bluuebunny/crossref_metadata_2025 huggingface dataset:
Cohesin still drives homologous recombination repair of DNA double-strand breaks in late mitosis
Authors: Ayra-Plasencia Jessel , Symington Lorraine , Machín Félix
Published: September 2023

The cohesin complex maintains sister chromatid cohesion from S phase to anaphase onset. Cohesin also plays roles in chromosome structure and DNA repair. At anaphase onset, the cohesin subunit Scc1 is cleaved to allow segregation in an orderly manner, although some residual cohesin subunits remain to maintain chromosome structure. Efficient DNA double-strand break (DSB) repair by homologous recombination (HR) with the sister chromatid also depends on cohesin. Here, we have tested whether residual cohesin is important during DSB repair in anaphase/telophase (late mitosis). Using the well-established MAT switching system, we first show that HR is molecularly functional in late mitosis, and then show that cohesin is required for its efficiency. During DSBs in late mitosis, the segregated sister loci get closer and have episodes of coalescence, which may favour repair by HR. Here, we also show that these cytological phenotypes also depend on cohesin. Finally, full-length Scc1 returns after DSBs in late mitosis, suggesting thatde novowidespread cohesin complexes can support these retrograde behaviours.
Assessing cortical excitability with electroencephalography: a pilot study with EEG-iTBS
Authors: Pellegrino Giovanni , Schuler Anna-Lisa , Cai Zhengchen , Marinazzo Daniele , Tecchio Franca , Ricci Lorenzo , Tombini Mario , di Lazzaro Vincenzo , Assenza Giovanni
Published: September 2023

Cortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). It remains to be investigated to what extent they scale with excitability and how they relate to each other. Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of cortical excitability and E/I of the stimulated hemisphere. M1 excitability and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. Enhancement of M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or consistency with each other. EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.
Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L
Authors: Barsoum Mirna , Sayadi-Boroujeni Roksaneh , Stenzel Alexander T. , Bussmann Philip , Lüscher-Firzlaff Juliane , Lüscher Bernhard
Published: September 2023

The trithorax protein ASH2L is essential for organismal and tissue development. As a subunit of COMPASS/KMT2 complexes, ASH2L is necessary for methylation of histone H3 lysine 4 (H3K4). Mono- and trimethylation at this site mark active enhancers and promoters, respectively, although the molecular relevance of H3K4 methylation is only partially understood. Due to the importance of ASH2L in all 6 COMPASS-like complexes and its long half-life, it has been difficult to define direct consequences. To overcome this limitation, we employed a PROTAC system, which allows the rapid degradation of ASH2L and addressing direct effects. Loss of ASH2L resulted in rapid inhibition of proliferation of mouse embryo fibroblasts. Shortly after ASH2L degradation, H3K4me3 decreased with its half-life revealing considerable variability between promoters. Subsequently, H3K4me1 increased at promoters and decreased at some enhancers. H3K27ac and H3K27me3, histone marks closely linked to H3K4 methylation, were affected with considerable delay. In parallel, chromatin compaction increased at promoters. Of note, nascent gene transcription was not affected early but overall RNA expression was deregulated late after ASH2L loss. Together, these findings suggest that downstream effects are ordered but relatively slow, despite the rapid loss of ASH2L and inactivation of KMT2 complexes. It appears that the systems that control gene transcription are well buffered and strong effects are only beginning to unfold after considerable delay.
Mapping the developmental potential of mouse inner ear organoids at single-cell resolution
Authors: Waldhaus Joerg , Jiang Linghua , Liu Liqian , Liu Jie , Duncan Robert Keith
Published: September 2023

Inner ear organoids recapitulate development and are intended to generate cell types of the otic lineage for applications such as basic science research and cell replacement strategies. Here, we use single-cell sequencing to study the cellular heterogeneity of late-stage mouse inner ear organoid sensory epithelia, which we validated by comparison with data sets of the mouse cochlea and vestibular epithelia. We resolved supporting cell sub-types, cochlear like hair cells, and vestibular Type I and Type II like hair cells. While cochlear like hair cells aligned best with an outer hair cell trajectory, vestibular like hair cells followed developmental trajectories similar toin vivoprograms branching into Type II and then Type I extrastriolar hair cells. These results highlight the transcriptional accuracy of the organoid developmental program but will also inform future strategies to improve synaptic connectivity and regional specification.
Multiplane HiLo microscopy with speckle illumination and non-local means denoising
Authors: Zheng Shuqi , Koyama Minoru , Mertz Jerome
Published: September 2023

