bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: Evidence from Danish Households
Authors: Lyngse Frederik Plesner , Kirkeby Carsten Thure , Denwood Matthew , Christiansen Lasse Engbo , Mølbak Kåre , Møller Camilla Holten , Skov Robert Leo , Krause Tyra Grove , Rasmussen Morten , Sieber Raphael Niklaus , Johannesen Thor Bech , Lillebaek Troels , Fonager Jannik , Fomsgaard Anders , Møller Frederik Trier , Stegger Marc , Overvad Maria , Spiess Katja , Mortensen Laust Hvas
Published: January 2022

1

The Omicron SARS-CoV-2 variant of concern (VOC lineage B.1.1.529), which became dominant in many countries during early 2022, includes several subvariants with strikingly different genetic characteristics. Several countries, including Denmark, have observed the two Omicron subvariants: BA.1 and BA.2. In Denmark the latter has rapidly replaced the former as the dominant subvariant.

Based on nationwide Danish data, we estimate the transmission dynamics of BA.1 and BA.2 following the spread of Omicron VOC within Danish households in late December 2021 and early January 2022.

Among 8,541 primary household cases, of which 2,122 were BA.2, we identified a total of 5,702 secondary infections among 17,945 potential secondary cases during a 1-7 day follow-up period. The secondary attack rate (SAR) was estimated as 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively.

We found BA.2 to be associated with an increased susceptibility of infection for unvaccinated individuals (Odds Ratio (OR) 2.19; 95%-CI 1.58-3.04), fully vaccinated individuals (OR 2.45; 95%-CI 1.77-3.40) and booster-vaccinated individuals (OR 2.99; 95%-CI 2.11-4.24), compared to BA.1. We also found an increased transmissibility from unvaccinated primary cases in BA.2 households when compared to BA.1 households, with an OR of 2.62 (95%-CI 1.96-3.52). The pattern of increased transmissibility in BA.2 households was not observed for fully vaccinated and booster-vaccinated primary cases, where the OR of transmission was below 1 for BA.2 compared to BA.1.

We conclude that Omicron BA.2 is inherently substantially more transmissible than BA.1, and that it also possesses immune-evasive properties that further reduce the protective effect of vaccination against infection, but do not increase its transmissibility from vaccinated individuals with breakthrough infections.
Single-cell mapping links neurogenesis and angiogenesis in aggressive breast cancer
Authors: Wik Elisabeth , Aziz Sura , Finne Kenneth , Kleftogiannis Dimitrios , Askeland Cecilie , Knutsvik Gøril , Krüger Kristi , Svanøe Amalie A. , Birkeland Even , Kjølle Silje , Davidsen Benedicte , Stefansson Ingunn M. , Vethe Heidrun , Akslen Lars A.
Published: January 2022

The tumor microenvironment (TME) is important for cancer growth and progression. While angiogenesis is an established hallmark of cancer, the role of nerve fibers is less studied. Here, we investigated neurogenesis and angiogenesis in breast cancer and found them to be closely associated. Single-cell based spatial mapping by imaging mass cytometry (IMC) indicated close proximity between neural and vascular structures. Subsequent validation by tissue-based markers of neurogenesis and angiogenesis, supported by proteomics and transcriptomics data of tissues and cell lines, supported a link between these processes. A consolidated neuro-angiogenic signature score was linked to high-grade breast cancer and reduced patient survival, also within the low-grade luminal tumor subgroup. Our findings support that neurogenesis and angiogenesis are related in aggressive breast cancer and might possibly improve tumor stratification and clinical management.
Comparative analysis of machine learning algorithms on the microbial strain-specific AMP prediction
Authors: Vishnepolsky Boris , Grigolava Maya , Managadze Grigol , Gabrielian Andrei , Rosenthal Alex , Hurt Darrell E. , Tartakovsky Michael , Pirtskhalava Malak
Published: January 2022

