bluuebunny/crossref_metadata_2025 huggingface dataset:
Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation
Authors: Ocansey Sharon , Pullen Debbie , Atkinson Patricia , Clarke Antonia , Hadonou Medard , Crosby Charlene , Short John , Lloyd Ian Christopher , Smedley Damian , Assunta Albanese ,   Genomics England Research Consortium, Shah Pratik , McEntagart Meriel
Published: October 2021

DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco–Sjogren and Wolcott–Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.
Primary immunodeficiency and the microbiome
Authors: Al-Nesf Maryam Ali , Morgan David , Mohamed-Ali Vidya
Published: October 2021

Purpose of review

The current understanding of the relationship of the microbiota to clinical manifestation in patients with primary immunodeficiency, specifically the inflammatory processes caused by or that result in microbial dysbiosis, and their potential therapeutic options in primary immunodeficiency diseases (PID), is the basis of this review.

Recent findings

PIDs are heterogeneous diseases with variable presentations, genetic backgrounds, complications, and severity. The immune-mediators may be extrinsic, such as therapeutic regimens that patients are on, including immunoglobin, biologics, antibiotics and diet, or intrinsic, like cytokines, microRNA and microbiome. The microbiome in PID, in particular, appears to play a crucial role in helping the host's immune system maintain hemostatic control in the intestine. Many of the clinical manifestations and complications of PID may be attributed to inflammatory and immune dysregulatory processes connected to the imbalances of the diet-microbiota-host-immunity axis, as shown by data pointing to the loss of microbial diversity, dysbiosis, in PID.

The gut microbiome is a promising area of study in PID. Although the connection of the microbiome to humoral immunodeficiency is evident, the possibility of utilizing the association of humoral and cellular immunodeficiency and the microbiome for therapeutic benefit is still under investigation.
Analysis of Emergency Department Visits and Unplanned Readmission After Bariatric Surgery: An Experience From a Tertiary Referral Center
Authors: Makki Hayder , Mahdy Tarek , Emile Sameh H. , Nofal Heba , Asaad Yaser , Abdulateef Omar , Rasheed Marwan , Madyan Amr
Published: October 2021

Background:

Bariatric surgery is the most effective treatment of morbid obesity. As the number of bariatric procedures performed has increased, visits to the emergency department (ED) and readmissions have subsequently increased. The present study aimed to assess the rates and indications for of ED visits and readmission after bariatric surgery and to identify the predictors of hospital readmission.

Patients and Methods:

This was a retrospective cohort study on patients who underwent bariatric surgery from January 2018 to April 2020. The percentage of ED visits and unplanned readmission was estimated and the indications and management of each were analyzed. The association of age, sex, body mass index, and type of procedure with readmission was assessed.

Results:

Of 582 patients who underwent bariatric surgery in the study period, 204 (35%) required ED visits, and 42 (7.2%) required readmission. The mean age of patients was 33 years, and the mean body mass index was 43 kg/m2. The most common indication for ED visits was abdominal pain (41.2%). In all, 64.8% of ED visits and 43% of readmissions were unrelated to bariatric surgery complications. A total of 94.1% of patients who required ED visits and 71.4% of readmitted patients were managed conservatively. The most common procedure followed by readmission was laparoscopic sleeve gastrectomy (50%) then one-anastomosis gastric bypass (21.4%). Age, sex, body mass index, and procedure type were not significantly associated with higher readmission.

Conclusions:

The rates of ED visits and readmission in our cohort were 35% and 7.2%, respectively. Most cases of ED visits were not related to adverse effects of bariatric surgery and the majority of which were managed conservatively.
BREAst screening Tailored for HEr (BREATHE) - A Study Protocol On Personalised Risk-based Breast Cancer Screening Programme
Authors: Liu Jenny , Ho Peh Joo , Ling Tan Tricia Hui , Yeoh Yen Shing , Chew Ying Jia , Mohamed Riza Nur Khaliesah , Khng Alexis Jiaying , Goh Su-Ann , Wang Yi , Oh Han Boon , Chin Chi Hui , Kwek Sing Cheer , Zhang Zhi Peng , Seng Ong Desmond Luan , Quek Swee Tian , Tan Chuan Chien , Wee Hwee Lin , Li Jingmei , Choong Iau Philip Tsau , Hartman Mikael
Published: October 2021

Background

Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore.