Significance

HiLo microscopy synthesizes an optically-sectioned image from two images, one obtained with uniform and another with patterned illumination, such as laser speckle. Speckle-based HiLo has the advantage of being robust to aberrations, but is susceptible to residual speckle noise that is difficult to control. We present a computational method to reduce this residual noise without compromising spatial resolution. In addition, we improve the versatility of HiLo microscopy by enabling simultaneous multiplane imaging (here 9 planes).

Aim

Our goal is to perform fast, high contrast multiplane imaging with a conventional camera-based fluorescence microscope.

Approach

Multiplane HiLo imaging is achieved with the use of a single camera and z-splitter prism. Speckle noise reduction is based on the application of a non-local means (NLM) denoising method to perform ensemble averaging of speckle grains.

Results

We demonstrate the capabilities of multiplane HiLo with NLM denoising both with synthesized data and by imaging cardiac and brain activity in zebrafish larvae at 40 Hz frame rates.

Conclusions

Multiplane HiLo microscopy aided by NLM denoising provides a simple tool for fast, opticallysectioned volumetric imaging that can be of general utility for fluorescence imaging applications.
An actomyosin network organizes niche morphology and responds to feedback from recruited stem cells
Authors: Warder Bailey N. , Nelson Kara A. , Sui Justin , Anllo Lauren , DiNardo Stephen
Published: September 2023

Summary

Stem cells often rely on signals from a niche, which in many tissues adopts a precise morphology. What remains elusive is how niches are formed, and how morphology impacts function. To address this, we leverage theDrosophilagonadal niche, which affords genetic tractability and live-imaging. We have previously shown mechanisms dictating niche cell migration to their appropriate position within the gonad, and the resultant consequences on niche function. Here, we show that once positioned, niche cells robustly polarize filamentous actin (F-actin) and Non-muscle Myosin II (MyoII) towards neighboring germ cells. Actomyosin tension along the niche periphery generates a highly reproducible smoothened contour. Without contractility, niches are misshapen and exhibit defects in their ability to regulate germline stem cell behavior. We additionally show that germ cells aid in polarizing MyoII within niche cells, and that extrinsic input is required for niche morphogenesis and function. Our work reveals a feedback mechanism where stem cells shape the niche that guides their behavior.
Identification of functional white matter networks in BOLD fMRI
Authors: Eby Alexa L. , Remedios Lucas W. , Kim Michael E. , Li Muwei , Gao Yurui , Gore John C. , Schilling Kurt G. , Landman Bennett A.
Published: September 2023

White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer’s Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between subject populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.
Microglial 25-hydroxycholesterol mediates neuroinflammation and neurodegeneration in a tauopathy mouse model
Authors: Toral-Rios Danira , Long Justin M , Ulrich Jason D. , Yu Jinsheng , Strickland Michael R. , Han Xianlin , Holtzman David M , Cashikar Anil G , Paul Steven M
Published: September 2023

Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology.Ch25his a DAM gene encoding cholesterol 25-hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
Representational similarity supports rapid context retrieval during fear discrimination in ventral hippocampus
Authors: Rozeske Robert R. , Runtz Léonie , Keinath Alexandra T. , Sossin Aaron , Brandon Mark P.
Published: September 2023