The evolution of drug-resistant pathogenic microbial species is a major global health concern. Naturally occurring, antimicrobial peptides (AMPs) are considered promising candidates to address antibiotic resistance problems. A variety of computational methods have been developed to accurately predict AMPs. The majority of such methods are not microbial strain-specific (MSS): they can predict whether a given peptide is active against some microbe, but cannot accurately calculate whether such peptide would be active against a particular microbial strain. Due to insufficient data on most microbial strains, only a few MSS predictive models have been developed so far. To overcome this problem, we developed a novel approach that allows to improve MSS predictive models (MSSPM), based on properties, computed for AMP sequences and characteristics of genomes, computed for target microbial strains. New models can perform predictions of AMPs for microbial strains that do not have data on peptides tested on them. We tested various types of feature engineering as well as different machine learning (ML) algorithms to compare the predictive abilities of resulting models. Among the ML algorithms, Random Forest and AdaBoost performed best. By using genome characteristics as additional features, the performance for all models increased significantly—on average by 7%—relative to models relying on AMP sequence-based properties only. Our novel MSS AMP predictor is freely accessible as part of DBAASP database resource at https://dbaasp.org/tools?page=genome-prediction
The adapted Activity-By-Contact model for enhancer-gene assignment and its application to single-cell data
Authors: Hecker Dennis , Ardakani Fatemeh Behjati , Karollus Alexander , Gagneur Julien , Schulz Marcel H.
Published: January 2022

Identifying regulatory regions in the genome is of great interest for understanding the epigenomic landscape in cells. One fundamental challenge in this context is to find the target genes whose expression is affected by the regulatory regions. A recent successful method is the Activity-By-Contact (ABC) model (Fulco et al., 2019) which scores enhancer-gene interactions based on enhancer activity and the contact frequency of an enhancer to its target gene. However, it describes regulatory interactions entirely from a gene’s perspective, and does not account for all the candidate target genes of an enhancer. In addition, the ABC-model requires two types of assays to measure enhancer activity, which limits the applicability. Moreover, there is no implementation available that could allow for an integration with transcription factor (TF) binding information nor an efficient analysis of single-cell data. We demonstrate that the ABC-score can yield a higher accuracy by adapting the enhancer activity according to the number of contacts the enhancer has to its candidate target genes and also by considering all annotated transcription start sites of a gene. Further, we show that the model is comparably accurate with only one assay to measure enhancer activity. We combined our generalised ABC-model (gABC) with TF binding information and illustrate an analysis of a single-cell ATAC-seq data set of the human heart, where we were able to characterise cell type-specific regulatory interactions and predict gene expression based on transcription factor affinities. All executed processing steps are incorporated into our new computational pipeline STARE. The software is available athttps://github.com/schulzlab/STARE.
Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin
Authors: Tolokh Igor S , Kinney Nicholas Allen , Sharakhov Igor V , Onufriev Alexey V
Published: January 2022

Background

Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of 3D chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.

Results

We have developed a coarse-grained dynamical model of theDrosophila melanogasternuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. Best agreement with the experiment is achieved when the simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development, including those that describe changes in chromatin induced by lamin depletion. Predicted positioning of all LADs at the NE is highly dynamic – the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome which also has a strong effect on the predicted radial positioning of individual TADs. Higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a 0.5kTincrease of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.

Conclusions

A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.
Ablation of colonic epithelial Reg4+ support cells induces Notch-independent regeneration and mesenchymal remodeling
Authors: Wheeler Timothy W , Zemper Anne E
Published: January 2022

The colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche.

Graphical Abstract
A novel nematode species from the Siberian permafrost shares adaptive mechanisms for cryptobiotic survival withC. elegansdauer larva
Authors: Shatilovich Anastasia , Gade Vamshidhar R. , Pippel Martin , Hoffmeyer Tarja T. , Tchesunov Alexei V. , Stevens Lewis , Winkler Sylke , Hughes Graham M. , Traikov Sofia , Hiller Michael , Rivkina Elizaveta , Schiffer Philipp H. , Myers Eugene W , Kurzchalia Teymuras V.
Published: January 2022

Some organisms in nature have developed the ability to enter a state of suspended metabolism called cryptobiosis1when environmental conditions are unfavorable. This state-transition requires execution of a combination of genetic and biochemical pathways1,2,3that enable the organism to survive for prolonged periods. Recently, nematode individuals have been reanimated from Siberian permafrost after remaining in cryptobiosis. Preliminary analysis indicates that these nematodes belong to the generaPanagrolaimusandPlectus4. Here, we present precise radiocarbon dating indicating that thePanagrolaimusindividuals have remained in cryptobiosis since the late Pleistocene (∼46,000 years). Phylogenetic inference based on our genome assembly and a detailed morphological analysis demonstrate that they belong to an undescribed species, which we namedPanagrolaimus n. sp. Comparative genome analysis revealed that the molecular toolkit for cryptobiosis inPanagrolaimus n. sp. and inC. elegansis partly orthologous. We show that biochemical mechanisms employed by these two species to survive desiccation and freezing under laboratory conditions are similar. Our experimental evidence also reveals thatC. elegansdauer larvae can remain viable for longer periods in suspended animation than previously reported. Altogether, our findings demonstrate that nematodes evolved mechanisms potentially allowing them to suspend life over geological time scales.
Assessment of Out of Pocket Expenditure and associated factors for availing COVID-19 vaccination by the beneficiaries in Bengaluru: South India
Authors: Dodderi Sunil Kumar , Lakshmi H , Srividya J , Manjula S , Swathi R S
Published: January 2022

