. Furthermore, there is a tremendous opportunity for business growth due to the imminent increase in demand for tower infrastructure. But based on the challenging financial position the business currently finds itself in, he might not have the option to keep the business.

Expected learning outcomes:

To develop a decision-making framework and strategy to navigate the business life-cycle stages, from survival to growth

Understand the concepts of uncertainty, risk, and liquidity premiums that apply to entrepreneurship

Understand the stress-related implications for entrepreneurs

Understand the psychological costs and benefits of entrepreneurship

Understand the personal financial implications for entrepreneurship
Epidemics and Chinese firms' stock returns: is COVID-19 different?
Authors: Nguyen Quang Thi Thieu , Anh Dao Le Trang , Gan Christopher
Published: July 2021

Purpose

This study investigates the Chinese stocks' returns during different epidemic periods to assess their effects on firms' market performance.

Design/methodology/approach

The study employs an event study method on more than 3,000 firms listed on Shanghai and Shenzhen stock exchanges during periods of SARS, H5N1, H7N9 and COVID-19

Findings

Epidemics' effect on firms' stock returns is persistent up to 10 days after the event dates. Although the impact varies with types and development of the disease, most firms experience a negative impact of the epidemics. Among the epidemics, COVID-19 has the greatest impact, especially when it grows into a pandemic. The epidemics' impact is uneven across industries. In addition, B-shares and stocks listed on Shanghai Stock Exchange are more negatively influenced by the epidemic than A-shares and those listed on Shenzhen Stock Exchange.

Research limitations/implications

The results of the study contribute to the limited literature on the effects of disease outbreaks as an economic shock on firm market performance. Given the possibility of other epidemics in the future, the study provides guidance for investors in designing an appropriate investing strategy to cope with the epidemic shocks to the market.

Originality/value

The research is novel in the way it compares and assesses the economic impact of different epidemics on firms and considers their impact at different development stages.
The Covid-19 pandemic and technical efficiency of Russian firms: a stochastic frontier production function approach
Authors: Singh Parul , Arora Kashika , Siddiqui Areej Aftab
Published: July 2021

Purpose

This paper aims to undertake the efficiency analysis in the form of stochastic frontier to estimate a Cobb–Douglas production function by controlling for the heterogeneity across Russian firms by including firm size, ownership, age, innovation activity and market competition.

Design/methodology/approach

During the peak period of Covid-19, certain firms witnessed either a decrease or increase in sales. Using this segregation of firms from World Bank’s Covid-19 impact surveys follow-up to the Enterprise Survey for Russia, this study empirically investigates the determinants of technical efficiency of these firms focusing on the role of government assistance.

Findings

The findings suggest that by segregating firms in terms of sales, different internal factors can enable in steering through pandemic situation besides just depending on external assistance.

Originality/value

One of the few papers to analyse the impact of the pandemic on Russian firms by considering World Bank Covid Survey.
Key factors of entrepreneurial university transformation: a model development using ISM method and MICMAC analysis
Authors: Novela Selly , Syarief Rizal , Fahmi Idqan , Arkeman Yandra
Published: July 2021

Purpose

This study aims to develop a new entrepreneurial university model that will provide a comprehensive picture and explain how universities can become entrepreneurial by considering several factors, both internal and external.

Design/methodology/approach

This research collected data by conducting a survey and elaborates on the judgments of informants who are experts in their fields. The gathered data were analyzed with the ISM method and MICMAC analysis.

Findings

This study identifies key factors of entrepreneurial university transformation, specifically, five key success factors and one constraint factor.

Research limitations/implications

This study has limitations in terms of its in conducting interview techniques. Data collection, which should be maximized in producing agreement through focus group discussions, can more acutely identify factors through consensus.

Practical implications

This study provides an overview of how universities may transform, following a path to become entrepreneurial by paying attention to the factors driving this transformation. The model demonstrates that while the university plays a central role, the participation of other parties within the ecosystem is also important.

Originality/value

This modeling technique deconstructs a complex system into several sub-systems, so that it can be studied in greater depth. Using ISM and MICMAC, a hard system methodology, this study advances a different and more comprehensive model.
Leader moral disengagement and follower knowledge hiding. A moderated mediation model of follower Machiavellianism and trust in the leader
Authors: Erkutlu Hakan , Chafra Jamel
Published: July 2021

Purpose

This study aims to build a moderated mediation model to investigate the roles that trust in the leader and follower Machiavellianism can play in the relationship between moral disengagement of the leader and hiding of knowledge of the followers.

Design/methodology/approach

Data were gathered from eight universities in Turkey using a set of 72 matched leader (dean)–follower (faculty member) questionnaires. The hypotheses were tested with multiple regression, moderated regression and bootstrapping analyses.