Methods/Design

Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ∼3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score.

Discussion

For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

Trial registration

Not applicable.
Clinical observation of high-flow nasal cannula with non-rebreather mask use on severe or critically ill COVID-19 diabetic patients
Authors: Tareq Bhuiyan AFM , Nath Sudipta Deb , Hossain Md Jakir , Das Shuva , Das Moumita , Ahsan Moinul , Ziad Md. Iftekher-E-Alam , Padma Fahmida Khatun , Dey Rana , Shamsul Alam AKM , Zehan Farial Hoque , Saha Ayan
Published: October 2021

Background and aims

Prevalence of diabetes is a vital factor in COVID-19’s clinical prognosis. This study aimed to investigate and compare the efficacy of High-flow Nasal Cannula (HFNC) with/without non-rebreather mask (NRM) use on critical COVID-19 patients with/without diabetes.

Methods

For analysis and comparison, epidemiological, biochemical, and clinical data were collected from 240 HFNC (±NRM) treated severe and critical COVID-19 patients (diabetic = 136; non-diabetic = 104) admitted into ICUs of five hospitals in Chattogram, Bangladesh.

Results

59.1% of patients with fever had diabetes (p=0.012). ICU stay was longer for diabetic patients (9.06±5.70) than non-diabetic patients (7.41±5.11) (p=0.020). Majority of the hypertensive patients were diabetic (68.3%; p<0.001). Majority of diabetic patients (70.4%; p<0.005) had elevated creatinine levels. Partial pressure of oxygen (mmHg) after HFNC (only) administration was significantly (p=0.031) higher in non-diabetic patients (69.30±23.56) than in diabetic patients (61.50±14.49). Diabetic (62.64±13.05) and non-diabetic patients (59.40±13.22) had almost similar partial pressure of oxygen (mmHg) from HFNC with NRM. Patients with elevated RBS required NRM with HFNC five times (AOR=5.1, 1.2-20.8) higher than others. Besides age, and hypertension were significantly associated with the HFNC+NRM treated diabetic patients. Factors those affected the HFNC only treated patients were fever and impaired glucose tolerance.

Conclusions

The results of this study imply that oxygen supply with HFNC and NRM may be beneficial for the elderly/hypertensive diabetic patients with COVID-19 associated AHRF; and that increased blood glucose level could be a determinant for the need of HFNC + NRM treatment.

Highlights

Elderly diabetic patients required both HFNC and NRM to increase oxygen saturation.

Hypertension may be a factor for diabetic patients with COVID-19 requiring HFNC and NRM together.

‘HFNC + NRM’-combination therapy might be needed when blood glucose levels rise.
COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort
Authors: Ward Andrew , Sarraju Ashish , Lee Donghyun , Bhasin Kanchan , Gad Sanchit , Beetel Rob , Chang Stella , Bonafede Mac , Rodriguez Fatima , Dash Rajesh
Published: October 2021

Introduction

Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort.

Methods

We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression.

Results

There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38–1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95–1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98–1.25) and MI (HR 0.93, 95% CI 0.85–1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19–1.56) and PE (HR 1.82, 95% CI 1.57–2.10) in patients with COVID-19.

Conclusion

In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.
Molecular evidence of coinfection with acute respiratory viruses and high prevalence of SARS-CoV-2 among patients presenting flu-like illness in Bukavu city, Democratic Republic of Congo
Authors: Ntagereka Patrick Bisimwa , Basengere Rodrigue Ayagirwe , Baharanyi Tshass Chasinga , Kashosi Théophile Mitima , Buhendwa Jean-Paul Chikwanine , Bisimwa Parvine Basimane , Kusinza Aline Byabene , Mugumaarhahama Yannick , Shukuru Dieudonné Wasso , Patrick Simon Baenyi , Tonui Ronald , Birindwa Ahadi Bwihangane , Mukwege Denis
Published: October 2021

The coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with clinical manifestation cases are almost similar to those of common respiratory viral infections. This study determined the prevalence of SARS-CoV-2 and other acute respiratory viruses among patients with flu-like symptoms in Bukavu city Democratic republic of Congo. We screened 1352 individuals with flu-like illnesses seeking treatment in 10 health facilities. Nasopharyngeal swabs specimens were collected to detect SARS-CoV-2 using real-time reverse transcription-polymerase chain reaction (RT-PCR) and 10 common respiratory viruses were detected by multiplex reverse transcription polymerase chain reaction assay. Overall, 13.9% (188/1352) patients were confirmed positive for SARS-CoV-2. Influenza A 5.6% (56/1352), and Influenza B 0.9% (12/1352) were the most common respiratory viruses detected. Overall more than two cases of the other acute respiratory viruses were detected. Frequently observed symptoms associated with SARS-CoV-2 positivity were shivering (47.8%; OR= 1.8; CI: 0.88-1.35), cough (89.6%; OR=6.5, CI: 2.16-28.2), myalgia and dizziness (59.7%; OR=2.7; CI: 1.36-5.85). Moreover, coinfection was observed in 12 (11.5%) specimens. SARS-CoV-2, and Influenza A were the most co-occurring infections, accounting for 33.3% of all positive cases. This study demonstrates cases of COVID-19 infections co-occurring with other acute respiratory infections in Bukavu city during the ongoing outbreak of COVID-19. These data emphasize the need for routine testing of multiple viral pathogens for better prevention and treatment plans.
Fatigue does not increase limb asymmetry or induce proximal joint power shift during sprinting in habitual, multi-speed runners
Authors: Vial Shayne , Cochrane Wilkie Jodie , Anthony Mitchell , Turner Mitchell , Blazevich J.
Published: October 2021

The ability to shift from walking and jogging to sprinting gaits, even when fatigued after prolonged effort, would have been as useful to our hunter-gatherer ancestors as it is to modern athletes. During prolonged jogging, joint moment and work decrease in the distal (ankle) joint but increase at proximal (hip/knee) joints as fatigue progresses, and such adaptations might be expected to occur in sprinting. Fatigue is also thought to increase inter-limb kinematic and force production asymmetries, which are speculated to influence injury risk. However, the effects of running-related fatigue on sprint running gait have been incompletely studied, so these hypotheses remain untested. We studied 3-D kinematics and ground reaction force production in dominant (DL) and non-dominant (NDL) legs during both non-fatigued and fatigued sprinting in habitual but uncoached running athletes. Contrary to the tested hypotheses, relative between-leg differences were greater in non-fatigued than fatigued sprinting. When not fatigued, DL produced greater propulsive impulse through both greater positive and negative work being done at the ankle, whilst NDL produced more vertical impulse, possibly resulting from the greater hip flexion observed prior to the downwards acceleration of the foot towards the ground. Whilst few changes were detected in DL once fatigued, NDL shifted towards greater horizontal force production, largely resulting from an increase in plantarflexion (distal-joint) moments and power. After fatiguing running, therefore, inter-limb asymmetry was reduced during sprinting and no distal-to-proximal shift in work/power was detected. Speculatively, these adaptations may help to attenuate decreases in running speed whilst minimising injury risk.

Significance

The ability to attain fast running speeds may critically determine success in tasks such as prey chase- and-capture in hunter-gatherer societies as well as success in modern sports competitions. At times, sprint running may have to be performed whilst fatigued from previous, longer-distance running, when speeds are reduced, and injury risk may be higher. Previous work indicated that fatigue prompts a proximal shift in joint work and power production and an increase in inter-limb asymmetry. On the contrary, we show that relative ankle positive and negative joint work was maintained in the face of fatigue and that inter-limb asymmetry was reduced in a group of runners experienced, but not formally instructed, in both long-distance and sprint running.
Colon Innervating TRPA1 Positive Nociceptors Influence Mucosal Health In Mice
Authors: Kumar Vibhu , Kumar Vijay , Devi Kirti , Kumar Ajay , Khan Rehan , Singh Ravindra Pal , Rajarammohan Sivasubramanian , Kondepudi Kanthi Kiran , Chopra Kanwaljit , Bishnoi Mahendra
Published: October 2021

Introduction

Transient receptor potential ankyrin-1 positive (TRPA1+ve) nociceptors, primarily present as peptidergic neuronal afferents in the colon are sensors of disturbance in lower gastrointestinal tract including pain induced by different pathologies. Their therapeutic role in the alleviation of chronic pain (receptor antagonism and receptor desensitization) associated with inflammatory bowel diseases (IBD) is reported. However, there is limited literature available about their role in formation and sustenance of the mucosal layer, and its interaction with host physiology as well as luminal microbial community. The aim of this study focuses on the effects of nociceptive TRPA1 channel desensitization on colonic mucus production and gut health.