Background

Government of India has introduced COVID 19 vaccination in Jan 2021. There are no studies on out of pocket expenditure in COVID-19 vaccination in India, hence this study was undertaken to estimate the out of pocket expenditure for availing COVID 19 vaccine, to assess the factors associated with out of pocket expenditure for COVID vaccination and adverse events following immunisation.

Methods

This is a cross-sectional study conducted during Sep 2021-Dec 2021 of a medical college. A total of 438 study subjects above 18 years fulfilling inclusion and exclusion criteria were studied using probability proportional to population size. Data was collected using interview method by pre-tested semi structured proforma and analysed using descriptive & inferential statistics.

Results

The mean direct cost in Government vaccination centre was 3.24± 6.74 INR, indirect cost 809.10±1076.35 INR, total cost was 812.34 ±1079.49 INR.The mean direct cost in private vaccination centre was 1446.9±1845.65 INR, indirect cost 1140±1398 INR and total cost was 2586.90±2241.54 INR.

The mean total cost was OOPE for COVID 19 vaccination was 852.80 ±1128.512 INR, out of which direct cost was only 36.17(±359.20). The higher mean OOPE was found in loss of wages 670.02 INR. The factors associated with higher out of pocket expenditure was type of vaccine (P=0.031, OR=2.141, 95% CI=1.07-4.24) occupation of the study subject (P=0.000, OR=2.043, 95% CI= 1.37-3.03), reported stress following vaccination (P= 0.018, OR=1.72, 95%CI=1.098-2.703), adverse event within 48hrs (P=0.006, OR=2.125, 95% CI= 1.248-3.62), received any medication for adverse event (P=0.041, OR= 1.721, 95% CI= 1.022-2.84)

Conclusion

Majority of the study subjects utilized public facility. The higher mean out of pocket expenditure was for indirect cost loss of wages. This study shows that type of vaccine, occupation of the study subject and adverse event within 48 hrs, had 2 times higher out of pocket expenditure compared to other factors. Among the AEFI, fever was the most common, followed by pain at the injection site and myalgia.
The Correlation Between Brain Performance Capacity and COVID-19: A Cross-sectional Survey and Canonical Correlation Analysis
Authors: Liu Y , Chen X , Xian JS , Wang R , Ma K , Xu K , Yang X , Wang FL , Mu N , Wang S , Lai Y , Li T , Yang CY , Quan YL , Feng H , Wang LH , Chen TN
Published: January 2022

Objective

To generate a concept of brain performance capacity (BPC) with sleep, fatigue and mental workload as evaluation indicators and to analyze the correlation between BPC and the impact of COVID-19.

Methods

A cluster sampling method was adopted to randomly select 259 civil air crew members. The measurements of sleep quality, fatigue and mental workload (MWL) were assessed using the Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI-20) and NASA Task Load Index. The impact of COVID-19 included 7 dimensions scored on a Likert scale. Canonical correlation analysis (CCA) was conducted to examine the relationship between BPC and COVID-19.

Results

A total of 259 air crew members participated in the survey. Participants’ average PSQI score was 7.826 (SD = 3.796), with 49.8% reporting incidents of insomnia, mostly of a minor degree. Participants’ MFI was an average 56.112 (SD = 10.040), with 100% reporting some incidence of fatigue, mainly severe. The weighted mental workload (MWL) score was an average of 43.084 (SD = 17.543), with reports of mostly a mid-level degree. There was a significant relationship between BPC and COVID-19, with a canonical correlation coefficient of 0.507 (P=0.000), an eigenvalue of 0.364 and a contribution rate of 69.1%. All components of the BPC variable set: PSQI, MFI and MWL contributed greatly to BPC, with absolute canonical loadings of 0.790, 0.606 and 0.667, respectively; the same was true for the COVID-19 variable set, with absolute canonical loadings ranging from 0.608 to 0.951.

Conclusion

Multiple indicators to measure BPC and the interrelationship of BPC and COVID-19 should be used in future research to gain a comprehensive understanding of anti-epidemic measures to ensure victory in the battle against the spread of the disease.
Are high urea values before intravenous immunoglobulin replacement a risk factor for COVID-related mortality?
Authors: Aytekіn Gökhan , Atayik Emel
Published: January 2022

Objective

Since the World Health Organization accepted The Coronavirus Disease 2019 (COVID-19) as a pandemic and there is still no effective treatment, it becomes crucial that the physicians interested in COVID-19 treatment share all the data they acquire, particularly in vulnerable patient groups, to reduce morbidity and mortality.

