bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-Concussion Assessment as a diagnostic and mechanistic framework for treating patients with Long COVID
Authors: Davidson Bradley S. , Noteboom Lily , Pierro Hannah , Kantor Cayce , Stoot Daniel , Stoot Fred , Linseman Daniel , Hale Troy , Gorgens Kim
Published: September 2022

Introduction

Despite first coming into view over two years ago, effective diagnostic and treatment pathways for Long COVID continue to evade the medical community. The overlap in neurological-based symptoms and neuroinflammatory origin indicates that the framework of post-concussion syndrome may provide insight into new diagnostics and treatment for patients with Long COVID. The objective of this investigation was to determine whether tools from the four common domains of concussion assessment were sensitive to differentiate between patients with Long COVID from a reference group who was infected with Sars-CoV-2 and does not have Long COVID.

Methods

In this prospective cohort design, each participant self reported their group (Acute, n=28) and Long COVID Group (n=33). Each participant underwent an examination in four assessment categories: symptoms, vestibular nystagmography, Automated Neuropsychological Assessment Metrics (ANAM), and a series of balance tasks.

Results

Total Symptom scores were separated into functional classifications and showed clear success as a tool to differentiate between Acute and Long COVID. Five of the 33 people in the Long COVID had detectable central lesions, which increases the risk of developing long COVID by 64% (Relative Risk=1.64). A wide variety of objective and quantitative measures from post-concussion care are sensitive to the Long COVID condition. Prolonged latency during random saccades eye tracking was present (p<0.01, d=0.87) in the Long COVID group corresponding to the King-Devick rapid reading test, which was highly sensitive to Long COVID (p<0.01, d=1.34). ANAM reaction time subtests had similarly large effects (p<0.01, d=0.93-1.09). Balance performance with corrupted sensory feedback was also sensitive (p<0.01, d=0.96).

Discussion

Our results indicate that long-standing and validated post-concussion symptom questionnaires may be used for quantifying the severity of Long COVID. Some of the most sensitive measures (especially the King-Devick rapid reading test) are easy to implement clinically and may be effective at tracking patient progress in the context of Long COVID treatment. The results point to wide deficits in motor integration and provide a rationale for treating the subset of Long COVID patients with similar rehabilitation strategies as patients with post-concussion syndrome.
Contractile work and biarticular mechanisms of the triceps surae muscles facilitate net ankle mechanical work at high walking speeds
Authors: Kharazi Mohamadreza , Bohm Sebastian , Theodorakis Christos , Mersmann Falk , Arampatzis Adamantios
Published: September 2022

Increasing walking speed is accompanied by an enhancement of the mechanical power and work performed at the ankle joint despite the decrease of the intrinsic muscle force potential. We measured Achilles tendon (AT) elongation and, based on an experimentally determined AT-force-elongation relationship; we quantified AT-force as a proxy of the triceps surae muscle force at four walking speeds (slow 0.7 m.s-1, preferred 1.4 m.s-1, transition 2.0 m.s-1 and maximum 2.6±0.3 m.s-1). Further, we investigated the mechanical power and work of the triceps surae muscles at the ankle joint (TSA) and the mechanical power and work of the biarticular gastrocnemii at the ankle and knee joint. We found a ~21% decrease of maximum AT-force at the two higher speeds compared to the preferred; however, the net TSA-work increased as a function of walking speed. An earlier plantarflexion accompanied by increased activation of the triceps surae muscles and a knee-to-ankle energy transfer via the biarticular gastrocnemii enhanced the net TSA-mechanical work by 1.7 and 2.4-fold in the transition and maximum walking speeds, respectively. Our findings provide first time evidence for different mechanistic participation of the monoarticular soleus muscle and the biarticular gastrocnemii for the speed-related enhancement of net TSA-work.
Hydraulic tradeoffs underlie enhanced performance of polyploid trees under soil water scarcity
Authors: Losada JM , Blanco-Moure N , Fonollá A , Martínez-Ferrí E , Hormaza JI
Published: September 2022

Polyploid trees are excellent candidates to reduce crop water footprint and mitigate the increasingly reduced availability of freshwater for irrigation in many regions of the world due to climate change. Yet, the relationships between aerial organ morpho-anatomy of woody polyploids with their functional hydraulics under water stress remain understudied.

We evaluated growth-associated traits, aerial organ xylem anatomy, and physiological parameters of diploid, triploid, and tetraploid genotypes of the woody perennial genus Annona (Annonaceae), testing their performance under long-term soil water reduction.

