bluuebunny/crossref_metadata_2025 huggingface dataset:
MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression
Authors: Farnsworth Dylan A. , Inoue Yusuke , Johnson Fraser D. , de Rappard-Yuswack Georgia , Lu Daniel , Shi Rocky , Somwar Romel , Ladanyi Marc , Unni Arun M. , Lockwood William W.
Published: May 2022

MEK inhibitors have yielded limited efficacy in KRAS-mutant lung adenocarcinoma (LUAD) patients due to drug resistance. We established trametinib-resistant KRAS-mutant LUAD cells and describe a state of “drug addiction” in a subset of resistant cases where cells are dependent on trametinib for survival. Dependence on ERK2 suppression underlies this phenomenon whereby trametinib removal hyperactivates ERK and results in ER stress and apoptosis. Amplification of KRASG12C occurs in drug-addicted cells and blocking mutant specific activity with AMG 510 rescues the lethality after trametinib withdrawal. Furthermore, increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study represents the first instance of this phenotype associated with KRAS amplification and demonstrates that acquired genetic changes that develop in the background of MAPK suppression can have unique consequence. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.
You will know by its tail: a method for quantification of heterogeneity of bacterial populations using single cell MIC profiling
Authors: Pacocha Natalia , Zapotoczna Marta , Makuch Karol , Bogusławski Jakub , Garstecki Piotr
Published: May 2022

Severe non-healing infections are often caused by multiple pathogens or by genetic variants of the same pathogen exhibiting different levels of antibiotic resistance. For example, polymicrobial diabetic foot infections double the risk of amputation compared to monomicrobial infections. Although these infections lead to increased morbidity and mortality, standard antimicrobial susceptibility methods are designed for homogenous samples and are impaired in quantifying heteroresistance. Here, we propose a droplet-based label-free method for quantifying the antibiotic response of the entire population at the single-cell level. We usedPseudomonas aeruginosaandStaphylococcus aureussamples to confirm that the shape of the profile informs about the coexistence of diverse bacterial subpopulations, their sizes, and antibiotic heteroresistance. These profiles could therefore indicate the outcome of antibiotic treatment in terms of the size of remaining subpopulations. Moreover, we studied phenotypic variants of aS. aureusstrain to confirm that the profile can be used to identify tolerant subpopulations, such as small colony variants, associated with increased risks for the development of persisting infections. Therefore, the profile is a versatile instrument for quantifying the size of each bacterial subpopulation within a specimen as well as their individual and joined heteroresistance.
SPTLC1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins
Authors: Lone Museer A. , Aaltonen Mari J. , Zidell Aliza , Pedro Helio F. , Morales Saute Jonas Alex , Mathew Shalett , Mohassel Payam , Bonnemann Carsten , Shoubridge Eric A. , Hornemann Thorsten
Published: May 2022

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased sphingolipid synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause the peripheral sensory neuropathy HSAN1 due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.
Selenocyanate Derived Se-Incorporation into the Nitrogenase Fe Protein Cluster
Authors: Buscagan Trixia M. , Kaiser Jens T. , Rees Douglas C.
Published: May 2022

The nitrogenase Fe protein mediates ATP-dependent electron transfer to the nitrogenase MoFe protein during nitrogen fixation, in addition to catalyzing MoFe protein independent substrate (CO2) reduction and facilitating MoFe protein metallocluster biosynthesis. The precise role(s) of the Fe protein Fe4S4 cluster in some of these processes remains ill-defined. Herein, we report crystallographic data demonstrating ATP-dependent chalcogenide exchange at the Fe4S4 cluster of the nitrogenase Fe protein when potassium selenocyanate is used as the selenium source. The observed chalcogenide exchange illustrates that this Fe4S4 cluster is capable of core substitution reactions under certain conditions, adding to the Fe protein’s repertoire of unique properties.
Divergent transcriptional response to thermal stress among life stages could constrain coral adaptation to climate change
Authors: Ruggeri Maria , Zhang Yingqi , Aglyamova Galina V. , Kenkel Carly D.
Published: May 2022