Methods

The study included 81 adult (Female: 27, Male: 54) COVID-19 patients who were hospitalized for the treatment of COVID-19 between April 2020 and September 2020 and were followed-up, treated and consulted in the immunology clinic for intravenous immunoglobulin (IVIG) treatment.

Results

The univariate analysis found that the number of days of hospitalization in service, being intubated, number of IVIG treatment days, and the urea value before IVIG treatment were independent risk factors for mortality (p:0.043, p:0.001, p:0.074, p:0.004, respectively). As a result of multivariate analysis, being intubated and urea value before IVIG treatment were found to be independent risk factors for mortality (p:0.001 and p:0.009).

It was found that for 60 mg/dL level of urea value before IVIG treatment, the sensitivity value for mortality in COVID-19 patients was 46.2%, and the specificity was 35.5% (p:0.029)

Conclusion

The study found that urea values before IVIG treatment were a risk factor for mortality in patients who received IVIG treatment for COVID-19. This is important as it indicates that BUN values should be closely monitored in patients given IVIG treatment for COVID-19. It also suggests that when resources are limited and risk stratification is required in COVID-19 patients, BUN values can be helpful.
Current prices versus minimum costs of production for CFTR modulators
Authors: Guo Jonathan , Wang Junzheng , Zhang Jingchun , Fortunak Joseph , Hill Andrew
Published: January 2022

Background

While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of a select few countries. Despite this, there is currently limited evidence regarding access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment.

Methods

Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries.

Results

Costs of production for tezacaftor/ivacaftor/elexacaftor are estimated at $5676 [$4811-6539] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for tezacaftor/ivacaftor/elexacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion.

Conclusion

Tezacaftor/ivacaftor/elexacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy in LMICs, thereby exacerbating existing international inequalities in CF care. Urgent action is needed to increase availability of triple combination treatment worldwide.

Funding

None
Presentation collateral patterns and outcomes after endovascular thrombectomy for large vessel occlusion stroke
Authors: Regenhardt Robert W , Lev Michael H , He Julian , Dmytriw Adam A , Vranic Justin E , Rabinov James D , Stapleton Christopher J , Patel Aman B , Singhal Aneesh B , Gonzalez R Gilberto
Published: January 2022

Background

Endovascular thrombectomy (EVT) revolutionized large vessel occlusion (LVO) stroke. However, treatment decisions and prognostication are challenging without advanced imaging. We sought to determine the relationship of simple CTA collateral patterns and outcomes after EVT.

Methods

We identified patients with anterior LVO who underwent guideline based EVT from a single center from 2019-2020. Inclusion criteria were available CTA and 90-day modified Rankin Scale (mRS). Arterial-phase CTA collaterals were categorized as malignant, other, or symmetric.

Results

Among 74 patients, the median age was 75 and 49% were female. Collaterals were symmetric (36%), malignant (24%), or other (39%). Comparing collateral patterns there were no differences in demographics, presentations, time from last well, good reperfusion, or intracerebral hemorrhage. Median NIHSS was 18 for malignant, 19 for other, and 11 for symmetric (p=0.02). Intracranial ICA occlusions were present in 28% of malignant, 3% of other, and 11% of symmetric (p=0.04). Ninety-day mRS ≤2 was achieved in 17% of malignant, 38% of other, and 67% of symmetric. Collateral pattern was a significant determinant of 90-day mRS ≤2 (aOR=6.62, 95%CI=2.24,19.53; p=0.001) in a multivariable model including age, NIHSS, baseline mRS, thrombolysis, LVO location, and good reperfusion.

Conclusions

Simple CTA collateral pattern is a robust determinant of 90-day outcomes after EVT. Further prospective studies are needed to understand how collateral pattern can guide EVT treatment decisions and long-term prognosis.
RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds
Authors: Zwierzchowski-Zarate Amy N. , Kashmer Omar M. , Collazo-Lopez Josue E. , White Charles L. , Diamond Marc I.
Published: January 2022

Tau aggregation causes neurodegenerative tauopathies, and trans-cellular propagation of tau assemblies of unique structure, i.e. strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregationin vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formationin vitroand has been observed in association with neurofibrillary tangles in human brain. We tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. Three RNA homopolymers, polyA, polyU, and polyC all bound tau, but only polyA triggered seed and fibril formation.