The dorsal and ventral regions of the hippocampus (dCA1 and vCA1) are critical for contextual fear conditioning tasks, yet the dynamics of hippocampal neuronal representations during memory acquisition, retrieval, and extinction processes have yet to be fully elucidated. The canonical theory is that the hippocampus generates and retrieves spatial maps of contexts during memory acquisition and retrieval. It is hypothesized the hippocampus prevents memory interference by generating context representations that are dissimilar and the prediction follows that representation dissimilarity facilitates discrimination between contexts. Here, we developed a context fear memory retrieval task and combined it with 1-photon neuronal imaging in dCA1 and vCA1 of freely behaving mice to test this prediction. We identified several phenomena specific to vCA1. First, fear conditioning induced an immediate and strong representational change that was predictive of freezing behavior. During context discrimination, vCA1 representations of the threatening and neutral contexts became more similar. Third, during threatening context memory retrieval, vCA1 expressed rapid and strong context representations. These unexpected results suggest that representational similarity in vCA1 facilitates faster and more efficient network state transitions. In further support of this view, both phenomena of representational similarity and rapid context recall were no longer observed in vCA1 once fear behavior was extinguished. Together, these results reveal that vCA1 unexpectedly generates similar population codes, promoting faster transitions between network states essential for contextual fear memory retrieval.

Highlights

We established a novel context teleportation task that allows population level hippocampal recordings during key moments of threat memory acquisition, retrieval, and extinction.

The ventral region of CA1 (vCA1) exhibited the greatest change in neural representation during fear memory acquisition, compared to dorsal CA1 (dCA1).

After fear conditioning, representations for threatening and neutral contexts were more similar in vCA1 compared to dCA1, yet representational similarity in vCA1 supported rapid context memory retrieval.

Context fear memory extinction reversed the context representation in vCA1 to patterns observed prior to fear conditioning.

Graphical Abstract
Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
Authors: Devkota Sujan , Zhou Rui , Nagarajan Vaishnavi , Maesako Masato , Do Hung , Noorani Arshad , Overmeyer Caitlin , Bhattarai Sanjay , Douglas Justin T. , Saraf Anita , Miao Yinglong , Ackley Brian D. , Shi Yigong , Wolfe Michael S.
Published: September 2023

Alzheimer’s disease is characterized pathologically by cerebral deposition of 42-residue amyloid β-peptide (Aβ42), proteolytically produced from amyloid precursor protein (APP) by β- and γ-secretases.1Although mutations in APP and presenilin, the catalytic component of γ-secretase, cause familial Alzheimer’s disease (FAD), a role for Aβ42 as the primary disease driver has not been clearly established and remains controversial.2,3Here we show through comprehensive analysis of the multi-step proteolysis of APP substrate C99 by γ-secretase that FAD mutations are consistently deficient in early proteolytic events, not later events that produce secreted Aβ peptides. Cryo-electron microscopy revealed that a substrate mimetic traps γ-secretase at the transition state for intramembrane proteolysis, and this structure closely aligns with activated enzyme-substrate complex captured by molecular dynamics simulations.In silicosimulations and fluorescence lifetime imaging microscopy in cultured cells support stabilization by FAD mutations of enzyme-substrate and/or enzyme-intermediate complexes. Neuronal expression of C99 and/or presenilin-1 inCaenorabditis elegansled to age-dependent synaptic loss only when one of the transgenes carried an FAD mutation. Designed mutations that stabilize the enzyme-substrate complex and block proteolysis likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the released products—of γ-secretase cleavage of substrates in FAD pathogenesis.
Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration
Authors: Bedard Madigan L. , Murray Jackson G. , Huang Xi-Ping , Nowlan Alexandra C. , Conley Sara Y. , Mott Sarah E. , Loyack Samuel J. , Cline Calista A. , Clodfelter Caroline G. , Dasgupta Nabarun , Roth Bryan L. , McElligott Zoe A.
Published: September 2023

Xylazine has been found in the unregulated drug supply at increasing rates, usually in combination with fentanyl. It has become critical to understand its basic pharmacology, how it impacts behavior, and how it interacts with fentanyl in rodent models of opioid administration. Despite commentary from scientists, politicians, and public health officials, it is not known if xylazine impacts the efficacy of naloxone, the opioid receptor antagonist used to reverse opioid induced respiratory depression. Furthermore, few studies have examined the effects of xylazine alone, without co-administration of ketamine. Here, we examine the impact of xylazine alone and in combination with fentanyl on several key behaviors in male and female mice. We demonstrate differential locomotor responses by dose and sex to xylazine. Surprisingly, our results further indicate that naloxone precipitates withdrawal from xylazine and a fentanyl/xylazine combination, in both sexes, with enhanced sensitivity in females. Further, we show that xylazine is a full agonist at the kappa opioid receptor, a potential mechanism for its naloxone sensitivity.