The ability for adaptation to keep pace with environmental change largely depends on how efficiently selection can act on heritable genetic variation. Complex life cycles may either promote or constrain adaptation depending on the integration or independence of fitness-related traits over development. Reef-building corals exhibit complex life cycles and are sensitive to increasing temperatures, highlighting the need to understand the heritable potential of the thermal stress response and how it is regulated over development. Here we used tag-based RNA-seq to profile global gene expression in inshore and offshoreP. astreoidesadults and their offspring recruits in response to a 16-day heat stress, and larvae from separate families in response to a 4-day heat stress, to test whether gene expression patterns differentiating adult populations, and potentially underlying differences in thermal tolerance, persist in thermally naive life stages. Host developmental stage had a major effect on both host and symbiont expression, despite symbionts being directly inherited from parent colonies, and modulated the response to thermal stress, suggesting the holobiont response to selection varies across life stages. Populations also exhibited origin-specific treatment responses, but the magnitude of the response differed among populations and life stages. Inshore parents and their juvenile offspring exhibited a more robust response to heat stress compared to offshore-origin corals, indicating expression plasticity may be heritable. However, larval populations exhibited the opposite response, possibly due to stage-specific differences or exposure duration. Overall, this study shows that putatively adaptive regulatory variation can be heritable, but the identity of thermally responsive genes are stage-specific, which will have major implications for predicting the evolutionary response of corals in a changing environment.
Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification
Authors: Reilly Molly B. , Tekieli Tessa , Cros Cyril , Aguilar G. Robert , Lao James , Toker Itai Antoine , Vidal Berta , Leyva-Díaz Eduardo , Bhattacharya Abhishek , Cook Steven J. , Smith Jayson J. , Kovacevic Ismar , Gulez Burcu , Fernandez Robert , Bradford Elizabeth F. , Ramadan Yasmin H. , Kratsios Paschalis , Bao Zhirong , Hobert Oliver
Published: May 2022

Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 12 homeobox genes in 20 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 20 neuron classes had no homeobox gene function ascribed to them before, while in the other 10 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analysis, 111 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.
Minimal functional domains of the core polarity regulator Dlg
Authors: Khoury Mark J. , Bilder David
Published: May 2022

The compartmentalized domains of polarized epithelial cells arise from mutually antagonistic actions between the apical Par complex and the basolateral Scrib module. In Drosophila, the Scrib module proteins Scribble (Scrib) and Discs-large (Dlg) are required to limit Lgl phosphorylation at the basolateral cortex, but how Scrib and Dlg could carry out such a ‘protection’ activity is not clear. We tested Protein Phosphatase 1α (PP1) as a potential mediator of this activity but demonstrate that a significant component of Scrib and Dlg regulation of Lgl is PP1-independent and found no evidence for a Scrib-Dlg-PP1 protein complex. However, the Dlg SH3 domain plays a role in Lgl protection and, in combination with the N-terminal region of the Dlg HOOK domain, in recruitment of Scrib to the membrane. We identify a ‘minimal Dlg’ comprised of the SH3 and HOOK domains that is both necessary and sufficient for Scrib localization and epithelial polarity function in vivo.

Summary Statement

A minimal SH3-HOOK fragment of Dlg is sufficient to support epithelial polarity through mechanisms independent of the PP1 phosphatase.
Long Term Virucidal Activity of Rosin Soap on Surfaces
Authors: Bell Stephen H , Fairley Derek J , Kettunen Hannele , Vuorenmaa Juhani , Orte Juha , Bamford Connor G G , McGrath John W
Published: May 2022

Microbiocidal products for decontaminating both animate and inanimate surfaces that may act as vectors for disease transmission are a well-established method for inactivating viruses of clinical significance. There are a wide variety of such microbiocidal products that can be purchased commercially, many with different active ingredients. We have recently shown that Rosin soap (derived from Tall Oil that has been produced by trees) is a highly effective virucidal product against enveloped viruses like influenza A virus and SARS-CoV-2 when tested in solution. Here we further demonstrate that Rosin soap retains its virucidal activity against influenza A virus and SARS-CoV-2 when applied to surfaces, such as plastic, glass and steel, either before or after virus inoculation. The virucidal activity extended out to seven days post administration. Together, our results show the potential for Rosin soap-based disinfectants to be used as a surface coating to protect against clinically relevant enveloped viruses, such as influenza viruses and coronaviruses.
Then and NOW: A Prospective Population-Level Validation of the Abbott ID NOW SARS-CoV-2 Device Implemented in Multiple Settings for Testing Asymptomatic and Symptomatic Individuals
Authors: Stokes William , Venner Allison A. , Buss Emily , Tipples Graham , Berenger Byron M.
Published: May 2022

IMPORTANCE

Since December, 2020, the ID NOW was implemented for use in 4 different populations across Alberta: in mobile units as part of community outbreak response, COVID-19 community collection sites, emergency shelters and addiction treatment facilities (ES), and hospitals.