PolyA:tau seeds and fibrils were sensitive to RNase. The origin of RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas other inducers produced strains that sectored. Finally, we found that soluble, but not insoluble, seeds from Alzheimer’s disease (AD) brain were sensitive to RNase. Thus, RNA specifically induces stable tau strains, and may trigger the formation of dominant pathological assemblies that propagate in AD, and possibly other tauopathies.
MUCOSECRETORY LUNG DISEASE: DIFFERENT ASSEMBLIES OF JAG1 AND JAG2 DETERMINE TRACHEOBRONCHIAL CELL FATE
Authors: Reynolds Susan D. , Hill Cynthia L. , Alsudayri Alfahdah , Lallier Scott W. , Wijeratne Saranga , Tan ZhengHong , Chiang Tendy , Cormet-Boyaka Estelle
Published: January 2022

Mucosecretory lung disease compromises airway epithelial function and is characterized by goblet cell hyperplasia and ciliated cell hypoplasia. These cell types are derived from tracheobronchial stem/progenitor cells via a Notch dependent mechanism. Although specific arrays of Notch receptors regulate cell fate determination, the function of the ligands Jagged1 (JAG1) and Jagged2 (JAG2) is unclear. This study used primary human bronchial air-liquid- interface cultures, gamma secretase inhibition, and neutralizing antibodies to show: 1) JAG1 and JAG2 were necessary for secretory progenitor cell fate determination; 2) JAG2 suppressed squamous differentiation; and 3) pausing of the ciliated cell differentiation process after Notch inhibition. Histological, cell fractionation, cell surface biotinylation, and ubiquitination analyses demonstrated that all cells were JAG1 positive but that little JAG1 was present on the cell surface. In contrast, JAG2 was expressed in a positive-negative pattern and was abundant on the cell surface. Glycogen synthase kinase 3 (GSK3) and tankyrase inhibition studies showed that GSK3 regulated JAG2 trafficking, and that this mechanism was WNT-independent. Collectively, these data indicate that variation in JAG2 trafficking creates regions of high, medium, and low ligand expression. Thus, distinct assemblies of JAG1 and JAG2 may regulate Notch signal strength and determine the fate of tracheobronchial stem/progenitor cells.

Abstract Figure

Graphical Abstract

Different assemblies of JAG1 and JAG2 may determine Notch signal strength and cell fate within the tracheobronchial epithelium. A cell which interacts with JAG1+ cells (blue squares) receives a low Notch signal (light yellow square). A cell which interacts with a mixture of JAG1+ and JAG1+/JAG2+ cells (purple squares) receives a medium (med) Notch signal (medium yellow square). A cell which interacts with JAG1+/JAG2+ cells receives a high Notch signal (bright yellow square).
A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Anti-apoptotic Protein in Kidney Cancer
Authors: Grubb Treg , Maganti Smruthi , Krill-Burger John Michael , Fraser Cameron , Stransky Laura , Radivoyevitch Tomas , Sarosiek Kristopher A. , Vazquez Francisca , Kaelin William G. , Chakraborty Abhishek A.
Published: January 2022

Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute’s Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-XL, but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-XL levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-XL dependence. Transcriptional profiling, however, identified a ‘BCL-XL dependency’ mRNA signature, which included elevated mesenchymal gene expression in BCL-XL dependent cells. Promoting mesenchymal transition increased BCL-XL dependence; whereas, conversion to a more differentiated state overcame BCL-XL dependence in kidney cancer cells. The ‘BCL-XL dependency’ mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-XL protein and justify further testing on BCL-XL blockade as a potential way to target a clinically aggressive subset of human kidney cancers.

One Sentence Summary

Cell state, but not pVHL and/or HIF status, defines the dependency of kidney cancer cells on the BCL-XL anti-apoptotic protein.
Group dynamics and habitat use of the Giant Otter, Pteronura brasiliensis (Zimmermann, 1780), in seasonally flooded forest in the Araguaia River, Central Brazil: A 10-years study
Authors: Leles Benaya , Georgiadis George , Susana Thais , Kaczmarek Nils , Brandão Reuber , Campello Silvana
Published: January 2022