Methods

TRPA1+ve nociceptors were desensitized by rectal administration of capsazepine. Ileum, colon was harvested and cecum content was collected. We performed morphological/histological analysis, gut permeability alteration, gene expression changes, colon metabolite profiling, and gut microbial abundance in these animals.

Results

We found that presence of TRPA1-positive nociceptors is required for mucus layer integrity, using an intra-rectal capsazepine-induced TRPA1 desensitization model. Desensitization of TRPA1 positive nociceptors resulted in damaged mucosal lining, resultant increase in gut permeability and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions.

Conclusion

These results suggest that caution may need to be exercised before employing TRPA1 desensitization as a therapeutic option to alleviate pain caused due to IBD.
PathoClock and PhysioClock in mice recapitulate human multimorbidity and heterogeneous aging
Authors: Salimi Shabnam , Pettan-Brewer Christina , Ladiges Warren C
Published: October 2021

Multimorbidity is a public health concern and an essential component of aging and healthspan but understudied because investigative tools are lacking that can be translatable to capture similarities and differences of the aging process across species and variability between individuals and individual organs. To help address this need, body organ disease number (BODN) borrowed from human studies was applied to C57BL/6 (B6) and CB6F1 mouse strains at 8, 16, 24 and 32 months of age, as a measure of systems morbidity based on pathology lesions to develop a mouse PathoClock resembling clinically based Body Clock in humans, using Bayesian inference. A mouse PhysioClock was also developed based on measures of physiological domains including cardiovascular, neuromuscular, and cognitive function in the same two mouse strains so that alignment with BODN was predictable. The results revealed between- and within-age variabilities in PathoClock and PhysioClock, as well as between-strain variabilities. Both PathoClock and PhysioClock correlated with chronological age more strongly in CB6F1 than C57BL/6. Prediction models were then developed, designated as PathoAge and PhysioAge, using regression models of pathology and physiology measures on chronological age. PathoAge better predicted chronological age than PhysioAge as the predicted chronological and observed chronological age for PhysioAge were complex rather than linear. In conclusion, PathoClock and PhathoAge can be used to capture biological changes that predict BODN, a metric developed in human, and compare multimorbidity across species. These mouse clocks are potential translational tools that could be used in aging intervention studies.
V-type H+ ATPase Activity is Required for Embryonic Dorsal-Ventral Symmetry Breaking
Authors: Schatzberg Daphne , Thomas Christopher F. , Reidy Patrick , Hadyniak Sarah E. , Skidanova Viktoriya , Lawton Matthew , Dojer Luz , Kitchloo Shweta , Zuch Daniel T. , Bradham Cynthia A.
Published: October 2021

The mechanism for embryonic dorsal-ventral (DV) symmetry breaking is idiosyncratic to the species, then converges on polarized expression of BMP signaling ligands. Here, we show that V-ATPase (VHA) activity is an early requirement for DV symmetry breaking in sea urchin embryos. In these basal deuterostomes, DV specification is mediated by ventral Nodal expression that leads to the establishment of a BMP signaling gradient. Nodal expression occurs downstream from p38 MAPK, which is transiently asymmetrically active. We show that VHA activity is required for DV symmetry breaking upstream from both p38 MAPK and Nodal. We rescue VHA-mediated ventralization by enforcing Nodal signaling asymmetry. We identify a VHA-dependent DV voltage gradient and also find that VHA activity is required for hypoxia inducible factor (HIF) activation. However, neither hyperpolarization nor HIF activation account for the dorsalizing effects of VHA, implicating a third unknown pathway that connects VHA activity to p38 MAPK symmetry breaking.