OBJECTIVE

Diagnostic evaluation of the ID NOW in various real world settings among symptomatic and asymptomatic individuals

DESIGN

Depending on the implemented site, the ID NOW was tested on patients with symptoms suggestive of COVID-19, asymptomatic close contacts or asymptomatic individuals as part of outbreak point prevalence screening. From Jan – April, a select number of sites also switched from using oropharyngeal swabs to combined oropharyngeal + nasal (O+N) swabs. For every individual tested, two swabs were collected: one for ID NOW testing and the other for either reverse-transcriptase polymerase chain reaction (RT-PCR) confirmation of negative ID NOW results or for variant testing of positive ID NOW results.

RESULTS

A total of 129,112 paired samples were analyzed (16,061 RT-PCR positive). 81,697 samples were from 42 COVID-19 community collection sites, 16,924 from 69 rural hospitals, 1,927 from 9 ES, 23,802 samples from 6 mobile units that responded to 356 community outbreaks, and 4,762 from 3 community collection sites and 1 ES using O+N swabs for ID NOW testing. ID NOW sensitivity was highest among symptomatic individuals presenting to community collection sites [92.5%, 95% confidence interval (CI) 92.0-93.0%, n=10,633 RT-PCR positive] and lowest for asymptomatic individuals associated with community outbreaks (73.9%, 95% CI 69.8-77.7%, n=494 RT-PCR positive). Specificity was greater than 99% in all populations tested, but positive predictive value (PPV) was lower among asymptomatic populations (82.4–91.3%) compared to symptomatic populations (96.0-96.9%). There was no statistically significant differences in sensitivity with respect to age, gender, NP vs OP swab for RT-PCR confirmation, variants of concern, or with combined oropharyngeal and nasal swabs using COVID-19 ID NOW testing.

CONCLUSIONS

Sensitivity of ID NOW SARS-CoV-2 testing is highest when used on symptomatic community populations not seeking medical care. Sensitivity and PPV drops by approximately 10% when tested on asymptomatic populations. Using combined oropharyngeal and nasal swabs did not improve ID NOW performance.
Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer
Authors: Ricordel C. , Chaillot L. , Vlachavas E. I. , Logotheti M. , Jouannic A. , Desvallees T. , Lecuyer G. , Aubry M. , Kontogianni G. , Mastrokalou C. , Jouan F. , Jarry U. , Corre R. , Guen Y. Le , Guillaudeux T. , Lena H. , Chatziioannou A. , Pedeux R.
Published: May 2022

Introduction

Circulating Tumor Cells (CTC) have been studied in various solid tumors but clinical utility of CTC in Small Cell Lung Cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics.

Patients and methods

CTC-CPC is a monocentric prospective non-interventional study including treatment-naïve newly diagnosed SCLC. CD56+CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment and submitted to Whole-exome-sequencing (WES).

Results

Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+CTC at diagnosis. High numeration of CD56+CTC (>7/ml) at diagnosis was associated with ES-SCLC. Comparing CD56+CTC isolated at diagnosis and relapse, we identify differentially altered oncogenic pathways (e.g. DLL3 or MAPK pathway).

Conclusions

We report a versatile method of CD56+CTC detection in SCLC. Numeration of CD56+CTC at diagnosis is correlated with disease extension. Isolated CD56+CTC are tumorigenic and a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC.
Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling
Authors: Drake Zachary C. , Seffernick Justin T. , Lindert Steffen
Published: May 2022

Structural mass spectrometry offers several techniques for the characterization of protein structures. Covalent labeling (CL) in combination with mass spectrometry can be used as an analytical tool to study and determine structural properties of protein-protein complexes. Degrees of modification obtained from CL experiments for specific labeled residues can be compared between the unbound and bound states of complexes. This analysis can yield insights into structural features of these protein assemblies, specifically the proximity of specific residues to the protein-protein interface. However, this data is sparse and does not unambiguously elucidate protein structure. Thus, computational algorithms are needed to deduce structure from the CL data. In this work we present a novel hybrid method that combines models of protein complex subunits generated with AlphaFold with differential CL data via a CL-guided protein-protein docking in Rosetta. In a benchmark set, the RMSD (root-mean-square deviation) of the best-scoring models was below 3.6 Å for 5/5 complexes with inclusion of CL data, whereas the same quality was only achieved for 1/5 complexes without CL data. The average improvement in RMSD observed upon inclusion of CL data was 5.2 Å. This study suggests that our integrated approach can successfully use data obtained from CL experiments to distinguish between nativelike and non-nativelike models.