Polyploids displayed contrasting phenotypes, vigorous triploids and dwarf tetraploids, but consistently showed stomatal size-density trade-off. The vessel elements in aerial organs were ∼1.5 times wider in polyploids compared with diploids, but triploids displayed the lowest vessel density. Sap flow velocity, measured in vivo through a novel method, was 10-fold faster in flower carpels than in second leaf vein orders. Triploid leaves displayed the slowest velocity in the leaves but the fastest in the carpels. Plant hydraulic conductance was higher in well-irrigated diploids at the cost of consuming more belowground water, but diploids showed less tolerance than polyploids to soil water deficit.

The phenotypic disparity of atemoya polyploids associates with contrasting leaf and stem xylem porosity traits that coordinate to regulate water balances between the trees and the belowground and aboveground environment. Polyploid trees displayed a better performance under soil water scarcity, opening the possibility for deeper research on the factors underlying this behaviour and use them for a more sustainable agricultural and forestry production.
End-to-End Differentiable Blind Tip Reconstruction for Noisy Atomic Force Microscopy Images
Authors: Matsunaga Yasuhiro , Fuchigami Sotaro , Ogane Tomonori , Takada Shoji
Published: September 2022

Observing the structural dynamics of biomolecules is vital to deepening our understanding of biomolecular functions. High-speed (HS) atomic force microscopy (AFM) is a powerful method to measure biomolecular behavior at near physiological conditions. In the AFM, measured image profiles on a molecular surface are distorted by the tip shape through the interactions between the tip and molecule. Once the tip shape is known, AFM images can be approximately deconvolved to reconstruct the surface geometry of the sample molecule. Thus, knowing the correct tip shape is an important issue in the AFM image analysis. The blind tip reconstruction (BTR) method developed by Villarrubia1 is an algorithm that estimates tip shape only from AFM images using mathematical morphology operators. While the BTR works perfectly for noise-free AFM images, the algorithm is susceptible to noise, or it is difficult to determine a threshold parameter against noise. To overcome this issue, we here propose an alternative BTR method, called end-to-end differentiable BTR, based on a modern machine learning approach. In the method, we introduce a loss function and a regularization term to prevent overfitting to noise, and the tip shape is optimized with automatic differentiation and backpropagations developed in deep learning frameworks. Using noisy pseudo-AFM images of myosin V motor domain as test cases, we show that our end-to-end differentiable BTR is robust against noise in AFM images. The method can also detect a double-tip shape and deconvolve doubled molecular images. Finally, application to real HS-AFM data of myosin V walking on an actin filament shows that the method can reconstruct the accurate surface geometry of actomyosin consistent with the structural model. Our method serves as a general post-processing for reconstructing hidden molecular surfaces from any AFM images. Codes are available at https://github.com/matsunagalab/differentiable_BTR.
A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation
Authors: Lothstein Katherine E. , Chen Fei , Mishra Pankaj , Smyth Danielle J. , Wu Wenhui , Lemenze Alexander , Kumamoto Yosuke , Maizels Rick M. , Gause William C.
Published: September 2022

Intestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-β mimic (TGM), an ES molecule secreted byHeligmosomoides polygyrus(Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in anin vivowound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. This included enhanced early accumulation and persistence of macrophages in TGM-treated wounds during the initial inflammatory phase. Additionally, the percentage of alternatively activated (M2) macrophages expressing CD206 was reduced with TGM treatment during early and mid-stage wound healing. scRNAseq analysis of TGM-treated wounds indicate upregulation of multiple wound healing-associated genes without expression of CD206 within macrophage subsets. Experiments with truncated TGM constructs revealed that the TGFβ-R binding domain was essential in enhancing the wound healing response. In summary, TGM can accelerate skin wound healing and pro-restorative maturation through its interaction with the TGF-β receptor and stimulate the recruitment and reprogramming of specific macrophage subsets. This study indicates a role for TGM as a potential novel therapeutic option for enhanced wound healing.

One-Sentence Summary

A helminth-derived protein leads to rapid wound closure, skin regeneration, and reprogramming of macrophage activation through TGF-βR binding.
Design principles of 3D epigenetic memory systems
Authors: Owen Jeremy A. , Osmanović Dino , Mirny Leonid A.
Published: September 2022

