bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemoproteomics identifies proteoform-selective caspase-2 inhibitors
Authors: Castellón José O. , Ofori Samuel , Armenta Ernest , Burton Nikolas , Boatner Lisa M. , Takayoshi Evan E. , Faragalla Marina , Zhou Annie , Tran Ky , Shek Jeremy , Yan Tianyang , Desai Heta S. , Backus Keriann M.
Published: October 2023

Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all twelve human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive non-catalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and atobacco etch virus(TEV) protease activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2. Focused analogue synthesis combined with chemoproteomic target engagement analysis in cellular lysates and in cells yielded both pan-caspase reactive molecules and caspase-2 selective lead compounds together with a structurally matched inactive control. Application of this focused set of tool compounds to stratify caspase contributions to initiation of intrinsic apoptosis, supports compensatory caspase-9 activity in the context of caspase-2 inactivation. More broadly, our study highlights future opportunities for the development of proteoform-selective caspase inhibitors that target non-conserved and non-catalytic cysteine residues.
Cortico-thalamic communication for action coordination in a skilled motor sequence
Authors: Li Yi , An Xu , Mulcahey Patrick J. , Qian Yongjun , Xu X. Hermione , Zhao Shengli , Mohan Hemanth , Suryanarayana Shreyas M. , Bachschmid-Romano Ludovica , Brunel Nicolas , Whishaw Ian Q. , Huang Z. Josh
Published: October 2023

The coordination of forelimb and orofacial movements to compose an ethological reach-to-consume behavior likely involves neural communication across brain regions. Leveraging wide-field imaging and photo-inhibition to survey across the cortex, we identified a cortical network and a high-order motor area (MOs-c), which coordinate action progression in a mouse reach-and-withdraw-to-drink (RWD) behavior. Electrophysiology and photo-inhibition across multiple projection neuron types within the MOs-c revealed differential contributions of pyramidal tract and corticothalamic (CTMOs) output channels to action progression and hand-mouth coordination. Notably, CTMOsdisplay sustained firing throughout RWD sequence and selectively enhance RWD-relevant activity in postsynaptic thalamus neurons, which also contribute to action coordination. CTMOsreceive converging monosynaptic inputs from forelimb and orofacial sensorimotor areas and are reciprocally connected to thalamic neurons, which project back to the cortical network. Therefore, motor cortex corticothalamic channel may selectively amplify the thalamic integration of cortical and subcortical sensorimotor streams to coordinate a skilled motor sequence.
Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank
Authors: Hillary Robert F. , Gadd Danni A. , Kuncheva Zhana , Mangelis Tasos , Lin Tinchi , Ferber Kyle , McLaughlin Helen , Runz Heiko ,   Biogen Biobank Team, Marioni Riccardo E. , Foley Christopher N. , Sun Benjamin B.
Published: October 2023

Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1,468 proteins in 53,752 UK Biobank participants. A set of 683 independent vQTLs are identified across 571 proteins, all of which are newly discovered. They include 65 variants that lack conventional additive main effects on protein levels. Over 1,400 GEIs are identified between 142 proteins and 101 lifestyle and metabolic exposures. GEI analyses uncover biological mechanisms that explain why 13/65 vQTL-only sites lack corresponding main effects. Stratified analyses also highlight how age, sex and genotype can interact to modify relationships between biomarkers and health-related traits. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.
Analysis of Global Ischemic Heart Disease Burden from Multiple Perspectives
Authors: Wang Lian , Yan Xisheng , Xu Zhengwen
Published: October 2023

Background

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that poses a significant risk to human health. It has become essential to update the global prevalence, incidence, and mortality of IHD to examine secular trends.

Methods

The prevalence, incidence, death rates, and disability-adjusted life years (DALYs) of IHD were obtained from the Global Burden of Disease Study 2019 to assess the disease burden. We used joinpoint regression analysis to detect temporal changes and estimate the annual percent of change (APC) of each trend segment. The annual percentage change (EAPC) to access the temporal trends of the disease burden of IHD. Additionally, an analysis of the associated risk factors for IHD was conducted.

Results

The global number of IHD prevalence cases has increased from 96.90 million to 197.22 million, along with an increase in incidence, death, and DALYs from 1990 to 2019. After adjusting for age standardization, all indicators have shown a decrease. The decline was more pronounced among females. The number of IHD cases increased with age. In 1990 and 2019, the highest age-standardized prevalence rate (ASPR) of IHD was observed in North Africa, the Arabian Peninsula, and surrounding countries. The ASPR and age-standardized incidence rate (ASIR) of IHD were highest in low-middle SDI regions. High systolic blood pressure was the main driving force for IHD.