Graphical Abstract
Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14
Authors: Tomasek Kathrin , Leithner Alexander , Glatzova Ivana , Lukesch Michael S. , Guet Călin C. , Sixt Michael
Published: October 2021

A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on dendritic cells as a previously undescribed binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of pathogenic bacteria to CD14 lead to reduced dendritic cell migration and blunted expression of co-stimulatory molecules, both rate-limiting factors of T cell activation. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease.
Rapid cell-free characterization of multi-subunit CRISPR effectors and transposons
Authors: Wimmer Franziska , Mougiakos Ioannis , Englert Frank , Beisel Chase L.
Published: October 2021

CRISPR-Cas biology and technologies have been largely shaped to-date by the characterization and use of single-effector nucleases. In contrast, multi-subunit effectors dominate natural systems, represent emerging technologies, and were recently associated with RNA-guided DNA transposition. This disconnect stems from the challenge of working with multiple protein subunits in vitro and in vivo. Here, we apply cell-free transcription-translation (TXTL) to radically accelerate the characterization of multi-subunit CRISPR effectors and transposons. Numerous DNA constructs can be combined in one TXTL reaction, yielding defined biomolecular readouts in hours. Using TXTL, we mined phylogenetically diverse I-E effectors, interrogated extensively self-targeting I-C and I-F systems, and elucidated targeting rules for I-B and I-F CRISPR transposons using only DNA-binding components. We further recapitulated DNA transposition in TXTL, which helped reveal a distinct branch of I-B CRISPR transposons. These capabilities will facilitate the study and exploitation of the broad yet underexplored diversity of CRISPR-Cas systems and transposons.

HIGHLIGHTS

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PAM-DETECT for rapid determination of PAMs for Type I CRISPR-Cas systems in TXTL

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Mining of Type I orthologs and characterization of extensively self-targeting systems

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TXTL-based assessment of DNA target recognition and transposition by CRISPR transposons

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Identification of a distinct branch of Type I-B CRISPR transposons
Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice
Authors: Bai Yunhong , Treins Caroline , Volpi Vera G. , Scapin Cristina , Ferri Cinzia , Mastrangelo Rosa , Touvier Thierry , Florio Francesca , Bianchi Francesca , Del Carro Ubaldo , Baas Frank F. , Wang David , Miniou Pierre , Guedat Philippe , Shy Michael E. , D’Antonio Maurizio
Published: October 2021

Charcot Marie Tooth diseases type 1A (CMT1A), caused by duplication of Peripheral Myelin Protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene are the two most common forms of demyelinating CMT (CMT1) and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modeled by MpzR98C/+ mice that also show ER-stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER-stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER-stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analyzed by behavioral, neurophysiological, morphological and biochemical measures. Both MpzR98C/+ and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild type values. Taken together our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in Amyotrophic Lateral Sclerosis and Multiple Sclerosis animal models, these data demonstrate its potential in managing UPR and ER-stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases.
Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers
Authors: Mugarza Edurne , van Maldegem Febe , Boumelha Jesse , Moore Christopher , Rana Sareena , Sopena Miriam Llorian , East Philip , Ambler Rachel , Anastasiou Panayiotis , Clavijo Pablo Romero , Valand Karishma , Cole Megan , Molina-Arcas Miriam , Downward Julian
Published: October 2021

Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harbouring KRASG12C mutations, but drug resistance frequently develops. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect anti-tumour immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterised how KRASG12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition upregulates interferon signaling via Myc inhibition, leading to reduced tumour infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumour model. KRASG12C inhibition fails to sensitize cold tumours to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.

One sentence summary

KRAS inhibition mobilizes anti-tumour immunity in immunogenic lung cancer models through derepressing interferon signaling via repression of Myc.
Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis
Authors: Gupta Shikha , Dovey Oliver M. , Domingues Ana Filipa , Cyran Oliwia W. , Cash Caitlin M. , Giotopoulos George , Rak Justyna , Cooper Jonathan , Gozdecka Malgorzata , Asby Ryan J. , Al-Jabery Noor , Hernandez-Hernandez Victor , Prabakaran Sudhakaran , Huntly Brian J. , Vassiliou George S. , Pina Cristina
Published: October 2021

Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of pre-malignancy to cancer. To investigate this, we initiated pre-leukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA-sequencing of pre-leukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of pre-leukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. In other words, transcriptional variability confers forward momentum to cell fate systems, with differential multi-stage impact throughout cancer evolution.