We carried out monthly surveys of the giant otter population between 2010 and 2020 in a study area comprised of 1,500 hectares of igapó flooded forest with oxbow lakes in the Cantão region of central Brazil. We recorded 16-32 resident adults in the study area each year, distributed in 4-8 groups. Resident groups exhibited extensive home range overlap, with each group using several lakes and larger lakes used in rotation by up to six groups. Dens and campsites were also shared by multiple groups, but lakes were used by only one group at a time, and encounters between groups were very rare. 24 adult otters were observed to join an existing group. Some individuals changed groups multiple times. Resident adult turnover was high. Each year an average of 36% of resident adults were new immigrants, and 72% of groups left the area within two years. Resident groups had, on average, one litter every three years, and annual cub production showed high variability and a negative correlation to the number of new immigrants in the area. No pairs of giant otters reproduced successfully during the study. Groups of three otters formed through the recruitment of an adult individual by an existing pair and reproduced as successfully as larger groups. Group dynamics and territorial behavior in the Cantão flooded forest ecosystem, where optimal giant otter habitat is continuous in all directions, were found to be different from that reported in areas composed of patchy (isolated oxbow lakes) or linear (rivers) habitat. This suggest that giant otter social and territorial behavior is plastic and adapts to the spatial characteristics of the habitat.
The commercialist identity of mid-tier firm auditors: a precarious balancing of priorities
Authors: Harber Michael , Willows Gizelle D.
Published: January 2022

Purpose

This paper aims to extend our understanding of how mid-tier firm auditors legitimise and institutionalise the logic of commercialism within their profession. This paper is responsive to research that shows how Big Four auditors have restructured the market and re-cast the relationality between the two logics to forge an identity that suits them commercially. Such research provides insight into auditor agency and intentionality, illustrating how auditors maintain and indeed grow their status and role within society.

Design/methodology/approach

Semi-structured interviews with audit executives situated in a strategically challenging regulatory context are interpreted through a theoretical framework developed from institutional complexity theory, coupled with the understanding that institutional logics are a socially constructed phenomenon.

Findings

Mid-tier auditors appear to be as commercially orientated as their Big Four counterparts, expressing the logics of professionalism and commercialism as highly complementary. In response to competitive pressures and the difficulty of replicating the multi-disciplinary practice business model of the Big Four, mid-tier auditors present a competitive and contrasting identity as “more devoted experts”, using various legitimation techniques and “heroic” representations. This identity representation is strategic, allowing them to forge a consistent and coherent “collective identity defining story” designed to counter the “versatile expert” identity of the Big Four and establish social legitimacy with their potential client base.

Originality/value

These findings contribute to our understanding of how mid-tier auditors are “catching up” to the Big Four in the construction of their commercial business model. By shedding light on the rhetoric and “identity experimentation” of auditors, the findings can aid legislators and regulators to exercise democratic control over the profession and promulgate regulations that better align auditors’ interests with the public interest. As regulators encourage mid-tier firms to compete with the Big Four and lower supply concentration in the market, this study believes the tensions inherent in the logics, as well as the strategic necessity for firms to represent themselves in a favourable manner, will become more prominent.
N-containing heterocyclic benzotriazole derivatives as new corrosion inhibitor for mild steel contained in emulsion
Authors: Xiong Sang , Wu Hao , Liu Zhiyuan
Published: January 2022

Purpose

N-containing heterocyclic benzotriazole derivatives as new corrosion inhibitor for mild steel contained in emulsion were synthesized, and their inhibition behaviors for mild steel (MS) contained in emulsion were investigated by experiments and theoretical calculations, and this study aims to prove that two new inhibitors have excellent inhibition efficiency for steel corrosion.

Design/methodology/approach

2-(1H-benzo[d][1,2,3]triazol-1-yl)-N,N-dioctylacetamide (BTN) and O-(3-(1H-benzo[d] [1,2,3]triazol-1-yl)propyl) S-(2-(dioctylamino)-2-oxoethyl) carbonodithioate (BTSC) as a new corrosion inhibitor were synthesized, and their inhibition behaviors for MS contained in emulsion were investigated by gravimetric experiment, electrochemical tests and theoretical calculations.

Findings

Results of gravimetric experiment, electrochemical tests show that BTSC exhibit excellent inhibition performance, and it has a higher inhibition efficiency of 96.6% than that BTN. The resultant adsorption films from BTN/BTSC adsorbed on MS, effectively inhibiting the corrosion of MS is mainly through chemisorption and follow to Langmuir’s adsorption isotherm.

Originality/value

Experimental and theoretical calculations display that two new synthesized inhibitors are excellent corrosion inhibitor for MS contained in emulsion. Electrons of inhibitors mainly focus on the C, N, S and O atoms, which demonstrate these atoms are the centers of negative charge, and they supply electrons to Fe atoms through coordination bonds.
Silver bank: vulnerability and risks during cyberattacks
Authors: Horna César Jhonnatan , Toro Leonardo , Regalado-Pezua Otto
Published: January 2022

Learning outcomes

The learning outcome of this paper is to identify and interpret the risks linked to cyber-security and their impact on the organization. Analyze business management regarding cyber-security and information technology (IT) risk management. Evaluate and propose decision-making strategies for IT projects.