Conclusions

IHD has shown a decline in morbidity and mortality worldwide, but is on the rise in some less developed regions. The risk of incidence and death from IHD is higher in males. Paying more attention to the occurrence of IHD in the elderly is key to prevention. There exists a strong correlation between social development and the rates of morbidity and mortality associated with IHD. The inequity in global health is especially apparent in the context of this disease.
Effects of Different Intensity of Work Physical Activity on Sleep Disorder in Patients with Cholesterol
Authors: Cao Yiwen , Feng Rui
Published: October 2023

Background

High cholesterol level is an important risk factor for cardiovascular disease. We believe that it is important to improve sleep disorders in patients with hyperlipidemia by exploring the effects of different intensities of physical activity on patients with hyperlipidemia.

Objective

The purpose of this study is to explore the relationship between sleep disorder and different intensity of work physical activity in patients with high cholesterol.

Method and Materials

This study used a randomly selected American population from the National Health and Nutrition Survey (NHANES) from 2017 to 2018 as the survey sample, consisting of 1515 individuals (770 males and 745 females, with an average age of 60.53 ± 14.232 years). The Categorical variable uses the Chi-squared test, and the measurement variable uses the rank sum test to calculate the test statistics, which is considered statistically significant (two-sided test) with P<0.05. After single factor analysis, we take physical activity at work as independent variable, take statistically significant variables in Demography (gender, race, marital status, income poverty ratio, physical activity, current health status) as covariates, and take sleep disorder as dependent variable to conduct binary logistic regression analysis.

Results

After excluding all the confounding factors, there was a significant correlation between work physical activity and sleep disorder (P<0.001), and the OR was 1.251 (95% Cl: 1.096-1.429).

Conclusion

Physical activity at work is a risk factor for sleep disorder in patients with high cholesterol, and the increased risk of sleep disorder caused by intense physical activity at work is particularly obvious.
Online trend estimation and detection of trend deviations in sub-sewershed time series of SARS-CoV-2 RNA measured in wastewater
Authors: Ensor Katherine B. , Schedler Julia , Sun Thomas , Schneider Rebecca , Mulenga Anthony , Wu Jingjing , Stadler Lauren B. , Hopkins Loren
Published: October 2023

Wastewater surveillance has proven a key public health tool to understand a wide range of community health diseases and has proven to be especially critical to health departments throughout the SARS CoV-2 pandemic. The size of the population served by a wastewater treatment plant (WWTP) may limit the targeted insight about community disease dynamics. To investigate this concern, samples of wastewater were obtained at lift stations upstream of WWTPs within the sewer network. First, an online, semi-automatic time series model is fitted to the weekly measurements of WWTP samples to estimate the viral trend for the community and compared to the time series observations from the lift stations. Second, deviations from the WWTP trend are identified using an Exponentially Weighted Moving Average (EWMA) control chart. The analysis reveals that the lift stations display slightly different dynamics than the larger WWTP, highlighting the more granular insight gleaned from sampling sites which represent smaller populations. Discussion focuses on the use of our methods to support rapid public health decision-making based on additional, targeted samples in times of concern.
Cumulative Remnant Cholesterol as a causal risk factor for Ischemic Heart Disease: A Prospective Cohort Study
Authors: Zhao Xuemei , Wang Yifei , Li Wei , Gao Haibo , Wu Haotian , Yu Jiaxin , Wang Guiping , Wu Shouling , Liu Xiaokun
Published: October 2023

Background

While previous studies have established a significant correlation between baseline remnant cholesterol (RC) and ischemic heart disease (IHD), the enduring impact of RC on incident IHD remains to be elucidated. This study aimed to investigate the association between cumulative remnant cholesterol(cumRC) and IHD susceptibility.

Methods

Participating from the Kailuan Study (2006-2010) were enrolled, excluding those with prior myocardial infarction, coronary artery revascularization and cancer across three consecutive examinations. The cumRC derived by multiplying the average RC with the interval between the two consecutive assessments. Participants were segmented into quartiles based on cumRC levels: Q1 (cumRC<2.69mmol/l); Q2 (2.69≤cumRC<4.04mmol/l); Q3(4.04≤cumRC<5.65mmol/l) and Q4 (cumRC≥5.65mmol/l). The correlation between cumRC and IHD risk was ascertained by using multivariable Cox proportional hazard models.

Result

The analysis encompassed 42,639 participants. Over an average tracking period of 9.97 years, 1,205 instances of IHD were identified. IHD susceptibility augmented with rising cumRC quartiles. After adjusting for potential confounders, the hazard ratios for IHD events were 1.06 (0.88-1.29) for Q2, 1.30 (1.08-1.56) for Q3 and 1.69 (1.42-2.01) for Q4, relative to Q1. Elevated cumRC was significantly associated with a heightened IHD risk, a trend consistent in both subgroup and sensitivity analyses.