One-Sentence Summary

We present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.
Unveiling a Novel Memory Center in Humans: Neurochemical Identification of theNucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology
Authors: Ávila Camila de , Gugula Anna , Trenk Aleksandra , Intorcia Anthony J. , Suazo Crystal , Nolz Jennifer , Plamondon Julie , Khatri Divyanshi , Tallant Lauren , Caron Alexandre , Błasiak Anna , Serrano Geidy E. , Beach Thomas G. , Gundlach Andrew L. , Mastroeni Diego F.
Published: September 2023

Background

Thenucleus incertus(NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle (4V) of the human brain with an ‘unknown’ function. More than a century later, the neuroanatomy of the NI including its forebrain target regions has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using several markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus.

Methods

Histochemical staining of serial, coronal sections (30 µm) of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal marker, microtubule-associated protein-2 (MAP2), two markers present in rat NI, glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in a major population of NI neurons in diverse species.RLN3and vesicular GABA transporter 1 (vGAT1) mRNA was detected by multiplex, fluorescence in situ hybridization. Postmortem pons sections containing the NI from an Alzheimer’s disease (AD) case were immunostained for phosphorylated-tau (AT8 antibody), to explore potential relevance to neurodegenerative diseases. Lastly, sections of human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR, as SST is expressed in interneurons targeted by RLN3 projections in rodents.

Results

In the dorsal, anterior-medial region of the human pons, neurons containing RLN3– and MAP2-IR, andRLN3/vGAT1mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67– and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3– and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3, and DG areas of the hippocampus, in the absence ofRLN3mRNA. In the DG, RLN3– and SST-IR were co-localized in a small population of neurons.

Conclusions

Aspects of the anatomy of the human NI are shared across species, including a population of RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.

Graphical Abstract

Created with BioRender.com
Context-dependent decision-making in the primate hippocampal-prefrontal circuit
Authors: Elston Thomas W. , Wallis Joni D.
Published: September 2023

What is good in one scenario might be bad in another. Despite the ubiquity of such contextual reasoning in everyday choice, how the brain flexibly utilizes different valuation schemes across contexts remains unknown. We addressed this question by monitoring neural activity from the hippocampus (HPC) and orbitofrontal cortex (OFC) of two monkeys performing a state-dependent choice task. We found that HPC neurons encoded state information as it became available and then, at the time of choice, relayed this information to OFC via theta synchronization. During choice, OFC represented value in a state-dependent manner: many OFC neurons uniquely coded for value in only one state but not the other. This suggests a functional dissociation whereby HPC encodes contextual information that is broadcast to OFC via theta synchronization to select a state-appropriate value subcircuit, thus allowing for contextual reasoning in value-based choice.
An adapted stem cell-derived microglia protocol for the study of microgliopathies and other neurological disorders
Authors: Dorion Marie-France , Casas Diana , Yaqubi Moein , Fleming Peter , Chen Carol X.-Q. , Piscopo Valerio E. C. , Nicouleau Michael , Goldsmith Taylor M. , Shlaifer Irina , MacDonald Adam , Dudley Roy W. R. , Hall Jeffrey A. , Antel Jack P. , Stratton Jo Anne , Durcan Thomas M. , Piana Roberta La , Healy Luke M.
Published: September 2023

Background

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a primary microgliopathy caused by pathogenic variants in the colony-stimulating factor 1 receptor (CSF1R) gene. Since CSF1R signaling is crucial for microglia development, survival and function, induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial defects caused by ALSP patient-specificCSF1Rvariants.

Methods

Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an ALSP patient carrying a c.2350G > A (p.V784M)CSF1Rvariant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL.

Results

The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to primary human microglia and with higher phagocytic and inflammatory competence at ∼3-fold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression. Finally, ALSP patient-derived cells showed surprisingly high phagocytic capacity, which was associated with higher lysosomal content.