Case overview/synopsis

Silver Bank is a financial entity with broad national coverage. Its growth was directly related to its investments in customer service. The entire organization is focused on satisfying its clients’ needs, improving their experience and making them loyal to the company. However, it did not pay enough attention to a threat that, with time, had become more pronounced: cyber-attacks. Its efforts to fight against this threat were only temporary solutions, as gaps in its IT system made it an easy target for criminals until the arrival of Iván Ramírez, who proposes a holistic solution to decrease the probability and severity of these attacks. However, past experiences, ignorance and budget constraints make it a difficult task to convince the bank’s board of directors to implement the proposed solution.

Complexity academic level

The case can be used as teaching material in upper-level undergraduate and graduate management courses: –undergraduate courses: information technology management, IT project analysis and management – MBA or graduate courses: information technology management, strategic management and security governance.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Testing factor models in an emerging market: evidence from India
Authors: Singh Kewal , Singh Anoop , Prakash Puneet
Published: January 2022

Purpose

This paper aims to investigate the explanatory power of the Fama-French five-factor model and compares it to the other asset pricing models. In addition, the paper examines the contributions of two additional factors: profitability and investment factor. The authors test the alternative four-factor models.

Design/methodology/approach

The authors use stock returns data of BSE-500 listed firms for the Indian market, an emerging market, from 1999 to 2020, thus covering the post-Asian crisis and pre- and post-financial crisis (2007–2008) periods. The authors employ 75 and 96 portfolios based on different factors. To check the performance of asset pricing models, the authors also used the GRS F-statistics and factor spanning tests.

Findings

The authors find that the five-factor model and alternative four-factor model outperform the three-factor model. Contrary to the findings for the US, but similar to the Chinese stock market, the value factor is significant for the Indian stock market. Simultaneously, the authors also find that the investment factor has no explanatory power in the presence of the profitability factor in their sample.

Originality/value

To the best of the authors' knowledge, this is the most comprehensive study using data more than two decades. These results are based on 75 (25 × 3) portfolios based on size, value, profitability and investment. The authors also tested these results based on 96 (32 × 3) portfolios to check robustness, and these results still hold. Furthermore, the authors find that factors based on 2 × 3 sorting have higher explanatory power than those based on 2 × 2 and 2 × 2 × 2 × 2 sorting.
Can reviews predict reviewers’ numerical ratings? The underlying mechanisms of customers’ decisions to rate products using Latent Dirichlet Allocation (LDA)
Authors: Poushneh Atieh , Rajabi Reza
Published: January 2022

Purpose

Two valuable pieces of information – reviews and their corresponding numerical ratings – are accessible to potential customers before they make a purchasing decision. An extensive body of marketing literature has scrutinized the influence of customers’ reviews by linking such aspects as the volume and valance of reviews with product sales and customers’ purchase intention. The aim of this study, for which dual coding theory was used, was to understand the relationship between reviews and their corresponding numerical ratings.

Design/methodology/approach

The authors used the latent Dirichlet allocation technique to categorize customers’ reviews. The present findings contribute to the literature by showing the underlying mechanisms that customers use to interpret reviews and associate them with numerical ratings.

Findings

The gradient boosted decision tree model demonstrates that non-abstract-dominant reviews (reviews mainly consist of tangible objects, actions, events or affective words) are significant predictors of their corresponding numerical ratings. However, abstract-dominant reviews (i.e. those consisting primarily of intangible objects, events or actions) cannot predict their associated numerical ratings.

Originality/value

The present findings contribute to the literature by showing the underlying mechanisms that customers use to interpret reviews and associate them with numerical ratings.
How does diplomat partners’ employment situation affect their adjustment abroad? Evidence from the German Foreign Service
Authors: Rosenbaum-Feldbrügge Matthias , Waibel Stine , Fliege Herbert , Bellinger Maria M. , Rüger Heiko
Published: January 2022

Purpose

Previous research indicates that accompanying partners often struggle to find employment upon international relocations. This study aims to highlight diplomat’s partners’ employment situation and to examine how unrealized professional aspirations affect their socio-cultural and psychological adjustment in the foreign environment.