Conclusion

Elevated cumRC significantly correlates with a higher risk of IHD, suggesting that consistent monitoring and regulation of RC might be instrumental in IHD prevention.
Turn-On Protein Switches for Controlling Actin Binding in Cells
Authors: Effiong Unyime M. , Khairandish Hannah , Ramirez-Velez Isabela , Wang Yanran , Belardi Brian
Published: October 2023

Within a shared cytoplasm, filamentous actin (F-actin) plays numerous and critical roles across the cell body. Cells rely on actin-binding proteins (ABPs) to organize F-actin and to integrate its polymeric characteristics into diverse cellular processes. Yet, the multitude of ABPs that engage with and shape F-actin make studying a single ABP’s influence on cellular activities a significant challenge. Moreover, without a means of manipulating actin-binding subcellularly, harnessing the F-actin cytoskeleton for synthetic biology purposes remains elusive. Here, we describe a suite of designed proteins, Controllable Actin-binding Switch Tools (CASTs), whose actin-binding behavior can be controlled with external stimuli. CASTs were developed that respond to different external inputs, providing options for turn-on kinetics and enabling orthogonality. Being genetically encoded, we show that CASTs can be inserted into native protein sequences to control F-actin association locally and engineered into new structures to control cell and tissue shape and behavior.
Biosynthesis- and Metabolomics-guided discovery of antimicrobial cyclopeptides against drug-resistant clinical isolates
Authors: Cheng Zhuo , He Bei-Bei , Lei Kangfan , Gao Ying , Shi Yuqi , Zhong Zheng , Liu Hongyan , Liu Runze , Zhang Haili , Wu Song , Zhang Wenxuan , Tang Xiaoyu , Li Yong-Xin
Published: October 2023

Antimicrobial resistance remains a significant global threat, contributing significantly to mortality rates worldwide. Ribosomally synthesized and post-translationally modified peptides (RiPPs) have emerged as a promising source of novel peptide antibiotics due to their diverse chemical structures. Here, we reported the discovery of new Avi(Me)Cys-containing cyclopeptide antibiotics through a synergistic approach that combines rule-based genome mining, automated metabolomic analysis, and heterologous expression. We first bioinformatically identified 1,172 RiPP biosynthetic gene clusters (BGCs) responsible for Avi(Me)Cys-containing cyclopeptides from a vast pool of over 50,000 bacterial genomes. Subsequently, we successfully established the connection between three newly identified BGCs and the synthesis of five new peptide antibiotics. Notably, massatide A displayed excellent activity against a spectrum of gram-positive pathogens, including drug-resistant clinical isolates like linezolid-resistantS. aureusand methicillin-resistantS. aureus, with a minimum inhibitory concentration (MIC) of 0.25 μg/mL. The remarkable performance of massatide A in an animal infection model, coupled with a low risk of resistance and favorable safety profile, positions it as a promising candidate for antibiotic development. Our study highlights the potential of Avi(Me)Cys-containing cyclopeptides in expanding the arsenal of antibiotics against multi-drug-resistant bacteria, offering promising drug leads in the ongoing battle against infectious diseases.
Structure of the Thin Filament in Human iPSC-derived Cardiomyocytes and its Response to Heart Disease
Authors: Woldeyes Rahel A. , Nishiga Masataka , Vander Roest Alison S. , Engel Leeya , Giri Prerna , Montenegro Gabrielle C. , Dunn Alexander R. , Spudich James A. , Bernstein Daniel , Schmid Michael F. , Wu Joseph C. , Chiu Wah
Published: October 2023

Cardiovascular diseases are a leading cause of death worldwide, but our understanding of the underlying mechanisms is limited, in part because of the complexity of the cellular machinery that controls the heart muscle contraction cycle. Cryogenic electron tomography (cryo-ET) provides a way to visualize diverse cellular machinery while preserving contextual information like subcellular localization and transient complex formation, but this approach has not been widely applied to the study of heart muscle cells (cardiomyocytes). Here, we deploy an optimized cryo-ET platform that enables cellular-structural biology in human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). Using this platform, we reconstructed sub-nanometer resolution structures of the human cardiac muscle thin filament, a central component of the contractile machinery. Reconstructing the troponin complex, a regulatory component of the thin filament, from within cells, we identified previously unobserved conformations that highlight the structural flexibility of this regulatory complex. We next measured the impact of chemical and genetic perturbations associated with cardiovascular disease on the structure of troponin. In both cases, we found changes in troponin structure that are consistent with known disease phenotypes—highlighting the value of our approach for dissecting complex disease mechanisms in the cellular context.
Is developmental plasticity triggered by DNA methylation changes in the invasive cane toad (Rhinella marina)?
Authors: Yagound Boris , Sarma Roshmi R. , Edwards Richard J. , Richardson Mark F. , Lopez Carlos M. Rodriguez , Crossland Michael R. , Brown Gregory P. , DeVore Jayna L. , Shine Richard , Rollins Lee A.
Published: October 2023