The epigenetic state of a cell is associated with patterns of chemical modifications of histones (“marks”) across the genome, with different marks typical of active (euchromatic) and inactive (heterochromatic) genomic regions. These mark patterns can be stable over many cell generations—a form of epigenetic memory—despite their constant erosion due to replication and other processes. Enzymes that place histone marks are often stimulated by the same marks, as if “spreading” marks between neighboring histones. But this positive feedback may not be sufficient for stable memory, raising the question of what is. In this work, we show how 3D genome organization—in particular, the compartmental segregation of euchromatin and heterochromatin— could serve to stabilize an epigenetic memory, as long as (1) there is a large density difference between the compartments, (2) the modifying enzymes can spread marks in 3D, and (3) the enzymes are limited in abundance relative to their histone substrates. We introduce a biophysical model stylizing chromatin and its dynamics through the cell cycle, in which enzymes spread self-attracting marks on a polymer. We find that marks localize sharply and stably to the denser compartment, but over several cell generations, the model generically exhibits uncontrolled spread or global loss of marks. Strikingly, imposing limitation of the modifying enzymes—a plausible but oft-neglected element—totally changes this picture, yielding an epigenetic memory system, stable for hundreds of cell generations. Our model predicts a rich phenomenology to compare to experiments, and reveals basic design principles of putative epigenetic memory systems relying on compartmentalized 3D genome structure for their function.
Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in a Mouse Model of Parkinsonism
Authors: Chen Liqiang , Daniels Samuel , Dvorak Rachel , Chu Hong-Yuan
Published: September 2022

Degeneration of midbrain dopaminergic (DA) neurons causes a reduced motor output from the primary motor cortex (M1), underlying the motor symptoms of Parkinson’s disease (PD). However, cellular and circuitry mechanisms of M1 dysfunction in PD remain undefined. Using multidisciplinary approaches, we found that DA degeneration induces cell-subtype- and inputs-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. Physiological and anatomical analyses suggest that DA degeneration induces a loss of thalamocortical synapses to M1 PT neurons, resulting in an impaired thalamic driving of their activities. Moreover, we showed that the decreased thalamocortical connectivity are mediated by an excessive activation of NMDA receptors of M1 PT neurons. Further, the decreased thalamocortical transmission in parkinsonism can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that the reduced motor cortical outputs in parkinsonism are not only an immediate consequence of basal ganglia inhibition but also involves specific local circuitry adaptations within M1. This study reveals novel insight in the pathophysiology of parkinsonian motor deficits.
The Effect of Repeat Length on Marcal1-Dependent Single-Strand Annealing in Drosophila
Authors: Dewey Evan B. , Holsclaw Julie Korda , Saghaey Kiyarash , Wittmer Mackenzie E. , Sekelsky Jeff
Published: September 2022

Proper repair of DNA double strand breaks (DSBs) is essential to maintenance of genomic stability and avoidance of genetic disease. Organisms have many ways of repairing DSBs, including use of homologous sequences through homology-directed repair (HDR). While HDR repair is often error-free, in single-strand annealing (SSA) homologous repeats flanking a DSB are annealed to one another, leading to deletion of one repeat and the intervening sequences. Studies in yeast have shown a relationship between the length of the repeat and SSA efficacy. We sought to determine the effects of homology length on SSA in Drosophila, as Drosophila uses a different annealing enzyme (Marcal1) than yeast. Using an in vivo SSA assay, we show that 50 base pairs (bp) is insufficient to promote SSA and that 500-2000 bp is required for maximum efficiency. Loss of Marcal1 generally followed the same homology length trend as wild-type flies, with SSA frequencies reduced to about a third of wild-type frequencies regardless of homology length. Interestingly, we find a difference in SSA rates between 500 bp homologies that align to the annealing target either nearer or further from the DSB, a phenomenon that may be explained by Marcal1 dynamics. This study gives insights into Marcal1 function and provides important information to guide design of genome engineering strategies that use SSA to integrate linear DNA constructs into a chromosomal DSB.
Regulation of phage lambda packaging motor-DNA interactions: Nucleotide independent and dependent gripping and friction
Authors: Rawson Brandon , Ordyan Mariam , Yang Qin , Sippy Jean , Feiss Michael , Catalano Carlos E. , Smith Douglas E.
Published: September 2022

Many dsDNA viruses utilize ATP-powered “terminase” motors to package their genomes into procapsid shells. Here we use a single-molecule DNA grip/slip assay with rapid solution exchange to probe effects of nucleotide binding/dissociation in phage lambda motors containing both the large (TerL) and small (TerS) terminase subunits. Both subunits are required for packaging in vivo, but for some viruses (e.g., phages T4, HK97) packaging can be measured in vitro with only the catalytic TerL subunit. TerS facilitates initiation of packaging in vivo, but it has remained unclear if it plays any role during translocation. Surprisingly we measure frequent DNA gripping and high motor-DNA friction even in the absence of nucleotide. Such behavior was not observed in phage T4 motors containing only TerL, for which motor-DNA interactions were measured to be much weaker and significant gripping and friction was only observed with nucleotide present. For the lambda TerL/TerS holoenzyme, binding of nucleotide (ATP analogs or ADP) further increases gripping and friction, indicating there are both nucleotide independent and dependent interactions. Our findings suggest that TerS plays an important role in motor processivity, and that ATP-independent DNA gripping explains pausing observed during lambda packaging. We propose TerS acts as a “sliding clamp” to limit back slipping when TerL loses grip. Additionally, we show that the lambda packaging complex has a “DNA end clamp” mechanism that prevents the viral genome from completely exiting the capsid once packaging has initiated.
Impact of sample clarification by size exclusion on virus detection and diversity in wastewater-based epidemiology
Authors: Faleye Temitope O.C. , Skidmore Peter , Elyaderani Amir , Adhikari Sangeet , Kaiser Nicole , Smith Abriana , Yanez Allan , Perleberg Tyler , Driver Erin M. , Halden Rolf U. , Varsani Arvind , Scotch Matthew
Published: September 2022