Design/methodology/approach

This study applies OLS regression analysis to a sample of 220 partners of German Foreign Service diplomats who were surveyed regarding their locational adjustment, general stress and perceived quality of life using an online questionnaire. This study differentiates between working partners (19.5% of the total sample), non-working partners with a desire to obtain paid employment (65.5%) and partners who are unemployed by choice (15.0%).

Findings

The results demonstrate that partners’ employment situation and employment aspirations are important variables explaining differences in socio-cultural and psychological adjustment. Working partners reveal the highest levels of general stress, non-working partners with an employment desire report the lowest levels of locational adjustment and non-working partners without employment aspirations experience the highest quality of life.

Research limitations/implications

As this study has a cross-sectional design, the authors are not able to deal with potential issues of reverse causality.

Practical implications

Sending organizations should consider accompanying partners' unrealized employment aspirations by providing services with regard to job search and career development. Moreover, they should ensure the provision of services that support the work–life balance of working couples.

Originality/value

Previous research only sparsely examined the adjustment and well-being of partners accompanying foreign service employees, who are in contrast to business expatriates required to relocate every three to five years. Moreover, this study features the crucial role of partners' employment situation and discusses possibilities to promote spousal employment, as well as complementary measures to improve work–life balance for dual-earner couples.
A case study on a flexible floor plan design for South Korean apartments using two types of margins
Authors: Yoon Chaeshin , Kim Marie , Park Jinho , Lee Jeayoung
Published: January 2022

Purpose

The purposes of this study are to prove that the content of floor flexibility can be designed objectively with the use of margins, which are an architectural vocabulary visualizing the possibility of formal change, and to conduct a case study on how the existing typical floor plans of South Korean apartments change with the extension of flexibility: the usability of margins and the results.

Design/methodology/approach

This study reviews two housing projects with different methods of flexible housing design: one is the flexibility to change the sizes of spaces and the other is the flexibility to change the topology of spaces. In this paper, the architectural term “area margin” is used for the former and “linear margin” for the latter. These were applied to the case of current apartments in South Korea to transform them into floor plans with the two types of flexibility and investigated whether the proposed floor plans satisfy the required efficacy structurally and functionally.

Findings

This case study shows that margins can be used as architectural vocabularies representing flexible sizes of rooms and flexible boundaries with neighbors. The final form of the structural framework became homogeneous, even though it conserved its indigenous spatial characteristics of abundant natural sunlight and airflow. In addition, the transformed structural framework has higher rigidity than the original one, even though the transversal wall was cut off with a margin, as shown by the schematic representations in this paper.

Research limitations/implications

The alternative plan, designed as a modification process, is not representative as a flexible floor plan. Rather, it is thought more important to make a range of variations rather than prototyping a model. This study starts from the premise that it is desirable for apartment house plans to share and encourage variations rather than aiming at typical sizes and shapes. Furthermore, this study exemplified the process to modify the existing typical floor plan into a flexible one using margins. Through this modification, it is thought that the typology of the South Korean apartment, which has succeeded in gaining social consensus for half a century, can be preserved while accommodating social changes in the future.

Social implications

The control of future variations of floor plans will extend the socioeconomic and physical life of a building, enabling a reasonable reinvestment of resources.

Originality/value

This paper deals with a design method applying distinct visual symbols to different contexts of flexibility and using those as architectural vocabularies.
A BIM-based LCA tool for sustainable building design during the early design stage
Authors: Kamari Aliakbar , Kotula Bartlomiej Marek , Schultz Carl Peter Leslie
Published: January 2022

Purpose

A robust method in environmental load assessment of buildings is urgently required to reduce the environmental burden of the construction industry. While the industry utilizes the life cycle assessment (LCA) method to assess environmental impacts of detailed designs, the implementation of changes at that late stage of development is often expensive and undesirable. On the other hand, during the early design stages, the LCA method is severely limited by the lack of information available, e.g., uncertainty about final materials to be used. This research study investigates how building information modeling (BIM) can facilitate LCA analysis at an early design stage.

Design/methodology/approach

A literature review is conducted to establish a framework for BIM and LCA integration, which creates the foundation for the development of a new BIM-based LCA tool. The tool is empirically evaluated on a large case study of a residential building in Denmark.

Findings

Case study results show that the new tool facilitates decision-making in an integrated design process, providing reliable LCA results on an early stage model, while avoiding intermediate manual input by the end user in contrast to other commercial LCA tools.

Originality/value

A first prototype of a BIM-based tool is demonstrated, which allows professionals, small architectural companies, students and researchers to calculate the environmental loads of the building in the early design stage in an automated, transparent and time-saving manner.