Many organisms can adjust their development according to environmental conditions, including the presence of conspecifics. Although this developmental plasticity is common in amphibians, its underlying molecular mechanisms remain largely unknown. Exposure during development to either ‘cannibal cues’ from older conspecifics, or ‘alarm cues’ from injured conspecifics, causes reduced growth and survival in cane toad (Rhinella marina) tadpoles. Epigenetic modifications, such as changes in DNA methylation patterns, are a plausible mechanism underlying these developmental plastic responses. Here we tested this hypothesis, and asked whether cannibal cues and alarm cues trigger the same DNA methylation changes in developing cane toads. We found that exposure to both cannibal cues and alarm cues induced local changes in DNA methylation patterns. These DNA methylation changes affected genes putatively involved in developmental processes, but in different genomic regions for different conspecific-derived cues. Genetic background explained most of the epigenetic variation among individuals. Overall, the molecular mechanisms triggered by exposure to cannibal cues seem to differ from those triggered by alarm cues. Studies linking epigenetic modifications to transcriptional activity are needed to clarify the proximate mechanisms that regulate developmental plasticity in cane toads.
AToxoplasma gondiiO-glycosyltransferase that modulates bradyzoite cyst wall rigidity is structurally and functionally distinct from host homologues
Authors: Kumar Pranav , Tomita Tadakimi , Gerken Thomas A. , Ballard Collin J. , Lee Yong Sok , Weiss Louis M. , Samara Nadine L.
Published: October 2023

Infection with the Apicomplexan protozoanToxoplasma gondiican be life-threatening in immunocompromised hosts. Transmission frequently occurs through the oral ingestion ofT. gondiibradyzoite cysts, which transition to tachyzoites, disseminate, and then form cysts containing bradyzoites in the central nervous system, resulting in latent infection. There are currently no effective treatments to cure latent infection. Bradyzoites are encapsulated by a cyst wall that is critical for immune evasion, survival, and transmission. Cyst wall rigidity is influenced by the O-glycosylation of the mucin domain of the cyst wall protein CST1 by mucin-type O-glycosyltransferases (GalNAc-Ts). Here, we report the first structures of a protozoan GalNAc-T,T.gondii-GalNAc-T3 in the apo state and in complex with glycopeptide substrates. The structures reveal features that are strictly conserved in Apicomplexan homologues ofT.gondii-GalNAc-T3, including a unique 2ndmetal binding site that is coupled to substrate binding and enzymatic activityin vitroand cyst wall O-glycosylation inT. gondii. Additional structural features illustrate the divergence of GalNAc-Ts from parasite to host and highlight multiple druggable sites inT.gondii-GalNAc-T3 and its homologues in Apicomplexa that are responsible for a wide range of parasitic diseases.
Modularity of PRC1 Composition and Chromatin Interaction define Condensate Properties
Authors: Niekamp Stefan , Marr Sharon K. , Oei Theresa A. , Subramanian Radhika , Kingston Robert E.
Published: October 2023

Polycomb repressive complexes (PRC) play a key role in gene repression and are indispensable for proper development. Canonical PRC1 forms condensatesin vitroand in cells and the ability of PRC1 to form condensates has been proposed to contribute to maintenance of repression. However, how chromatin and the various subunits of PRC1 contribute to condensation is largely unexplored. Using single-molecule imaging, we demonstrate that nucleosomal arrays and PRC1 act synergistically, reducing the critical concentration required for condensation by more than 20-fold. By reconstituting and imaging PRC1 with various subunit compositions, we find that the exact combination of PHC and CBX subunits determine the initiation, morphology, stability, and dynamics of condensates. In particular, the polymerization activity of PHC2 strongly influences condensate dynamics to promote formation of structures with distinct domains that adhere to each other but do not coalesce. Using live cell imaging, we confirmed that CBX properties are critical for condensate initiation and that PHC polymerization is important to maintain stable condensates. Together, we propose that PRC1 can fine-tune the degree and type of condensation by altering its composition which might offer important flexibility of regulatory function during different stages of development.
KIF1C activates and extends dynein movement through the FHF cargo adaptor
Authors: Ali Ferdos Abid , Zwetsloot Alexander J. , Stone Caroline E. , Morgan Tomos E. , Wademan Richard F. , Carter Andrew P. , Straube Anne
Published: October 2023