One-sentence summary

Loss of Kat2a enhances transcriptional variability of ribosome biosynthetic programs and transiently accelerates pre-leukemia
Liposomal encapsulation of polysaccharides (LEPS) as an effective vaccine strategy to protect aged hosts against S. pneumoniae infection
Authors: Bhalla Manmeet , Nayerhoda Roozbeh , Tchalla Essi Y. I. , Abamonte Alexsandra , Park Dongwon , Simmons Shaunna R. , Pfeifer Blaine A. , Bou Ghanem Elsa N.
Published: October 2021

Despite the availability of licensed vaccines, pneumococcal disease caused by the bacteria Streptococcus pneumoniae (pneumococcus), remains a serious infectious disease threat globally. Disease manifestations include pneumonia, bacteremia, and meningitis, resulting in over a million deaths annually. Pneumococcal disease disproportionally impacts elderly individuals ≥65 years old. Interventions are complicated through a combination of complex disease progression and 100 different bacterial capsular polysaccharide serotypes. This has made it challenging to develop a broad vaccine against S. pneumoniae, with current options utilizing capsular polysaccharides as the primary antigenic content. However, current vaccines are substantially less effective in protecting the elderly. We previously developed a Liposomal Encapsulation of Polysaccharides (LEPS) vaccine platform, designed around limitations of current pneumococcal vaccines, that allowed the non-covalent coupling of polysaccharide and protein antigen content and protected young hosts against pneumococcal infection in murine models. In this study, we modified the formulation to make it more economical and tested the novel LEPS vaccine in aged hosts. We found that in young mice (2-3 months), LEPS elicited comparable responses to the pneumococcal conjugate vaccine Prevnar-13. Further, LEPS immunization of old mice (20-22 months) induced comparable antibody levels and improved antibody function compared to Prevnar-13. Importantly, LEPS protected old mice against both invasive and lung localized pneumococcal infections. In summary, LEPS is an alternative and effective vaccine strategy that protects aged hosts against different manifestations of pneumococcal disease.
Experimental evolution of extremophile levels of radiation resistance in Escherichia coli
Authors: Bruckbauer Steven T. , Minkoff Benjamin B. , Shinohara Takeshi , Lipzen Anna , Guo Jie , Wood Elizabeth A. , Sussman Michael R. , Pennacchio Christa , Cox Michael M.
Published: October 2021

Recent human development of high-level sources of ionizing radiation (IR) prompts a corresponding need to understand the effects of IR on living systems. One approach has focused on the capacity of some organisms to survive astonishing levels of IR exposure. Using experimental evolution, we have generated populations of Escherichia coli with IR resistance comparable to the extremophile Deinococcus radiodurans. Every aspect of cell physiology is affected. Cellular isolates exhibit approximately 1,000 base pair changes plus major genomic and proteomic alterations. The IR resistance phenotype is stable without selection for at least 100 generations. Defined and probable contributions include alterations in cellular systems involved in DNA repair, amelioration of reactive oxygen species, Fe metabolism and repair of iron-sulfur centers, DNA packaging, and intermediary metabolism. A path to new mechanistic discoveries, exemplified by an exploration of rssB function, is evident. Most important, there is no single molecular mechanism underlying extreme IR resistance.
Plant growth and phytoactive alkaloid synthesis in Mitragyna speciosa (kratom) in response to varying radiance
Authors: Zhang Mengzi , Sharma Abhisheak , León Francisco , Avery Bonnie , Kjelgren Roger , McCurdy Christopher R. , Pearson Brian J.
Published: October 2021

The dose-dependent consumptive effect of kratom and its potential application as an alternative source of medicine to mitigate opioid withdrawal symptoms has brought considerable attention to this plant. Increased interest in the application and use of kratom has emerged globally, including North America. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the impact of plant production environment on growth and kratom alkaloids synthesis is unavailable. To directly address this need, kratom plant growth, leaf chlorophyll content, and alkaloid concentration were evaluated under three lighting conditions: outdoor full sun, greenhouse unshaded, and greenhouse shaded. Nine kratom alkaloids were quantified using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Contents of six alkaloids to include: mitragynine, speciogynine, speciociliatine, mitraphylline, coynantheidine, and isocorynantheidine were not significantly impacted by lighting conditions, whereas 7-hydroxymitragynine was below the lower limit of quantification across all treatments. However, paynantheine concentration per leaf dry mass was increased by 40% and corynoxine was increased by 111% when grown under shade conditions in a greenhouse compared to outdoor full sun. Additionally, total alkaloid yield per plant was maximized when plants were under such conditions. Greenhouse cultivation generally promoted height and width extension, leaf number, leaf area, average leaf size, and total leaf dry mass, compared to outdoor full sun condition. Rapid, non-destructive chlorophyll evaluation correlated well (r2 = 0.68) with extracted chlorophyll concentrations. Given these findings, production efforts where low-light conditions can be implemented are likely to maximize plant biomass and total leaf alkaloid production.
Collaborative spaces: at the intersection of design and management
Authors: Bachnik Katarzyna , Moll Isa , Montaña Jordi
Published: October 2021

Purpose

Because of the differing perceptions held by each position or professional subculture, forming a collaborative and productive workplace with design and management teams can be challenging. In light of these anticipated obstacles to success in the workplace, this paper aims to ascertain the prospects for common undertakings within a business.