Conclusions

We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenicCSF1Rvariant, with preliminary characterization pointing toward functional alterations in migratory and phagocytic activities.
SignEEG v1.0 : Multimodal Dataset with Electroencephalography and Hand-written Signature for Biometric Systems
Authors: Mishra Ashish Ranjan , Kumar Rakesh , Gupta Vibha , Prabhu Sameer , Upadhyay Richa , Chhipa Prakash Chandra , Rakesh Sumit , Mokayed Hamam , Chakladar Debashis Das , De Kanjar , Liwicki Marcus , Liwicki Foteini Simistira , Saini Rajkumar
Published: September 2023

Handwritten signatures in biometric authentication leverage unique individual characteristics for identification, offering high specificity through dynamic and static properties. However, this modality faces significant challenges from sophisticated forgery attempts, underscoring the need for enhanced security measures in common applications. To address forgery in signature-based biometric systems, integrating a forgery-resistant modality, namely, noninvasive electroencephalography (EEG), which captures unique brain activity patterns, can significantly enhance system robustness by leveraging multimodality’s strengths. By combining EEG, a physiological modality, with handwritten signatures, a behavioral modality, our approach capitalizes on the strengths of both, significantly fortifying the robustness of biometric systems through this multimodal integration. In addition, EEG’s resistance to replication offers a high-security level, making it a robust addition to user identification and verification. This study presents a new multimodalSignEEG v1.0dataset based on EEG and hand-drawn signatures from 70 subjects. EEG signals and hand-drawn signatures have been collected withEmotiv InsightandWacom Onesensors, respectively. The multimodal data consists of three paradigms based on mental, & motor imagery, and physical execution: i) thinking of the signaturés image, (ii) drawing the signature mentally, and (iii) drawing a signature physically. Extensive experiments have been conducted to establish a baseline with machine learning classifiers. The results demonstrate that multimodality in biometric systems significantly enhances robustness, achieving high reliability even with limited sample sizes. We release the raw, pre-processed data and easy-to-follow implementation details.
Structure-based discovery of CFTR potentiators and inhibitors
Authors: Liu Fangyu , Kaplan Anat Levit , Levring Jesper , Einsiedel Jürgen , Tiedt Stephanie , Distler Katharina , Omattage Natalie S. , Kondratov Ivan S. , Moroz Yurii S. , Pietz Harlan L. , Irwin John J. , Gmeiner Peter , Shoichet Brian K. , Chen Jue
Published: September 2023

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
Optineurin is involved in regulating macrophage responses during mycobacterial infection
Authors: Ramachandran Gopalakrishna , Yeruva Chaitanya Veena , Swarup Ghanshyam , Raghunand Tirumalai R.
Published: September 2023

Autophagy has emerged as a critical innate immune mechanism for host elimination of intracellular pathogens, however, the role of the autophagy receptor optineurin during mycobacterial infection is not fully understood. To address this lacuna, we infected bone marrow-derived macrophages (BMDMs) derived from Optn+/+and Optn-/-mice withMycobacterium smegmatis, and observed the infection outcome at sequential time points. While low multiplicity of infection (MOI) did not show any significant difference between BMDMs from the two groups, at high MOI Optn-/-mice-derived macrophages showed significantly lower colony forming unit counts, as well as lower cell counts at 12 h and 24 h post-infection. Quantification of cell numbers and nuclear morphologies at various time points post-infection indicated a markedly higher cell death in the optineurin-deficient macrophages. Optineurin-deficient macrophages showed significantly lower levels of the autophagosomal protein LC3-II upon infection, indicating a potential role for optineurin in regulating autophagy during mycobacterial infection. Moreover, when stimulated by bacterial LPS, optineurin deficient macrophages, showed altered levels of the inflammatory cytokine pro-IL-1β. These observations taken together suggest a novel regulatory role for optineurin during mycobacterial infection, with its deficiency leading to an impairment in macrophage responses.
Nucleosome repositioning in chronic lymphocytic leukemia
Authors: Piroeva Kristan V. , McDonald Charlotte , Xanthopoulos Charalampos , Fox Chelsea , Clarkson Christopher T. , Mallm Jan-Philipp , Vainshtein Yevhen , Ruje Luminita , Klett Lara C. , Stilgenbauer Stephan , Mertens Daniel , Kostareli Efterpi , Rippe Karsten , Teif Vladimir B.
Published: September 2023