Cellular cargos move bidirectionally on microtubules due to the presence of opposite polarity motors dynein and kinesin. Many studies show these motors are co-dependent, whereby one requires the activity of the other, although the mechanism is unknown. Here, using in vitro motility assays, we show that the kinesin-3 KIF1C acts both as an activator and a processivity factor for dynein. Activation only requires a fragment of the non-motor tail of KIF1C (KIF1C-stalk) to bind the cargo adaptor HOOK3. Cryo-EM, crosslinking mass spectrometry and AlphaFold2 predictions reveal this binding site to be separate from that of two constitutive factors (FTS and FHIP), which link HOOK3 to small G-proteins on cargos. We provide a structural model for how the FTS-HOOK3-FHIP1B (FHF) complex is auto-inhibited and explain how the KIF1C-stalk relieves this inhibition. Collectively, our work provides a molecular explanation for co-dependency by revealing that the mutual activation of dynein and kinesin is mediated through their shared adaptor. Many adaptors bind both dynein and kinesins, suggesting this mechanism could be generalised to other bidirectional complexes.
RpoS activates formation ofSalmonellaTyphi biofilms and drives persistence in the gall bladder
Authors: Desai Stuti K. , Zhou Yiyang , Dilawari Rahul , Routh Andrew L. , Popov Vsevolod , Kenney Linda J.
Published: October 2023

The development of strategies for targeting the asymptomatic carriage ofSalmonellaTyphi in chronic typhoid patients has suffered owing to our basic lack of understanding of the molecular mechanisms that enable the formation ofS.Typhi biofilms. Traditionally, studies have relied on cholesterol-attached biofilms formed by a closely related serovar, Typhimurium, to mimic multicellular Typhi communities formed on human gallstones. In long-term infections,S.Typhi adopts the biofilm lifestyle to persist in vivo and survive in the carrier state, ultimately leading to the spread of infections via the fecal-oral route of transmission. In the present work, we studiedS.Typhi biofilms directly, applied targeted as well as genome-wide genetic approaches to uncover unique biofilm components that do not conform to the CsgD-dependent pathway established inS.Typhimurium. We undertook a genome-wideTn5mutation screen in H58, a clinically relevant multidrug resistance strain ofS.Typhi, in gallstone-mimicking conditions. We generated New Generation Sequencing libraries based on the ClickSeq technology to identify the key regulators, IraP and RpoS, and the matrix components Sth fimbriae, Vi capsule and lipopolysaccharide. We discovered that the starvation sigma factor, RpoS, was required for the transcriptional activation of matrix-encoding genes in vitro, and forS.Typhi colonization in persistent infections in vivo, using a heterologous fish larval model. AnrpoSnull mutant failed to colonize the gall bladder in chronic zebrafish infections. Overall, our work uncovered a novel RpoS-driven, CsgD-independent paradigm for the formation of cholesterol-attached Typhi biofilms, and emphasized the role(s) of stress signaling pathways for adaptation in chronic infections. Our identification of the biofilm regulators inS.Typhi paves the way for the development of drugs against typhoid carriage, which will ultimately control the increased incidence of gall bladder cancer in typhoid carriers.
Nonequilibrium bending fluctuations reveal microtubule mechanicsin-vivoand their regulation by glutamylation
Authors: Nishi Kengo , Raja Sufi , Pham An , Freeman Ronit , Roll-Mecak Antonina , MacKintosh Fred C. , Schmidt Christoph F.
Published: October 2023

Cells can be described as active composite materials. The mechanical properties of cells are controlled by complex polymer networks and are dynamically tuned for diverse cellular processes driven by force-generating motor proteins. Microtubules are the most rigid protein polymers in the cytoskeleton, and their material properties have been measuredin vitroby active bending or by analyzing thermal bending fluctuations. Microtubule mechanics in living cells are extremely difficult to probe directly, while fluctuations are difficult to interpret because they are generated by active forces in a surrounding cytoplasm with poorly understood material properties. Here we introduce a method to measure the elastic properties of microtubules in living cells by making use of motor-generated forces that drive bending fluctuations. Bending dynamics are governed by three main factors: microtubule material properties, cytoskeletal active forces, and the response characteristics of the surrounding cytoplasm. We show theoretically that, when one factor can be independently determined, the other two can be derived from observed fluctuations. Using this method we discovered that polyglutamylation, a post-translational modification enriched on microtubule arrays that need to withstand large mechanical forces such as those in axons or cilia, increases microtubule stiffness in living cells. Our work provides a theoretical and experimental framework to study microtubule mechanics and their regulation by tubulin modifications and microtubule effectors in complex cellular environments. The approach can be extended to other large aspect ratio cellular structures such as the endoplasmic reticulum or the mitochondrial network.
ARF1 compartments direct cargo flow via maturation into recycling endosomes
Authors: Stockhammer Alexander , Adarska Petia , Natalia Vini , Heuhsen Anja , Klemt Antonia , Bregu Gresy , Harel Shelly , Rodilla-Ramirez Carmen , Spalt Carissa , Oezsoy Ece , Leupold Paula , Grindel Alica , Fox Eleanor , Mejedo Joy O , Zehtabian Amin , Ewers Helge , Puchkov Dmytro , Haucke Volker , Bottanelli Francesca
Published: October 2023