Significance Statement

Structural mass spectrometry can be a powerful and versatile approach to characterize the structure of protein complexes. Data obtained from covalent labeling mass spectrometry can provide insights into higher order protein structure (particularly with respect to residue interactions and solvent accessibility) but needs to be supplemented by computational techniques to elucidate accurate, atomic-detail structural information. Here, we present a method to combine bioanalytical data obtained from covalent labeling with models generated using AlphaFold to accurately predict protein-protein complexes in Rosetta. Differential covalent labeling data can be used to determine the proximity of residues to the binding interface of complexes which we utilized to analyze computational models and improve structure prediction algorithms.
Keeping it close: The role of a Campus COVID Support Team (CCST) in sustaining a safe and healthy university campus during COVID-19
Authors: McDonnell Karen A , Vyas Amita , Castel Amanda , Nagaraj Nitasha , Landry Megan
Published: May 2022

It has been over 24 months since the start of the COVID-19 pandemic forced university campuses to shut down and then reopen under new safety guidelines. Now as we move into the subsequent years of the pandemic, we can look back and evaluate what has worked, improvements to be made, and plans for providing a sustained response for a campus community. In this article we detail one campus response to the COVID-19 pandemic and directions being taken to ensure a sustained campus COVID support team (CCST) is in hand to ensure the health and safety of the university community. The CCST was created to serve as a one-stop-shop to help the university community navigate COVID-19 policies and procedures. The responsibilities of the CCST include conducting case investigations for any positive COVID-19 tests within the university community, contact tracing for authorized university affiliates, epidemiological surveillance and mitigation efforts, and communication through real-time analysis and dashboards. Continuous monitoring procedures demonstrated the CCST conducted all case investigations within the post-testing 24-hour window, thus keeping the university test-positivity rate below 3%. Quality improvement surveys demonstrated a high level of satisfaction with the CCST efforts and provided areas for improvement and sustainability. Having a public health faculty led CCST enabled the university to act swiftly when COVID-19 positive cases were emerging and deter widespread campus COVID-19 outbreaks. The CCST timeliness and connectivity to the campus has demonstrated benefits to the health and safety of the campus.

Highlights

Universities are their own communities and having on campus COVID support teams can mitigate potential COVID-19 outbreaks.

Having a public health driven Campus COVID Support Team that can conduct case investigations within 24 hours of a positive test result has demonstrated benefits to taking responsive measures.

Continuous quality improvement efforts including surveys of the Campus COVID Support Team should be implemented for any COVID service efforts.
Essential oils of plants and their combinations as an alternative adulticides against Anopheles gambiae (Diptera: Culicidae) populations
Authors: Balboné Mahamoudou , Sawadogo Ignace , Soma Dieudonné Diloma , Drabo Samuel Fogné , Namountougou Moussa , Bayili Koama , Romba Rahim , Meda Georges Benson , Nebié Honorat Charles Roger , Dabire Roch K. , Bassolé Imae□l H. N. , Gnankine Olivier
Published: May 2022

The persistence of malaria and the increasing of resistance of Anopheles gambiae species to chemicals remain major public health concerns in sub-Saharan Africa. Faced to these concerns, the search for alternative vector control strategies as use of essential oils need to be implemented. Here, the five essential oils (EOs) from Cymbopogon citratus, Cymbopogon nardus, Eucalyptus camaldulensis, Lippia multiflora, Ocimum americanum obtained by hydro distillation were tested according to WHO procedures on Anopheles gambiae “Kisumu” and field strains collected in “Vallée du Kou”. Also, the binary combinations of C. nardus and O. americanum were examined. As results, among the EOs tested, L. multiflora was the most efficient regarding KDT50 and KDT95 and rate of morality values. Our current study showed that C8 (C.n 80% : O.a 20%) and C9 (C.n 90% : O.a 10%), were more toxic to Anopheles gambiae strain VK with the mortality rates reaching 80.7 and 100% at the 1% concentration, respectively. These two binary combinations shown a synergistic effect on the susceptible population. However, only C9 showed a synergistic effect on VK population. The bioactivity of the two EOs, Cymbopogon nardus and Ocimum americanum, was improved by the combinations at certain proportions and may constitute an alternative to pyrethroid resistance.
Immune defense in Drosophila melanogaster depends on diet, sex and mating status
Authors: Rai Kshama Ekanath , Yin Han , Bengo Arnie Lynn C. , Cheek Madison , Courville Robert , Bagheri Elnaz , Ramezan Reza , Behseta Sam , Shahrestani Parvin
Published: May 2022