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral blood B cells from patients with chronic lymphocytic leukemia (CLL) and healthy individuals at single-base-pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes—the nucleosome repeat length (NRL)—is shortened in CLL. This effect is stronger in the more aggressive IGHV-unmutated CLL subtype than in the IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites are linked to active chromatin remodeling and reduced DNA methylation. Nucleosomes lost or gained in CLL marks differential binding of 3D chromatin organizers such as CTCF as well as immune response–related transcription factors and delineated mechanisms of epigenetic deregulation. The principal component analysis of nucleosome occupancy in cancer-specific regions allowed the classification of samples between cancer subtypes and normal controls. Furthermore, patients could be better assigned to CLL subtypes according to differential nucleosome occupancy than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome repositioning detected in our study, such as changes in the NRL, can be exploited for liquid biopsy applications based on cell-free DNA to stratify patients and monitor disease progression.
Lean Six Sigma 4.0 – a framework and review for Lean Six Sigma practices in the digital era
Authors: Citybabu G. , Yamini S.
Published: September 2023

Purpose

Lean Six Sigma 4.0 has brought about a paradigm shift in customization, automation, value creation and digitalization to achieve excellence in human factors, operations and sustainable development. Despite its potential, LSS 4.0 is still in its nascent stage, with researchers striving to identify the key and relevant components of LSS in relation to Industry 4.0. The present study aims to address this knowledge gap through a literature review and subsequently provide a conceptual framework for LSS within the context of digital transformation.

Design/methodology/approach

In this study, the authors have conducted a thorough review of reputable articles published between 2011 and 2022, focusing on the integration of Lean Six Sigma (LSS) and Industry 4.0 (I4.0). By using appropriate keywords, the authors identified around 85 relevant articles. The main objective of this integrative literature review was to analyze and extract valuable knowledge from the existing literature on LSS and I4.0. Based on the authors’ findings, a conceptual framework was developed.

Findings

The review revealed the motivators, building blocks, tools and challenges of LSS 4.0. The conceptual framework delves into the key aspects of LSS 4.0, focusing on the dimensions of people, process and technology, as well as their subdimensions. These subdimensions serve as the building blocks for developing LSS 4.0 capabilities. The proposed framework visually represents the conceptualization and the relationships among its components.

Research limitations/implications

Only a few conceptual approaches to LSS are developed that include the concepts, new roles and elements of I4.0. As a result, this research investigates the gap in current LSS models preceding I4.0 and develops a conceptual framework to provide a novel and comprehensive summary of the new concepts and components driving nascent and current LSS practices in the digital era.

Practical implications

This study offers practical guidance for implementing LSS in the context of I4.0, emphasizing digital transformation. The findings highlight motivators, building blocks, tools, challenges and spread of LSS 4.0 practices, and present a conceptual framework of LSS 4.0. These insights can help organizations enhance their LSS capabilities and achieve excellence in human factors, operations and sustainable development.

Originality/value

This study aims to make a significant contribution to the model-building efforts of researchers focusing on LSS 4.0. By offering practical guidance, the points discussed in this study help enhance the implementation efforts of practitioners and organizations in the context of I4.0, with a specific focus on digital transformation. The guidance provided takes into account the perspectives of people, processes and technology, providing valuable insights for successful integration.
Construction of G2 continuous curve on point-cloud surface
Authors: Wang Kai , Wang Xiaoping
Published: September 2023

Purpose

The curve construction on surfaces is becoming more and more important in computer-aided design (CAD), computer graphics (CG) and the other related fields. This problem is often encountered in NC machining, tool path generation, automated fiber placement and so on. However, designing curves on curved surfaces is quite different from constructing a curve in Euclidean space. Therefore, the traditional methods of curve design are not suitable for constructing a continuous curve on surface. The authors need to perform interpolation directly on surface so that the final target curve is embedded into the given surface and also meets the continuous conditions.

Design/methodology/approach

Firstly, adopting a series of Hermite blending functions, the authors design a space curve passing the given knots on the point-cloud surface. Then, the authors construct a class of directrixes that are adopted to determine vector fields for projection. Finally, a complete G2 continuous curve embedded in point-cloud surfaces is constructed by solving the first-order ordinary differential equations (ODEs).