Cellular membrane homeostasis is maintained via a tightly regulated membrane and cargo flow between organelles of the endocytic and secretory pathways. Adaptor protein complexes (APs), which are recruited to membranes by the small GTPase ARF1, facilitate cargo selection and incorporation into trafficking intermediates. According to the classical model, small vesicles would facilitate bi-directional long-range transport between the Golgi, endosomes and plasma membrane. Here we revisit the intracellular organization of the vesicular transport machinery using a combination of CRISPR-Cas9 gene editing, live-cell high temporal (fast-confocal) or spatial (stimulated emission depletion (STED)) microscopy as well as correlative light and electron microscopy. We characterize novel tubulo-vesicular ARF1 compartments that harbor clathrin and different APs. Our findings reveal two functionally different classes of ARF1 compartments, each decorated by a different combination of APs. Perinuclear ARF1 compartments facilitate Golgi export of secretory cargo, while peripheral ARF1 compartments are involved in endocytic recycling downstream of early endosomes. Contrary to the classical model of long-range vesicle shuttling, we observe that ARF1 compartments shed ARF1 and mature into recycling endosomes. This maturation process is impaired in the absence of AP-1 and results in trafficking defects. Collectively, these data highlight a crucial role for ARF1 compartments in post-Golgi sorting.
A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer
Authors: Zheng Jia-Hao , Zhu Yu-Heng , Yang Jian , Ji Pei-Xuan , Zhao Rui-Kang , Duan Zong-Hao , Yao Hong-Fei , Jia Qin-Yuan , Yin Yi-Fan , Hu Li-Peng , Li Qing , Jiang Shu-Heng , Huo Yan-Miao , Liu Wei , Sun Yong-Wei , Liu De-Jun
Published: October 2023

BACKGROUND & AIMS

PDAC is characterized by significant matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, it is not clear the connection between matrix stiffness and the Warburg effect and the mechanisms of action in tumor progression.

METHODS

The relationship between matrix stiffness and the Warburg effect was investigated from clinical, cellular, and bioinformatical perspectives. The ChIP and luciferase reporter gene assays were used to clarify the regulation mechanism of matrix stiffness on the expression of CLIC1. The expression profile and clinical significance of CLIC1 were determined in GEO datasets and a TMA. Loss-of-function and gain-of-function technics were used to determine thein vitroandin vivofunctions of CLIC1. GSEA and western blotting revealed the underlying molecular mechanisms.

RESULTS

PDAC matrix stiffness is closely associated with the Warburg effect, and CLIC1 is a key molecule connecting tumor matrix stiffness and the Warburg effect. Increased CLIC1 expression induced by matrix stiffness correlates with poor prognosis in PDAC. CLIC1 acts as a promoter of glycolytic metabolism and facilitates tumor growth in a glycolysis-dependent manner. Mechanistically, CLIC1 inhibits the hydroxylation of HIF1α via ROS, which then increases the stability of HIF1α. Collectively, PDAC cells can sense extracellular matrix stiffness and upregulate the expression of CLIC1, which facilitates the Warburg effect through ROS/HIF1α signaling, thereby supporting tumor growth.

CONCLUSIONS

In the context of tumor therapy, targeted approaches can be considered from the perspectives of both extracellular matrix stiffness and tumor metabolism, of which CLIC1 is one of the targets.
Prioritizing the principles of circular economy among built environment professionals
Authors: Agyekum Kofi , Amudjie Judith , Pittri Hayford , Dompey Annabel Morkporkpor Ami , Botchway Edward Ayebeng
Published: October 2023

Purpose

Circular economy (CE) is guided by principles, the key being the R-framework. All R-frameworks have a hierarchy. Although several studies have prioritized these principles, there is still an urgent call for country-specific prioritization. This study prioritized circular economy (CE) principles among Ghana's built environment (BE) professionals.

Design/methodology/approach

An explanatory sequential mixed methods approach was adopted. Six principles of CE were identified through a review of related literature and incorporated into a questionnaire. In total, 162 questionnaire responses were received. The quantitative data were analyzed through descriptive and inferential analyses. The data were further validated via semi-structured interviews with eight interviewees of different professional backgrounds in the BE.

Findings

The findings revealed that BE professionals in Ghana highly perceived CE principles as important. The findings further revealed the order of prioritization of the CE principles as follows: (1) recycle, (2) reuse, (3) repair/remanufacture, (4) renewable energy usage, (5) redesign and (6) reduce. To further elaborate on these prioritized principles via the qualitative phase, the interviewees agreed to and confirmed the importance of the identified principles through their verbatim comments.