The use of wastewater-based epidemiology (WBE) for early detection of virus circulation and response during the SARS-CoV-2 pandemic increased interest in and use of virus concentration protocols that are quick, scalable, and efficient. One such protocol involves sample clarification by size fractionation using either low-speed centrifugation to produce a clarified supernatant or membrane filtration to produce an initial filtrate depleted of solids, eukaryotes and bacterial present in wastewater (WW), followed by concentration of virus particles by ultrafiltration of the above. While this approach has been successful in identifying viruses from WW, it assumes that majority of the viruses of interest should be present in the fraction obtained by ultrafiltration of the initial filtrate, with negligible loss of viral particles and viral diversity.

We used WW samples collected in a population of ∼700,000 in southwest USA between October 2019 and March 2021, targeting three non-enveloped viruses (enteroviruses [EV], canine picornaviruses [CanPV], and human adenovirus 41 [Ad41]), to evaluate whether size fractionation of WW prior to ultrafiltration leads to appreciable differences in the virus presence and diversity determined.

We showed that virus presence or absence in WW samples in both portions (filter trapped solids [FTS] and filtrate) are not consistent with each other. We also found that in cases where virus was detected in both fractions, virus diversity (or types) captured either in FTS or filtrate were not consistent with each other. Hence, preferring one fraction of WW over the other can undermine the capacity of WBE to function as an early warning system and negatively impact the accurate representation of virus presence and diversity in a population.
Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein
Authors: Jelinska Clare , Kannan Srinivasaraghavan , Frosi Yuri , Ramlan Siti Radhiah , Winnerdy Fernaldo , Lakshminarayanan Rajamani , Brown Christopher J , Phan Anh-Tuan , Rhodes Daniela , Verma Chandra
Published: September 2022

The death domain associated protein 6 (DAXX) is frequently upregulated in a number of common cancers where its suppression has been linked to reduced tumour progression. As a master regulator protein, with >70 reported protein interaction partners, the role of DAXX in its oncogenecity remains unclear. We designed and developed a set of novel stapled/stitched peptides that target a surface on the N-terminal helical bundle domain of DAXX which is the anchor-point for binding to multiple interaction partners (including Rassf1C, P53, Mdm2 and ATRX) and also for the auto regulation of the DAXX N-terminal SUMO interaction motif (SIM). We demonstrate that these peptides bind to and inhibit DAXX with an affinity higher than those reported for the known interaction partners and release the auto-inhibited SIM for interaction with SUMO-1. NanoBret assays show that the peptides enter cells and that their intracellular concentrations remain at nanomolar levels even after 24 hours, without causing membrane perturbation. Together our data suggest that these peptides are both tools for probing the molecular interactions of DAXX and potential precursors to the development of therapeutics.
Structural and Dynamical Properties of Elastin-Like Peptides near their Lower Critical Solution Temperature
Authors: Morozova Tatiana I. , García Nicolás A. , Matsarskaia Olga , Roosen-Runge Felix , Barrat Jean-Louis
Published: September 2022

Elastin-like peptides (ELPs) are artificially derived intrinsically disordered proteins (IDPs) mimicking the hydrophobic repeat unit in the protein elastin. ELPs are characterized by a lower critical solution temperature (LCST) in aqueous media. Here, we investigate the sequence GVG(VPGVG)3over a wide range of temperatures (below, around, and above the LCST) and peptide concentrations employing all-atom molecular dynamics simulations, where we focus on the role of intra- and inter-peptide interactions. We begin by investigating the structural properties of a single peptide that demonstrates a hydrophobic collapse with temperature, albeit moderate, as the sequence length is short. We observe a change in the interaction between two peptides from repulsive to attractive with temperature by evaluating the potential of mean force, indicating an LCST-like behaviour. Next, we explore dynamical and structural properties of peptides in multi-chain systems. We report the formation of dynamical aggregates with coil-like conformation, in which Val central residues play an important role. Moreover, the lifetime of contacts between chains strongly depends on the temperature and can be described by a power-law decay that is consistent with the LCST-like behaviour. Finally, the peptide translational and internal motion are slowed down by an increase in the peptide concentration and temperature.
HNF1α transcriptional activation and repression maintain human islet α and β cell function
Authors: Qian Mollie F. , Bevacqua Romina J. , Nguyen Vy M. , Liu Xiong , Zhao Weichen , Chang Charles A. , Gu Xueying , Dai Xiao-Qing , MacDonald Patrick E. , Kim Seung K.
Published: September 2022