Findings

The findings reveal that leader moral disengagement positively influences follower knowledge hiding, while trust in the leader mediates this influence and follower Machiavellianism not only moderates the relationship between leader moral disengagement and trust in the leader but also reduces the indirect relationship between leader moral disengagement and follower knowledge hiding through trust in the leader.

Research limitations/implications

Even though measurements of research variables were collected from different sources and with time separation, common method bias might have existed. Also, this research is carried out in a single cultural context posing the issue of the generalizability of our findings to other cultural contexts.

Originality/value

The main contribution of this study is to construct and investigate a conceptual model that focuses on the possible effect of moral disengagement of the leader on knowledge hiding by the followers. Also, by supporting the mediating role of trust in the leader, this research reveals that followers of leaders with high moral disengagement are more prone to indulge in the hiding of knowledge. Moreover, the moderating role of follower Machiavellianism, found in this study, provides an additional understanding that followers may vary in the degree to which they are sensitive to the leader's influence.
Role of religiosity and the mediating effect of luxury value perception in luxury purchase intention: a cross-cultural examination
Authors: Rehman Anis Ur , Al Shammari Serhan , Al-Mamary Yaser Hasan
Published: July 2021

Purpose

This study aims to explore the relationship between consumers’ religiosity, their perceived functional, individual and social value of luxury and their luxury purchase intention.

Design/methodology/approach

The proposed relationships were explored in an intercultural setting by using samples from two considerably different cultures, Saudi Arabia and India. The identified constructs were measured by adapting the established scales. Statistical tests including exploratory factor analysis, multi-group confirmatory factor analysis and covariance-based structural equation modeling were applied to test the conceptual model and research hypotheses.

Findings

The results show that religiosity is not found to be negatively related to luxury purchase intention in both samples. Moreover, it was found that the functional and social values produce positive mediating effects, whereas the individual values (materialism, hedonism) of luxury products negatively mediate the relationship between religiosity and consumer purchase intention.

Practical implications

This research suggests that a non-traditional strategy may be effective to market luxury goods to religious consumers such as suppressing the materialistic aspect to focus on the quality and functionality aspects of the products.

Originality/value

The role of luxury value perception as a mediator between religiosity and luxury purchase intentions has not been studied in the previous researches to the best of authors’ knowledge, and is therefore, the unique contribution of this study. This research addresses the gap in the existing body of knowledge by probing how religiosity effects perceptions of luxury value and resultant luxury purchase intention.
National risk assessment – the Croatian features
Authors: Cindori Sonja
Published: July 2021

Purpose

The purpose of this paper is to present the risk of the non-financial sector in Croatia concerning the threats of money laundering through the prism of national and supranational risk assessment. In addition to a brief overview of the financial sector, the specifics of the non-financial sector have been highlighted. This paper aims to emphasize the peculiarities of the non-financial sector, focusing on the consequences of arbitrary application on the right to professional secrecy and independence.

Design/methodology/approach

Specifics of the national risk assessment in Croatia have been analyzed using deductive and inductive methods. To provide an overview of the non-financial sector, the risk assessment at the supranational level has been discussed and compared with the national one. Particular attention has been paid to the areas of increased risk.

Findings

The effectiveness of risk assessment depends on several factors such as the characteristic of the sector being observed, the specifics of each profession or business, changes at the level of awareness-raising and efficient and coherent supervision. Most deficiencies were observed in the area of beneficial ownership identification, conducting due diligence, awareness of the risk exposure and permanent education.

Originality/value

By recognizing the risk profile faced by the non-financial sector, this paper seeks to point out their role as “Gatekeepers” that is far from being negligible. By analyzing the risk of money laundering in Croatia, the tendencies of harmonization with international standards are pointed out along with the occurrences indicated by the practice.
Entrepreneurial orientation, externalities and social entrepreneurship
Authors: Gauthier Jeffrey , Cohen David , Meyer Christopher R.
Published: July 2021

Purpose

The purpose of this paper is to consider how the dimensions of entrepreneurial orientation (EO) may support or diminish the creation of social value.

Design/methodology/approach

The approach applies Lumpkin and Dess’s multidimensional conceptualization of EO to the growing body of literature on social entrepreneurship.

Findings

Propositions on the effects of autonomy, competitive aggressiveness, innovativeness, proactiveness and risk-taking on social value creation are developed.

Research limitations/implications

The propositions offered in the paper suggest avenues for future empirical studies that seek to examine the impact of EO on social, rather than financial, performance.

Originality/value

A significant body of research has examined the relationship between EO and financial performance, but potential implications for social value creation remain unclear. This paper seeks to address this gap in understanding of EO and social entrepreneurship and argues that two components of EO may adversely impact the creation of social value.