Originality/value

Although there is a growing interest in research regarding CE in the Ghanaian construction industry, its principles have yet to be prioritized and ranked by professionals in the Ghanaian construction industry. This study unearths why, in terms of prioritization of the CE principles, the construction industry in Ghana does not follow the well-known hierarchy (i.e. reduce, reuse and recycle) in the order of high to low level of circularity.
Audit committee attributes, board of director’s independence and energy disclosure for environmental sustainability in Nigeria
Authors: Jibril Rabiu Saminu , Isa Muhammad Aminu , Maigoshi Zaharaddeen Salisu , Hamid Kabir Tahir
Published: October 2023

Purpose

This study aims to examine how audit committee (AC) attributes influence quality and quantity disclosure of energy consumed by the listed nonfinancial firms for the period of five years (2016–2020). The study aims at providing empirical evidence on how board of director’s independence influences the relationship between AC attributes and firms’ energy in achieving sustainable development goals (SDGs) on world climate policy.

Design/methodology/approach

The study obtained data from a sample of 83 listed nonfinancial firms, content analysis technique was used to compute energy disclosure indexes using global reporting initiative standards, while regression analysis was conducted to test the relationship among research variables.

Findings

The study revealed that AC independence, diversity and meetings were significantly related with energy disclosure. Also, the study found that other variables were insignificantly related with energy disclosure.

Research limitations/implications

The study is constrained for not considering all listed firms in the country. Furthermore, the study considered selected attributes, other important audit-committee size attributes such as audit-committee size, audit-committee size tenure could be study in by the future study.

Practical implications

The study’s findings would have practical implications for corporations and other business organizations seeking to actively involve the energy-related SDGs 7 and 13 in their business models and successfully communicate these efforts to stakeholders.

Originality/value

To the best of author’s knowledge, this is the first study that provides empirical evidence on the effect of AC attributes on the energy disclosure using effect of board independence as moderator in Nigeria.
Design and validation of a structured instrument to assess the influence of sustainable supply chain management practices on sustainable performance in hospitals
Authors: Duque-Uribe Veronica , Sarache William , Gutiérrez Elena Valentina
Published: October 2023

Purpose

The purpose of this paper is to design and validate a reliable and comprehensive instrument to assess the influence of sustainable supply chain management (SSCM) practices on sustainable performance in hospitals.

Design/methodology/approach

A systematic and mixed-method approach was used to create and validate an instrument for assessing the level of implementation of hospital SSCM practices and the perceived extent of environmental, social and economic performance. This includes the development of preliminary items and the evaluation of content and construct validity. Data from Colombian hospitals was collected. Structural equation modeling was used to test the structural model.

Findings

During the content validity phase, an initial version of the questionnaire consisting of 88 items was generated. This version was qualitatively and quantitatively reviewed and assessed by six academicians and two hospital practitioners, based on criteria of sufficiency, clarity, relevance and coherence. The computation of both individual and scale content validity indices, along with the qualitative feedback, led to the refinement of the questionnaire. The subsequent phase of construct validity involved the implementation of a pilot test with 55 responses gathered from Colombian hospitals. By considering the metrics of convergent validity and discriminant validity derived from the analysis of structural equation modeling, the final instrument was composed of 59 items. The results reveal that hospital SSCM practices can be conceptualized and measured through two dimensions: environmental and social. The former includes the underlying constructs of internal environmental management, green purchasing and green operations. The latter encompasses the constructs of working conditions and employee well-being, equity management, social purchasing and community development and participation. Sustainable performance is defined by its environmental, social and economic dimensions.

Practical implications

This study is intended to provide useful insights for hospitals, researchers and policymakers to measure and develop strategies to enhance the implementation of SSCM practices, thereby improving sustainable performance. As a matter of fact, the instrument has already been applied in a recent empirical study conducted in Colombia, aimed at addressing the influence of SSCM practices on sustainable performance in hospitals.

Originality/value

To the best of the authors’ knowledge, this is the first study to develop and empirically test an instrument for measuring the influence of SSCM on sustainable performance, both in the hospital setting and in an emerging country.
Psychological well-being of small enterprise employees: a multi-theoretical perspective
Authors: Tabala Agnes , Munene John C. , Kagaari James , Mafabi Samuel , Kyogabiirwe Jannat
Published: October 2023

Purpose

This paper aims to suggest a multi-theoretical explanation using a success story to explain psychological well-being (PWB) among employees of K.C, a small enterprise found in Uganda, a developing country in Africa.

Design/methodology/approach

The study used qualitative methodology. Based on in-depth interviews with K.C employees, a story was developed describing the practical experience, focusing on the context, actions, results and lessons learnt. Regarding the sample size, the saturation point was attained on the seventh participant.

Findings

Findings reveal that employees that possess psychological capital set targets and generate avenues that allow them to achieve set goals, with personal initiative that makes them proactive to accomplish work tasks and individual adaptability that enables them to adjust their emotions and behavior to fit in a complex working environment, which makes them to think, feel and act positively. Furthermore, several theories, including broaden and build, personal initiative and complex adaptive systems theory, explain the manifestations of PWB of employees in small enterprises.