HNF1A haploinsufficiency underlies the most common form of human monogenic diabetes (HNF1A-MODY) and hypomorphic HNF1A variants confer type 2 diabetes risk, but a lack of experimental systems has limited our understanding of how the transcription factor HNF1α regulates adult human islet function. Here, we combined human islet genetics, RNA sequencing, Cleavage Under Targets & Release Using Nuclease (CUT&RUN) chromatin mapping, patch-clamp electrophysiology and transplantation-based assays to elucidate HNF1α-regulated mechanisms in mature pancreatic α and β cells. shRNA-mediated suppression of HNF1A in primary human pseudoislets led to blunted insulin output and dysregulated glucagon secretion both in vitro and after transplantation into immunocompromised mice, recapitulating phenotypes observed in HNF1A-MODY patients. These deficits corresponded with altered expression of genes encoding factors critical for hormone secretion, including calcium channel subunits, ATP-transporters and extracellular matrix constituents. Additionally, HNF1A loss led to upregulation of transcriptional repressors, providing evidence for a mechanism of transcriptional de-repression through HNF1α. CUT&RUN mapping of HNF1α DNA-binding sites in primary human islets verified that a subset of HNF1α-regulated genes were direct targets. These data provide unprecedented mechanistic links between HNF1A loss and diabetic phenotypes in mature human α and β cells.
Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA
Authors: Isaac R. Stefan , Tullius Thomas W. , Hansen Katja G. , Dubocanin Danilo , Couvillion Mary , Stergachis Andrew B. , Churchman L. Stirling
Published: September 2022

Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with the majority of nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication machinery and selectively form a triple-stranded D-loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro and acts via a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila
Authors: Quintero Maria , Bangi Erdem
Published: September 2022

Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types that make up a tissue is essential to ensure that all cell lineages are produced at appropriate numbers and to mount regenerative responses to injury, infection, and other environmental stresses. Cancer-driving alterations change the intrinsic properties of transformed cells and disrupt stem cell regulation, cell fate decisions, and cell-cell communication within transformed tissue. However, mechanisms by which these processes are disrupted and co-opted to support tumorigenesis are not well understood. Here, we report a novel genetic platform, PromoterSwitch, that allows targeting of genetic manipulations to a small subset of cells of any tissue or cell type of interest and all their subsequent progeny. We use this technology to generate large, transformed clones derived from individual stem/progenitor cells in the adult Drosophila intestine. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes drive disruptions in cell fate decisions within transformed clones and changes in the relative abundance of different intestinal cell lineages. We also uncover a critical, context-dependent role for the differentiated, hormone-producing enteroendocrine (EE) cells in the growth and maintenance of transformed clones. Our analysis in different genetic contexts provides insights into how the intrinsic properties of transformed cells —dictated by the genetic alterations they carry— determine their response to their environment and dependence on niche signals. A better mechanistic understanding of disruptions of cell-cell communication, stem cell regulation, and cell fate decisions within tumors could reveal novel vulnerabilities and druggable regulatory nodes that can be exploited for therapy. Understanding how tissues respond to the emergence of cells with cancer-driving genetic alterations also provides insights into stem cell biology and epithelial homeostasis.
Top-down design of protein nanomaterials with reinforcement learning
Authors: Lutz Isaac D. , Wang Shunzhi , Norn Christoffer , Borst Andrew J. , Zhao Yan Ting , Dosey Annie , Cao Longxing , Li Zhe , Baek Minkyung , King Neil P. , Ruohola-Baker Hannele , Baker David
Published: September 2022