Post-mating immunosuppression has been widely accepted as a female trait in Drosophila melanogaster. Our results challenge this notion by presenting a mating-immunity trade-off in males as well as in females. When inoculated with the fungal pathogen, Beauveria bassiana, both males and females die faster compared to inoculated virgins, and survival is lower when inoculated flies are continuously mated compared to a single day of mating. Past studies with Beauveria bassiana have shown females to be more susceptible to infection than males. Our results challenge this finding as well, showing that the direction of sexual dimorphism in immune defense depends on mating status, specific Beauveria bassiana strain, and fly genotype. Moreover, we show that survival after fungal infection is largely influenced by diet, and that post-infection dietary improvements can help enhance survival. Post-mating suppression in Drosophila survival of B. bassiana infection presents study opportunities with potential applications for biological control of insect vectors of human disease and insect crop pests.
PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum
Authors: Kanyal Abhishek , Davies Heledd , Deshmukh Bhagyashree , Farheen Dilsha , Treeck Moritz , Karmodiya Krishanpal
Published: May 2022

Plasmodium falciparum is a deadly protozoan parasite and the causative agent of malaria, which accounts for close to 200 million cases and 400,000 deaths every year. It has been identified to possess a tightly regulated gene expression profile that is integrally linked to its timely development during the intraerythrocytic stage. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasite’s transcriptome. In this study, we characterize the solitary class I histone deacetylase PfHDAC1 and demonstrate that phosphorylation is required for its catalytic activity. PfHDAC1 binds to and regulates parasite genes responsible for housekeeping and stress-responsive functions. We show that PfHDAC1 activity in parasites is crucial for normal intraerythrocytic development and that its cellular abundance is correlated with parasitemia progression. We further show that PfHDAC1 has differential abundance and genomic occupancy in artemisinin drug-resistant vs sensitive parasites and that inhibition of its deacetylase activity can modulate the sensitivity of parasites to the drug. We also identify that artemisinin exposure can interfere with PfHDAC1 phosphorylation and its genomic occupancy. Collectively, our results demonstrate PfHDAC1 to be an important regulator of basic biological functions in parasites while also deterministic of responses to environmental stresses such as antimalarial drugs.
The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites
Authors: Looker Oliver , Dans Madeline G. , Bullen Hayley E. , Sleebs Brad E. , Crabb Brendan S. , Gilson Paul R.
Published: May 2022

Plasmodium falciparum parasites which cause malaria, traffic hundreds of proteins into the red blood cells (RBCs) they infect. These exported proteins remodel their RBCs enabling host immune evasion through processes such as cytoadherence that greatly assist parasite survival. As resistance to all current anti-malarial compounds is rising new compounds need to be identified and those that could inhibit parasite protein secretion and export would both rapidly reduce parasite virulence and ultimately lead to parasite death. To identify compounds that inhibit protein export we used transgenic parasites expressing an exported nanoluciferase reporter to screen the Medicines for Malaria Venture Malaria box of 400 anti-malarial compounds with mostly unknown targets. The most potent inhibitor identified in this screen was MMV396797 whose application led to export inhibition of both the reporter and endogenous exported proteins. MMV396797 mediated blockage of protein export and slowed the rigidification and cytoadherence of infected RBCs - modifications which are both mediated by parasite-derived exported proteins. Overall, we have identified a new protein export inhibitor in P. falciparum whose target though unknown, could be developed into a future anti-malarial that rapidly inhibits parasite virulence before eliminating parasites from the host.

Synopsis

Plasmodium falciparum exports proteins into its host cell to perform a myriad of functions required for survival. We adapted an assay to screen for small molecules that inhibit protein secretion and export. Screening the 400-compound Medicines for Malaria Venture (MMV) Malaria Box uncovered several potential export inhibitors. The most promising of these compounds, MMV396797, blocked protein export at the parasite and reduced host rigidification and cytoadherence, two functions which are mediated by exported proteins.
Inferring the T-cells repertoire dynamics of healthy individuals
Authors: Koraichi Meriem Bensouda , Ferri Silvia , Walczak Aleksandra M , Mora Thierry
Published: May 2022