Research limitations/implications

The study was limited by focusing on the context of a small enterprise. Future research may investigate other study contexts whose findings might be different. In addition, the study being hypothetical lacked statistical testing. It would be a meaningful effort if future studies statistically tested the suggested model. Irrespective of the limitations, the findings of this study remain significant.

Practical implications

In practice, employees may replicate these findings to nurture PWB which eventually contributes to enterprises’ success. This could provide answers to the psychological challenges experienced by employees of small enterprises, especially in the African developing countries like Uganda where this is a major challenge. Specifically, the workers of K.C enterprise may depend on their PWB to deal with workplace challenges and sustain the enterprise’s performance.

Social implications

Socially, there is need to embrace positive social relationships among employees at the work place which will translate into well-being of society.

Originality/value

This paper is exceptional because it uses a success story showing practical experiences of how PWB of employees in small enterprises is nurtured in Uganda. In addition, a multi-theoretical perspective is used to explain the manifestations in the story, which is the greatest contribution of this paper. Further, a conceptual model is still proposed, depicting psychological capital, personal initiative and individual adaptability as antecedents of PWB.
Proxy design: a method for involving proxy users to speak on behalf of vulnerable or unreachable users in co-design
Authors: Islind Anna Sigridur , Lundin Johan , Cerna Katerina , Lindroth Tomas , Åkeflo Linda , Steineck Gunnar
Published: October 2023

Purpose

Designing digital artifacts is not a linear, straightforward process. This is particularly true when applying a user-centered design approach, or co-design, with users who are unable to participate in the design process. Although the reduced participation of a particular user group may harm the end result, the literature on solving this issue is sparse. In this article, proxy design is outlined as a method for involving a user group as proxy users to speak on behalf of a group that is difficult to reach. The article investigates the following research question: How can roleplaying be embedded in co-design to engage users as proxies on behalf of those who are unable to represent themselves?

Design/methodology/approach

The article presents a design ethnography spanning three years at a cancer rehabilitation clinic, where digital artifacts were designed to be used collaboratively by nurses and patients. The empirical data were analyzed using content analysis and consisted of 20 observation days at the clinic, six proxy design workshops, 21 telephone consultations between patients and nurses, and log data from the digital artifact.

Findings

The article shows that simulated consultations, with nurses roleplaying as proxies for patients ignited and initiated the design process and enabled an efficient in-depth understanding of patients. Moreover, the article reveals how proxy design as a method further expanded the design. The study findings illustrate: (1) proxy design as a method for initiating design, (2) proxy design as an embedded element in co-design and (3) six design guidelines that should be considered when engaging in proxy design.

Originality/value

The main contribution is the conceptualization of proxy design as a method that can ignite and initiate the co-design process when important users are unreachable, vulnerable or unable to represent themselves in the co-design process. More specifically, based on the empirical findings from a design ethnography that involved nurses as proxy users speaking on behalf of patients, the article shows that roleplaying in proxy design is a fitting way of initiating the design process, outlining proxy design as an embedded element of co-design.
Culture–leadership intersections in support of deeper learning at a career and technical education center
Authors: Malin Joel R. , Poetter Thomas S. , Graft Jon , Durham Marni , Sprankles III William T.
Published: October 2023

Purpose

Although much can be learned from schools that regularly foster deeper learning, little research has been undertaken into how and why these schools have been effective or to elucidate key leadership and cultural characteristics. Moreover, there has been limited attention toward deeper learning within schools that focus on career and technical education (CTE), a major omission given the potentially elevated potential for deeper learning in these contexts. This study aims to partially rectify these issues by examining the intersections of leadership and culture at an innovative school that has demonstrated excellence whilst providing a curriculum centered on CTE.

Design/methodology/approach

This instrumental, insider, single-case study is focused on how leadership–cultural interactions have fostered and shaped students' opportunities to experience deeper learning. The authors take the perspective that it is largely through these leadership–cultural intersections that an organization and the work that happens within it takes on a particular meaning, direction and value. This study applies ethnographic methods, drawing upon formally and informally collected data over the past three years – e.g. from field notes, from leadership meetings and site visits; focus group interviews with students, parents, teachers, partners and school leaders; and additional artifacts.

Findings

The authors detail three interrelated features at this school, noting that it is: (1) driven by moral purpose; (2) open, collaborative and trusting; and (3) ambitious and entrepreneurial. The authors explain how/why such a culture has developed and to what effects, especially in relation to facilitating deeper learning.

Originality/value

Study findings meaningfully add to the literature regarding leadership for deeper learning, broadly and in relation to career and technical education and yield recommendations for educational leaders and policymakers.