Design/methodology/approach

This paper reports on an analysis of a survey conducted among design and business students who had the opportunity to work together on a joint project and present their recommendations for an actual market-based organization.

Findings

Despite differences between the groups, there is a common understanding of organizational goals and willingness to undertake a joint effort to achieve them. This is accomplished through leveraging one another’s professional expertise, building trust through finishing the business projects and discovering tangible end results. Any evident differences between the groups seem to complement one another, thus creating common ground for effective collaboration.

Research limitations/implications

This is a study of a limited number of students enrolled in two universities in Spain. To ensure generalizability, research extended to more higher education institutions is needed.

Practical implications

The authors strongly believe that students are the future of business. As a result, understanding how they perceive any tension, integration or responsibilities of design and management helps with curriculum development two-fold: first, student perceptions help address any issues that can increase or hinder chances for efficient collaboration; second, student perceptions address the larger issue of design–management integration in business.

Originality/value

The authors studied a unique environment for collaboration beyond traditional organizational divisions and allowed study behaviors of students representing two professional backgrounds.
Hybrid organizational forms in public sector’s digital transformation: a technology enactment approach
Authors: Faro Benjamin , Abedin Babak , Cetindamar Dilek
Published: October 2021

Purpose

The purpose of this paper is to examine how public sector organizations become nimbler while retaining their resilience during digital transformation.

Design/methodology/approach

The study adopts a hermeneutic approach in conducting deep expert interviews with 22 senior executives and managers of multiple organizations. The method blends theory and expert views to study digital transformation in the context of enterprise information management.

Findings

Drawing on technology enactment framework (TEF), this research poses that organizational form is critical in the enactment of technologies in digital transformation. By extending the TEF, the authors claim that organizations are not in pure bureaucratic or network organizational form during digital transformation; instead, they need a hybrid combination in order to support competing strategic needs for nimbleness and resilience simultaneously. The four hybrid organizational forms presented in this model (4R) allow for networks and bureaucracy to coexist, though at different levels depending on the level of resiliency and nimbleness required at each point in the continuous digital transformation journey.

Research limitations/implications

The main theoretical contribution of this research is to extend the TEF to illustrate that the need for coexistence of nimbleness with stability in a digital transformation results in a hybrid of networks and bureaucratic organization forms. This research aims to guide public sector organizations' digital transformation with extended the TEF as a tool for building the required organizational forms to influence the technology enactment to best meet their strategic needs in the digital era.

Practical implications

The results from expert interviews point to the fact that the hybrid organizational forms create a multi-modal organization, extending the understanding of enterprise information management. Depending on the department or business needs, a hybrid organizational form mode would be dominant. This dominance creates a paradox in organizations to handle both resilience and nimbleness. Therefore, the 4R model is provided as a guide to public sector managers and consultants to guide strutting their organization for digital transformation.

Originality/value

The model (4R), the extended TEF, shows that organizations still work towards networks and bureaucracy; however, they are not two distinct concepts anymore; they coexist at different levels in hybrid forms depending on the needs of the organization.
A systematic bibliometric review of the strategic entrepreneurship domain
Authors: Thomas Gareth H. , Douglas Evan J. , Yamada Jin-Ichiro , Senyard Julienne
Published: October 2021

Purpose

The strategic entrepreneurship (SE) literature exists at the intersection of the strategy and entrepreneurship literatures and has grown rapidly over the past two decades. This study aims to document the proliferation of research papers and identifies the major thematic clusters of topics and other summary information for the SE research domain.

Design/methodology/approach

This is a systematic bibliometric review of 586 articles published over the period 2009–2019 in 143 journals. The inductive quantitative assessment of these articles uses meta-data driven techniques that prioritize reproducibility and rigor in the process of literature analysis.