The adaptive immune system is a diverse ecosystem that responds to pathogens by selecting cells with specific receptors. While clonal expansion in response to particular immune challenges has been extensively studied, we do not know the neutral dynamics that drive the immune system in absence of strong stimuli. Here we learn the parameters that underlie the clonal dynamics of the T-cell repertoire in healthy individuals of different ages, by applying Bayesian inference to longitudinal immune repertoire sequencing (RepSeq) data. Quantifying the experimental noise accurately for a given RepSeq technique allows us to disentangle real changes in clonal frequencies from noise. We find that the data are consistent with clone sizes following a geometric Brownian motion, and show that its predicted steady state is in quantitative agreement with the observed power-law behaviour of the clone-size distribution. The inferred turnover time scale of the repertoire increases substantially with patient age, and depends on the clone size in some individuals.
Optimal Control Costs of Brain State Transitions in Linear Stochastic Systems
Authors: Kamiya Shunsuke , Kawakita Genji , Sasai Shuntaro , Kitazono Jun , Oizumi Masafumi
Published: May 2022

The brain is a system that performs numerous functions by controlling its states. Quantifying the cost of this control is essential as it reveals how the brain can be controlled based on the minimization of the control cost, and which brain regions are most important to the optimal control of transitions. Despite its great potential, the current control paradigm in neuroscience uses a deterministic framework and is therefore unable to consider stochasticity, severely limiting its application to neural data. Here, to resolve this limitation, we propose a novel framework for the evaluation of control costs based on a linear stochastic model. Following our previous work, we quantified the optimal control cost as the minimal Kullback-Leibler divergence between the uncontrolled and controlled processes. In the linear model, we established an analytical expression for minimal cost and showed that we can decompose it into the cost for controlling the mean and covariance of brain activity. To evaluate the utility of our novel framework, we examined the significant brain regions in the optimal control of transitions from the resting state to seven cognitive task states in human whole-brain imaging data. We found that, in realizing the different transitions, the lower visual areas commonly played a significant role in controlling the means, while the posterior cingulate cortex commonly played a significant role in controlling the covariances.

Significance Statement

The brain performs many cognitive functions by controlling its states. Quantifying the cost of this control is essential as it reveals how the brain can be optimally controlled in terms of the cost, and which brain regions are most important to the optimal control of transitions. Here, we built a novel framework to quantify control cost that takes account of stochasticity of neural activity, which is ignored in previous studies. We established the analytical expression of the stochastic control cost, which enables us to compute the cost in high-dimensional neural data. We identified the significant brain regions for the optimal control in cognitive tasks in human whole-brain imaging data.
CSF circulation and dispersion yield rapid clearance from intracranial compartments
Authors: Hornkjøl Martin , Valnes Lars Magnus , Ringstad Geir , Rognes Marie E. , Eide Per-Kristian , Mardal Kent-André , Vinje Vegard
Published: May 2022

In this paper we used a computational model to estimate the clearance of tracer driven by circulation of cere-brospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the CP in line with observation on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the SAS yield rapid clearance from both the SAS and the brain interstitial fluid (ISF) and can speed up intracranial clearance from years, as would be the case for purely diffusive flow, to days.
Genetic modification of the ant Lasius niger using CRISPR-Cas9 technology
Authors: Konu Mauno , Kulmuni Jonna , Viljakainen Lumi
Published: May 2022

CRISPR-Cas9 has become one of the most prominent gene editing tools available and it has been utilized in various organisms from bacteria to fungi, plants, and animals. In this study, we developed a CRISPR-Cas9 protocol for the black garden ant Lasius niger, a common and easily available study species for lab and field environments. To create indel mutations using CRISPR-Cas9 in L. niger, we targeted three different locations in a well-studied eye pigmentation gene cinnabar, generating several mutations that disrupt the ommochrome biosynthesis pathway and result in the lack of this pigment and therefore, abnormal eye coloration in adult workers. We also developed a protocol to collect L. niger eggs, inject them with CRISPR-Cas9 construct, and rear the eggs into mature adult workers with assistance of nursing workers. We demonstrated for the first time with L. niger that CRISPR-Cas9 is an excellent tool to create targeted mutations for this species. Our protocol can be referred to when developing similar studies for other species of ants and eusocial insects.
Interpretable deep learning to uncover the molecular binding patterns determining TCR–epitope interactions
Authors: Dens Ceder , Bittremieux Wout , Affaticati Fabio , Laukens Kris , Meysman Pieter
Published: May 2022