Findings

The authors’ main contribution is to overcome the problem of constructing G1 and G2 continuous curves on point-cloud surfaces and the authors’ schemes are based on the projection moving least square (MLS) surfaces and traditional differential geometric.

Originality/value

Based on the framework of projection MLS surfaces, a novel method to overcome the problem of constructing G2 continuous curves on point-cloud surfaces is proposed.
Development-ally focused: a review and reconceptualization of ally identity development
Authors: Martinez Larry , Sabat Isaac , Ruggs Enrica , Hamilton Kelly , Bergman Mindy , Dray Kelly
Published: September 2023

Purpose

Although allies have been shown to be effective at helping to ignite positive change for marginalized groups, the literature on ally identity development is fragmented.

Design/methodology/approach

We draw from developmental, contextual, and identity theories to review the existing literature and focus squarely on the ally experience, resulting in a synthesized process-based conceptualization of ally identity development.

Findings

At each stage, we discuss intrapersonal experiences individuals are likely to have internally, interpersonal experiences that are likely to occur with others, and catalysts for progression to subsequent stages. In doing so, we outline the multilevel factors that influence and are influenced by ally development in hopes of identifying what motivates or dissuades individuals from becoming more active allies.

Originality/value

We provide practitioners and scholars with a deeper understanding of the organizational and societal benefits associated with allyship behaviors, as well as tools for increasing their presence within organizations.
A dynamic capability view of career adaptation: an exploratory study
Authors: Finch David J. , Levallet Nadège , Saunders Chad , Field Evelyn , Ribeiro Jason , Raby Simon , Roberts Michael , Uzoka Faith-Michael , Campbell Alexandria
Published: September 2023

Purpose

Disruptive forces, such as the global pandemic and technological innovation, are leading to growing labor uncertainty. For organizations, being able to adapt is a key skill for employees, while adapting to different employment contexts is increasingly essential for career success. This study leverages career adaptability theory and integrated dynamic capabilities to isolate skills enabling career adaptation.

Design/methodology/approach

A qualitative study was conducted to develop a skills codebook using a Delphi technique to converge on career adaptation skills, which was validated against leading meta-skills frameworks and a purposeful sample of 15 occupational competency models.

Findings

The codebook phase identified 24 distinct meta-skills in 6 clusters: problem-solving, self-reliance, collaboration, communication, core literacies and core workplace skills. Findings confirmed that most of the skills identified by the experts were also present across the meta-skills frameworks.

Research limitations/implications

This study highlights research opportunities, including a recommendation to extend the codebook by conducting a large sample empirical study of occupational competency models.

Practical implications

Adaptive individuals remain attractive in the job market. With the proposed framework, individuals can systematically reflect on ways to develop career adaptation skills. Other stakeholders should support the development of skills that facilitate an individual's capacity to adapt to diverse employment contexts.

Originality/value

This study contributes to resolving the debate on skills contributing to career adaptation by combining the career adaptability theory and integrated dynamic capabilities, to produce a harmonized meta-skills codebook including labels, definitions and synonyms. This study validates the codebook against leading skills frameworks and occupational competency models.
Networking for innovation dynamics: a design-driven approach in the hospitality industry
Authors: Li Mimi , Xu Wenqing , Liu Weiwei , Cao Huiyi
Published: September 2023

Purpose

This study aims to explore the patterns and transformational dynamics of the executive–interpreter network in the innovation processes of small- and medium-sized enterprises in hospitality.

Design/methodology/approach

Grounded in social network theory and adopting a case-based approach, this study features a multi-case design focusing on three Chinese boutique hotels. Data were collected through Web page and document reviews, participant observations and semistructured interviews.

Findings

Results capture how executive–interpreter network dynamics contribute to innovation in small- and medium-sized hotels. Key factors in social networks (e.g. size, scope and strength) shift throughout innovation. This study presents a design-driven approach as a means of innovation. Findings also delineate the network development conditions under which innovation dynamically occurs in boutique hotels.