Findings

This study identifies six main themes in the strategic literature, namely, Sustainable Competitive Advantage; Knowledge Management; Ecosystems; Strategy; Entrepreneurialism; and Organization and Management. It also reports data on a variety of issues including research techniques, country of data, co-author count and trends and differences between journals based on their journal impact factors and calls for more research in key areas.

Originality/value

An innovative original analytical tool was developed to facilitate the analysis of research papers in this growing field. This online tool allows multiple tags to be attached to each paper by multiple authors working simultaneously to identify keywords and other aspects that were subsequently used to identify six main thematic areas within the SE literature. This paper highlights emerging research trends and identifies gaps in the literature that provide opportunities for further research in this field.
Applying the trans-theoretical model to determine the mediating effect self-efficacy in breakfast consumption among children
Authors: Mohajeri Mahsa , Narimani Sajad , Shahbazzadeh Fardin , Bahrampanah Saniyeh , Ghaderi Vida
Published: October 2021

Purpose

Regular breakfast with a variety of nutrients can lead to improving educational performance, learning ability, reducing behavioral problems in elementary students. This study aims to use the Trans-Theoretical Model (TTM) to assess the mediating effect of self-efficacy in regular breakfast consumption among children of Ardabil elementary schools.

Design/methodology/approach

This cross-sectional study was performed between 300 students from elementary schools of different regions of Ardabil city by cluster sampling method. The instrument used in this study was the TTM standard questionnaire. Data was analyzed with Spearman correlation and regression using SPSS v18 software to identify the mediating effects of self-efficacy.

Findings

The mean age (SD) OF children was 11.2 (1.26) and 50% of them were female. Self-efficacy was the strongest predictor in stage promotion (ß= 0.44,P= 0.001), as well as had a mediating effect on the impact of other constructs of the model such as experiential processes (ß= 0.35,P= 0.04) and pros (ß= 0.44,P= 0.03) with stages of change. Pros were a significant predictor of self-efficacy in the first equation (ß= 0.17,P= 0.001) and Pros were a significant predictor of stages of change in the second equation when mediated by self-efficacy (ß= 0.11,P= 0.03). In the third equation, both the mediator, myself-efficacy and the predictor, Pros of breakfast consumption, were significantly associated with stages of change. The mediating effects of self-efficacy on the association between experiential processes and stages of change were also confirmed. The increased standardized beta coefficients of experiential processes between equations 3(ß= 0.35) and 2(ß= 0.29).

Originality/value

Due to the importance of eating a healthy breakfast regularly in children, this study aimed to use TTM to assess mediating effects of self-efficacy in regular breakfast consumption in Ardabil elementary students.
Ethics and accounting education: does teaching stand-alone religious courses affect accounting students’ ethical decisions?
Authors: Ebaid Ibrahim El-Sayed
Published: October 2021

Purpose

Undergraduate accounting program at Umm Al-Qura University in Saudi Arabia is a unique case. The program includes 147 credit hours of which 28 credit hours are religious courses. This study aims to examine the effect of teaching these religious courses on students’ ethical perceptions and decisions.

Design/methodology/approach

A survey was conducted for a sample of accounting students at Umm Al-Qura University. The sample was divided into two groups; the first group includes students who did not study religious courses, while the second group includes students who study religious courses. The questionnaire contained three groups of questions that aimed to explore students’ perceptions of ethics in general, students’ perceptions of business ethics and explored their ethical attitudes regarding some accounting decisions that involve ethical dilemmas. Independent two-sample t-test and multiple regression analysis were used to determine whether the responses of the two groups were significantly different.

Findings

The findings of the study revealed that teaching religious courses led to an improvement in students’ perception of business ethics and an improvement in students’ ethical decision-making. However, the results of the independent sample t-test showed that this improvement was not significant. The results of the study also revealed that male students tend to make less ethical decisions than female students.

Research limitations/implications

The findings offer an indication for those responsible for managing the accounting program at Umm Al-Qura University to start developing the program so that some of the general religious courses are replaced with specialized courses in accounting ethics that focus directly on ethical dilemmas faced by the accountant when practicing the accounting profession.

Originality/value

This study contributes to the current literature related to examining the effect of teaching ethics courses on the ethical perception of accounting students by focusing on accounting students in Saudi Arabia as a context that has not been examined before.