The recognition of an epitope by a T-cell receptor (TCR) is crucial for eliminating pathogens and establishing immunological memory. Prediction of the binding of any TCR–epitope pair is still a challenging task, especially for novel epitopes, because the underlying patterns are largely unknown to domain experts and machine learning models. To achieve a deeper understanding of TCR–epitope interactions, we have used interpretable deep learning techniques to gain insights into the performance of TCR–epitope binding machine learning models. We demonstrate how interpretable AI techniques can be linked to the three-dimensional structure of molecules to offer novel insights into the factors that determine TCR affinity on a molecular level. Additionally, our results show the importance of using interpretability techniques to verify the predictions of machine learning models for challenging molecular biology problems where small hard-to-detect problems can accumulate to inaccurate results.
An Integrated 3D bioprinted “disease in a dish” lung cancer model to simultaneously study drug efficacy, toxicity and metabolism
Authors: Nandeesha NP , Rotella Madhuri , Vangala Subrahmanyam , Saxena Uday
Published: May 2022

Discovery and development of new drugs is a long, expensive and high risk proposition. Millions of dollars spent and decade plus years of time taken to discover a new drug have haunted pharma industry for many years.

In part, the reliance on animal models to make go or no go decisions for selecting drugs for human trials has been a problem because animal biology does not capture human disease in entirety. In recognition of this, the last decade has seen the emergence of more human like tools being developed in the hope of better prediction of human outcomes.

Towards that end we have developed a 3D bioprinted disease in a dish lung cancer model which uses human cells and includes ability to measure drug efficacy, toxicity and metabolism simultaneously. For drug profiling studies in our disease in a dish model we 3D bioprinted intestinal cells, layered below which were liver cells and finally underneath were target lung cancer cells. The idea was to simulate the path taken by an oral drug which encounters the gut, followed by liver and target organs. We demonstrate here that a 3D bioprinted disease model composed of human derived cells is able to concurrently measure in vitro drug efficacy, toxicity and metabolism. Such humanized models will help make early go or no go decisions on the potential of a drug to enter human trials.
Transposable element accumulation drives size differences among polymorphic Y Chromosomes in Drosophila
Authors: Nguyen Alison H. , Wang Weixiang , Chong Emily , Chatla Kamalakar , Bachtrog Doris
Published: May 2022

Y Chromosomes of many species are gene poor and show low levels of nucleotide variation, yet they often display high amounts of structural diversity. Dobzhansky cataloged several morphologically distinct Y Chromosomes in Drosophila pseudoobscura that differ in size and shape, but the molecular causes of their large size differences are unclear. Here we use cytogenetics and long-read sequencing to study the sequence content of polymorphic Y Chromosomes in D. pseudoobscura. We show that Y Chromosomes differ almost twofold in size, ranging from 30 to 60 Mb. Most of this size difference is caused by a handful of active transposable elements (TEs) that have recently expanded on the largest Y Chromosome, with different elements being responsible for Y expansion on differently sized D. pseudoobscura Y's. We show that Y Chromosomes differ in their heterochromatin enrichment and expression of Y-enriched TEs, and also influence expression of dozens of autosomal and X-linked genes. The same helitron element that showed the most drastic amplification on the largest Y in D. pseudoobscura independently amplified on a polymorphic large Y Chromosome in Drosophila affinis, suggesting that some TEs are inherently more prone to become deregulated on Y Chromosomes.
Managing escalating events: a case study from the pharmaceutical industry
Authors: Burnard Kevin John
Published: May 2022

Purpose

This paper presents a case study of the response of a pharmaceutical goods manufacturer to an unexpected disruptive event. Following a period of heavy rainfall, a small town within the UK was quickly overwhelmed by localised flash flooding. The sudden rise in ground water overwhelmed local drainage systems and caused flooding in several areas of the town. One of the impacted areas included the manufacturing facilities of a pharmaceutical goods producer. This case study explores the subsequent response of the organisation to the event.

Design/methodology/approach

Based on direct interviews and supporting documentation, this case study analyses the organisation's response and recovery activities in the face of escalating impacts. Drawing on identified theory, specific attention is placed on characterising severe events and the challenges of coordinating response activities.

Findings

Drawing on the evidence of this case study, this paper highlights the identified features of an effective response within escalating events. Without this response, events such as those experienced by the case study organisation carry the distinct possibility of developing into large scale disruptions. This study highlights the importance of established channels of authority and the ability to identify and contain impacts.