Practical implications

Practical implications center on how network dynamics help small- and medium-sized hotels innovate more effectively. These insights can assist hotel operators and prospective market entrants in improving their hotels’ performance and competitiveness.

Originality/value

This study blends social network theory with a design-driven approach to explore innovation mechanisms in small- and medium-sized hotels. It offers empirical evidence for practitioners regarding design-driven innovation. Findings enrich the body of knowledge on both design-driven innovation theory and hospitality innovation.
Taking stock of campus mentoring ecosystems: a peer assessment dialogue exercise
Authors: Packard Becky Wai-Ling , Montgomery Beronda L. , Mondisa Joi-Lynn
Published: September 2023

Purpose

The purpose of this study was to examine the experiences of multiple campus teams as they engaged in the assessment of their science, technology, engineering and mathematics (STEM) mentoring ecosystems within a peer assessment dialogue exercise.

Design/methodology/approach

This project utilized a qualitative multicase study method involving six campus teams, drawing upon completed inventory and visual mapping artefacts, session observations and debriefing interviews. The campuses included research universities, small colleges and minority-serving institutions (MSIs) across the United States of America. The authors analysed which features of the peer assessment dialogue exercise scaffolded participants' learning about ecosystem synergies and threats.

Findings

The results illustrated the benefit of instructor modelling, intra-team process time and multiple rounds of peer assessment. Participants gained new insights into their own campuses and an increased sense of possibility by dialoguing with peer campuses.

Research limitations/implications

This project involved teams from a small set of institutions, relying on observational and self-reported debriefing data. Future research could centre perspectives of institutional leaders.

Practical implications

The authors recommend dedicating time to the institutional assessment of mentoring ecosystems. Investing in a campus-wide mentoring infrastructure could align with campus equity goals.

Originality/value

In contrast to studies that have focussed solely on programmatic outcomes of mentoring, this study explored strategies to strengthen institutional mentoring ecosystems in higher education, with a focus on peer assessment, dialogue and learning exercises.
Cost optimization of acceptance sampling plan in a fuzzy supply chain environment
Authors: Thomas Julia T. , Kumar Mahesh
Published: September 2023

Purpose

The purpose of the paper is set to minimize the total cost of a manufacturing system when an acceptance sampling plan (ASP) is carried out in a fuzzy environment.

Design/methodology/approach

A fuzzy acceptance sampling plan (FASP) is employed for the inspection of the batch of products and a fuzzy cost optimization problem is formulated.

Findings

The extent of uncertainty determines an interval for the total cost function with upper and lower bounds. The effect of variation in the ambiguity of the proportion of defectives in the probability of acceptance is determined.

Practical implications

The proposed model is specifically designed for production and supply units with ASP for attributes. Still, the proportion of defectives in the inspection process is fuzzy.

Originality/value

Fuzzy probability distribution is used to model an optimal inspection plan for a general supply chain. Economic design of supply chain under fuzzy proportion of defectives is discussed for the first time.
A real-time discovery method for vehicle companion via service collaboration
Authors: Zhang Zhongmei , Hu Qingyang , Hou Guanxin , Zhang Shuai
Published: September 2023

Purpose

Vehicle companion is one of the most common companion patterns in daily life, which has great value to accident investigation, group tracking, carpooling recommendation and road planning. Due to the complexity and large scale of vehicle sensor streaming data, existing work were difficult to ensure the efficiency and effectiveness of real-time vehicle companion discovery (VCD). This paper aims to provide a high-quality and low-cost method to discover vehicle companions in real time.

Design/methodology/approach

This paper provides a real-time VCD method based on pro-active data service collaboration. This study makes use of dynamic service collaboration to selectively process data produced by relative sensors, and relax the temporal and spatial constraints of vehicle companion pattern for discovering more potential companion vehicles.

Findings

Experiments based on real and simulated data show that the method can discover 67% more companion vehicles, with 62% less response time comparing with centralized method.

Originality/value

To reduce the amount of processing streaming data, this study provides a Service Collaboration-based Vehicle Companion Discovery method based on proactive data service model. And this study provides a new definition of vehicle companion through relaxing the temporal and spatial constraints for discover companion vehicles as many as possible.