The multisubunit protein assemblies that play critical roles in biology are the result of evolutionary selection for function of the entire assembly, and hence the subunits in structures such as icosahedral viral capsids often fit together with remarkable shape complementarity1,2. In contrast, the large multisubunit assemblies that have been created byde novoprotein design, notably the icosahedral nanocages used in a new generation of potent vaccines3–7, have been built by first designing symmetric oligomers with cyclic symmetry and then assembling these into nanocages while keeping the internal structure fixed8–14, which results in more porous structures with less extensive shape matching between the components. Such hierarchical “bottom-up” design approaches have the advantage that one interface can be designed and validated in the context of the cyclic oligomer building block15,16, but the disadvantage that the structural and functional features of the assemblies are limited by the properties of the predesigned building blocks. To overcome this limitation, we set out to develop a “top-down” reinforcement learning based approach to protein nanomaterial design in which both the structures of the subunits and the interactions between them are built up coordinately in the context of the entire assembly. We developed a Monte Carlo tree search (MCTS) method17,18which assembles protein monomer structures in the context of an overall architecture guided by a loss function which enables specification of any desired overall structural properties such as shape and porosity. We demonstrate the power of the approach by designing hyperstable icosahedral assemblies more compact than any previously observed protein icosahedral structure (designed or naturally occurring), that have very low porosity and are robust to fusion and display of proteins as complex as influenza hemagglutinin. CryoEM structures of two designs are very close to the computational design models. Our top-down reinforcement learning approach should enable the design of a wide variety of complex protein nanomaterials by direct optimization of overall system properties.
MRCK controls myosin II activation in the polarized cortex of mouse oocytes and promotes spindle rotation and male pronucleus centration
Authors: Bourdais Anne , Dehapiot Benoit , Halet Guillaume
Published: September 2022

Asymmetric meiotic divisions in oocytes rely on spindle positioning in close vicinity to the cortex. In mouse oocytes arrested at metaphase II, eccentric spindle positioning is associated with a chromatin-induced remodeling of the overlying cortex, including the build-up of an actin cap surrounded by a ring of activated myosin II. While the role of the actin cap in promoting polar body formation was demonstrated, the role of ring myosin II, and its mechanism of activation, have remained elusive. Here, we show that ring myosin II activation requires Myotonic dystrophy kinase-Related Cdc42-binding Kinase (MRCK), downstream of polarized Cdc42. During anaphase-II, inhibition of MRCK resulted in spindle rotation defects and a decreased rate of polar body emission. Remarkably, some oocytes eventually achieved spindle rotation by disengaging one cluster of chromatids from the anaphase spindle. We show that the MRCK/myosin II pathway also regulates the flattening of the fertilization cone to initiate male pronucleus centration. These findings provide novel insights into mammalian oocyte polarization and the role of cortical myosin II in orchestrating asymmetric division.
Impact of COVID-19 pandemic on the incidence of suicidal behaviors: a retrospective analysis of integrated electronic health records in a 7.5-million population
Authors: Valero-Bover Damià , Fradera Marc , Carot-Sans Gerard , Parra Isabel , Piera Jordi , Pontes Caridad , Palao Diego
Published: September 2022

The COVID-19 pandemic has caused a remarkable psychological overwhelming and an increase of stressors that may trigger suicidal behaviors. However, its impact on the rate of suicidal behaviors has been poorly reported. We conducted a population-based retrospective analysis of all suicidal behaviors attended in healthcare centers of Catalonia (North-East Spain; 7.5-million inhabitants) between January 2017 and June 2022. We retrieved data from the episode, including an assessment of suicide risk and the individual’s socioeconomic and clinical characteristics. Data were summarized yearly and for the periods before and after the onset of the COVID-19 pandemic in Spain in March 2020. The analysis included 26,458 episodes of suicidal behavior (21,920 individuals); of them, 16,414 (62.0%) were suicide attempts. The monthly moving average ranged between 300 and 400 episodes until July 2020, and progressively increased to over 600 episodes monthly. In the post-pandemic period, suicidal ideation increased at the expense of suicidal attempts. Cases showed a lower suicide risk; the percentage of females and younger individuals increased, whereas the prevalence of classical risk factors, such as living alone or lacking a family network and a history of psychiatric diagnosis, decreased. In summary, suicidal behaviors have increased during the COVID-19 pandemic, with more episodes of suicidal ideations without attempt and younger and lower risk profiles.
Activity-based directed evolution of a membrane editor in mammalian cells
Authors: Tei Reika , Bagde Saket R. , Fromme J. Christopher , Baskin Jeremy M.
Published: September 2022

Cellular membranes contain numerous lipid species, and efforts to understand the biological functions of individual lipids have been stymied by a lack of approaches for controlled modulation of membrane composition in situ. Here, we present a strategy for editing phospholipids, the most abundant lipids in biological membranes. Our membrane editor is based upon a bacterial phospholipase D (PLD), which exchanges phospholipid head groups through hydrolysis or transphosphatidylation of phosphatidylcholine with water or exogenous alcohols. Exploiting activity-dependent directed enzyme evolution in mammalian cells, we developed and structurally characterized a family of “superPLDs” with up to 100-fold higher activity than wildtype PLD. We demonstrated the utility of superPLDs for both optogenetics-enabled editing of phospholipids within specific organelle membranes in live cells and biocatalytic synthesis of natural and unnatural designer phospholipidsin vitro. Beyond the superPLDs, activity-based directed enzyme evolution in mammalian cells is a generalizable approach to engineer additional chemoenzymatic biomolecule editors.
Intravenous administration of human umbilical cord mesenchymal stromal cells leads to an inflammatory response in the lung
Authors: Pichardo Alejandra Hernandez , Wilm Bettina , Liptrott Neill , Murray Patricia
Published: September 2022

Mesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in pre-clinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The ability of MSCs to modulate immune responses has been proposed as one of the mechanisms by which these cells provide therapeutic benefits, irrespective of whether they are sourced from bone marrow, adipose tissue or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the percentage, distribution and phenotype of neutrophils, monocytes and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 h, we observed a sharp increase in neutrophils, and pro-inflammatory monocytes and macrophages. Moreover, these immune cells localised in the vicinity of the MSCs suggesting an active role in their clearance. By 24 h, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 h later.
The development of digital thread: the relations to digital twin and its industrial applications
Authors: Zhang Yuxin , Dong Wei , Wang Junyan , Che Congcong , Li Lefei
Published: September 2022

Purpose

Through this research study, the authors found that digital thread has made significant progress in the life cycle management of the US Air Force. The authors hope that by reviewing similar studies in the aerospace field, the meaning of digital thread can be summarized and applied to a wider range of fields. In addition, theoretically, the definition of digital twin and digital thread are not unified. The authors hope that the comparison of digital thread and digital twin will better enable scholars to distinguish between the two concepts. Besides, the authors are also looking forward that more people will realize the significance of digital thread and carry out future research.

Design/methodology/approach

Complete research about digital thread and the relevant concept of the digital twin is conducted. First, by searching in Google Scholar with the keyword “digital thread”, the authors filter results and save literature with high relevance to digital thread. The authors also track these papers’ references for more paper of digital thread and digital twin. After removing the duplicate and low-relevance literature, 72 digital thread-related literature studies are saved and further analyzed from the perspective of time development, application field and research directions.

Findings

Digital thread application in industries other than the aviation manufacturing industry is still relatively few, and the research on the application of digital thread in real industrial scenarios is mainly at the stage of framework design and design-side decision optimization. In addition, the digital thread needs a new management mechanism and organizational structure to realize landing. The new management mechanism and the process can adapt to the whole life cycle management process based on the digital thread, manage the data security and data update, and promote the digital thread to play a better effect on the organizational management.

Practical implications

Based on a review of digital thread, future research directions and usage suggestions are given. The fault diagnosis of high-speed train bogie as an example shows the effectiveness of the method and also partially demonstrates the advantages and effects brought by the digital thread connecting the data models at various stages.

Originality/value

This paper first investigates and analyzes the theoretical connotation and research progress of digital thread and gives a complete definition of digital thread from the perspective of the combination of digital thread and digital twins. Next, the research process of digital thread is reviewed, and the application fields, research directions and achievements in recent years are summarized. Finally, taking the fault diagnosis of high-speed train bogie as an example partially demonstrates the advantages and effects brought by the digital thread connecting the data models at various stages.
How technological, environmental and managerial performance contribute to the productivity change of Malaysian construction firms
Authors: Azman Mohd Azrai , Abdul-Samad Zulkiflee , Lee Boon L. , Skitmore Martin , Rajendra Darmicka , Chuweni Nor Nazihah
Published: September 2022

Purpose

Total factor productivity (TFP) change is an important driver of long-run economic growth in the construction sector. However, examining TFP alone is insufficient to identify the cause of TFP changes. Therefore, this paper employs the infrequently used Geometric Young Index (GYI) and stochastic frontier analysis (SFA) to measure and decompose the TFP Index (TFPI) at the firm-level from 2009 to 2018 based on Malaysian construction firms' data.

Design/methodology/approach

To improve the TFPI estimation, normally unobserved environmental variables were included in the GYI-TFPI model. These are the physical operation of the firm (inland versus marine operation) and regional locality (West Malaysia versus East Malaysia). Consequently, the complete components of TFPI (i.e. technological, environmental, managerial, and statistical noise) can be accurately decomposed.

Findings

The results reveal that TFP change is affected by technological stagnation and improvements in technical efficiency but a decline in scale-mix efficiency. Moreover, the effect of environmental efficiency on TFP is most profound. In this case, being a marine construction firm and operating in East Malaysia can reduce TFPI by up to 38%. The result, therefore, indicates the need for progressive policies to improve long-term productivity.

Practical implications

Monitoring and evaluating productivity change allows an informed decision to be made by managers/policy makers to improve firms' competitiveness. Incentives and policies to improve innovation, competition, training, removing unnecessary taxes and regulation on outputs (inputs) could enhance the technological, technical and scale-mix of resources. Furthermore, improving public infrastructure, particularly in East Malaysia could improve regionality locality in relation to the environmental index.