Originality/value

This paper outlines some of the key considerations and operational priorities within response activities. These priorities support the effective identification and resolution of disruptive events and their associated impacts.
Using secondary data in research on social sustainability in construction project management: a transition from “interview society” to “project-as-practice”
Authors: Goel Ashish
Published: May 2022

Purpose

Access to unbiased self-reported (primary) data for a normative concept like social sustainability has been a challenge for construction project management (CPM) scholars, and this difficulty has been further amplified by the ongoing COVID-19 pandemic. This paper aims to address this issue by asserting the suitability of secondary data as a methodologically sound but underutilized alternative and providing directions for secondary data-based research on social sustainability in a project setting.

Design/methodology/approach

By drawing on a framework for social sustainability and using “project-as-practice” approach as its point of departure, this conceptual paper identifies possibilities for utilizing multiple secondary sources in CPM research.

Findings

The paper provides a roadmap for identification of secondary sources, access to data, potential research designs and methods, limitations of and cautions in using secondary sources, and points to many novel lines of empirical enquiries to stimulate secondary data-based research on social sustainability in CPM.

Social implications

Indicated secondary sources and empirical opportunities can support research efforts that aim to promote societal welfare through construction projects.

Originality/value

The presented guidance will assist researchers in identifying, accessing and utilizing naturalistic, secondary data for designing and conducting empirical research that cuts across social sustainability and CPM. This, in turn, will facilitate methodological pluralism and “practice turn” in such research endeavors.
Exploration, exploitation, ambidexterity and the performance of international SMEs
Authors: Su Lixun , Cui Annie Peng , Samiee Saeed , Zou Shaoming
Published: May 2022

Purpose

This study aims to examine how international small and medium-sized enterprises (ISMEs) improve adaptive marketing capabilities (AMCs) through exploration, exploitation and ambidexterity (EEA) and thereby increase exporting performance. In addition, the present study attempts to examine conditions under which EEA can more effectively improve AMCs.

Design/methodology/approach

The theoretical model was tested by using survey data collected from 119 ISMEs based in the U.S. Partial least squares structural equation modeling was deployed to analyze the data.

Findings

The results show that exploration increases ISMEs’ performance through improving AMCs while ambidexterity reduces ISMEs’ performance through weakening AMCs. However, the negative influence of ambidexterity on AMCs attenuates in a dissimilar host country where ISMEs can conveniently learn new information. Finally, when ISMEs pursue exploitation in an either similar or dissimilar host country, their AMCs do not improve.

Research limitations/implications

We provide empirical evidence of SMEs increasing AMCs and firm performance via EEA within the context of exporting. However, we did not collect objective financial performance of ISMEs.

Practical implications

Our findings provide guidance for ISMEs’ marketing managers to build AMCs by learning something new. Moreover, the findings help ISMEs effectively identify and select the most appropriate international marketing strategy depending on the similarity between host and home countries.

Originality/value

Our findings contribute to the literature by explicating how ISMEs can heighten marketing capability to build competitive advantages in global markets through exploration. However, ISMEs should be cautious when pursuing ambidexterity, which may weaken AMCs and finally decrease firm performance. In addition, we identify external factors that influence effectiveness of EEA in building AMCs. By doing so, the findings help ISMEs understand how to increase AMCs so as to improve competencies in fast-changing global markets.
Talent development: a driver for strategic flexibility, innovativeness and financial performance
Authors: Kafetzopoulos Dimitrios
Published: May 2022

Purpose

The purpose of this study is to build a theory presenting talent development as a driver for innovativeness and strategic flexibility, and how these organizational capabilities affect financial performance.

Design/methodology/approach

As a methodological approach, this study uses a rich combination of literature review and exploratory interviews with managers and academicians. Moreover, a conceptual framework is tested by confirmatory factor analysis and finally structural equation modelling using the survey data from 462 Greek firms.

Findings

The results show the positive effect of talent development on strategic flexibility and innovativeness. Moreover, strategic flexibility is an influential firm capability for innovativeness and financial performance. This study also reveals the significance of innovativeness on financial performance.

Research limitations/implications

This study explores talent development and two certain organizational capabilities, but many other topics that affect business performance remain unexplored. The role of environmental characteristics could also be examined as a moderator in the proposed relationships.

Practical implications

This study offers clear implications for managers, proving that talent development is a major driving force behind strategic flexibility, innovativeness and financial performance in order for managers to allocate resources, and to develop and execute these capabilities as an integral part of business strategy.

Originality/value

This empirical study contributes to the literature by developing a research conceptual framework of three underdeveloped firm capabilities, investigating and explaining both their correlations and dynamic nature and their role in financial performance improvement.