Originality/value

This study contributes to knowledge by demonstrating how TFP components can be completely modelled using an aggregator index with good axiomatic properties and SFA. In addition, this paper is the first to apply and include the GYI and environmental variables in modelling construction productivity, which is of crucial importance in formulating appropriate policies.
Food start-ups: leveraging digital marketing and disruptive information systems innovations to survive in the post-COVID environment
Authors: Almansour Mohammed
Published: September 2022

Purpose

The COVID-19 pandemic impacted the food and beverage sector very severely. The complete breakdown of the supply chain and lack of customers was particularly challenging for start-ups in the industry. Those that survived were the ones who made a timely and smooth transition in business models to become more technology driven. However, the issues faced and the ground realities of the extent of struggle that these start-ups went through are less understood in the scholarly literature, with most accounts being anecdotal. The purpose of this paper is to address these issues.

Design/methodology/approach

The present study attempts to bridge this gap by conducting a qualitative study to collect data from 35 owners/employees of food and beverage start-ups and using the grounded theory approach to code it and identify key themes.

Findings

Content analysis of the 35 responses revealed three main themes: the impact of the COVID-19 pandemic on operations of food and beverage start-ups, challenges due to the onset of the COVID-19 pandemic and combating the pandemic, divided into seven subthemes: differences in operations pre- and post-COVID, key changes experienced in operations post-COVID, problems arising in operations due to the pandemic, problems in the use of digital marketing due to the pandemic, problems in the use of technological platforms due to the pandemic, using innovative approaches and technological innovations and using disruptive technologies.

Originality/value

The study contributes novel insights by investigating the changes experienced by food and beverage start-ups due to the pandemic, the innovations introduced by them and the perception about the role of disruptive technologies in their postpandemic operations of food and beverage start-ups.
A field study of age discrimination in the workplace: the importance of gender and race‒pay the gap
Authors: Drydakis Nick , Paraskevopoulou Anna , Bozani Vasiliki
Published: September 2022

Purpose

The study examines whether age intersects with gender and race during the initial stage of the hiring process and affects access to vacancies outcomes and wage sorting.

Design/methodology/approach

In order to answer the research question, the study collects data from four simultaneous field experiments in England. The study compares the labour market outcomes of younger White British men with those of older White British men and women, and with those of older Black British men and women. The study concentrates on low-skilled vacancies in hospitality and sales in the private sector.

Findings

The results of this study indicate that older White British men and women, as well as older Black British men and women, experience occupational access constraints and are sorted into lower-paid jobs than younger White British men. The level of age discrimination is found to be higher for Black British men and women. In addition, Black British women experience the highest level of age discrimination. These patterns may well be in line with prejudices against racial minority groups and stereotypical sexist beliefs that the physical strengths and job performance of women decline earlier than those do for men.

Practical implications

If prejudices against older individuals are present, then anti-discrimination legislation may be the appropriate response, especially for racial minorities and women. Eliminating age discrimination in selection requires firms to adopt inclusive human resources (HR) policies at the earliest stages of the recruitment process.

Originality/value

This research presents for the first-time comparisons of access to vacancies and wage sorting between younger male racial majorities and older male racial majorities, older female racial majorities, older male racial minorities, and older female racial minorities. In addition, the driven mechanism of the assigned differences is explored. Because the study has attempted to minimise the negative employer stereotypesvis-à-visolder employees, with respect to the employees' motivation, productivity, and health, such prejudices against older individuals may be considered taste-based discrimination.
Looking back three decades of hospitality and tourism technology research: a bibliometric approach
Authors: Shin Hyejo Hailey , Shin Seunghun , Gim Jaehee
Published: September 2022

Purpose

This study aims to identify the knowledge development and thematic evolvement in hospitality and tourism technology research, and to suggest potential directions for studies in hospitality and tourism research.

Design/methodology/approach

A total of 440 technology articles published from 1990 to 2022 were retrieved from six top-tier journals. By using bibliometric analysis, 440 technology articles were analyzed to discover the proportion of technology research in the hospitality and tourism discipline, knowledge development, intellectual turning points and thematic evolvement of hospitality and tourism technology research.

Findings

The findings indicated that the proportion of technology research has continuously increased over the past three decades. The findings revealed the key intellectual turning points in technology research. The topical trends showed the popular topics of technology research for the 1990s, 2000s, 2010s and from 2020. The thematic map analysis results described how the major themes in technology research have evolved and shifted.

Research limitations/implications

By synthesizing past three decades of hospitality and tourism technology research, this study provides an overview of how technology research has evolved in the context of hospitality and tourism and offers suggestions for future studies on technology.

Originality/value

To the best knowledge of the authors’ knowledge, this study is the first bibliometric analysis focusing on technology research in the hospitality and tourism discipline, thereby providing a broad understanding of how technology research has developed in the discipline.