bluuebunny/crossref_metadata_2025 huggingface dataset:
Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina
Authors: Morales Michael , Findley Anna P , Mitchell Diana M.
Published: October 2023

To clarify our understanding of glial phagocytosis in retinal development, we used real-time imaging of larval zebrafish to provide cell-type specific resolution of this process. We show that radial Müller glia frequently participate in microglial phagocytosis while also completing a subset of phagocytic events. Müller glia (MG) actively engage with dying cells through initial target cell contact and phagocytic cup formation after which an exchange of the dying cell from MG to microglia often takes place. Additionally, we find evidence that Müller glia cellular material, possibly from the initial Müller cell’s phagocytic cup, is internalized into microglial compartments. Previously undescribed Müller cell behaviors were seen, including cargo splitting, wrestling for targets, lateral passing of cargo to neighbors, and engulfment of what is possibly synaptic puncta. Collectively, our work provides new insight into glial functions and intercellular interactions, which will allow future work to understand these behaviors on a molecular level.

Summary Statement

Real-time imaging of developing zebrafish retinas reveals intercellular exchanges between Müller glial cells and to microglia during the clearance of apoptotic cells.
Landscape of Large-Scale Somatic Genomic Insertions in Non-Small Cell Lung Carcinoma Revealed by Nanopore Sequencing
Authors: Xie Dan , Xia Lin , Wang Zhoufeng , Zeng Tianfu , Pi Xuenan , Wang Huan , Zhu Guonian , Wu Xinyue , Li Yangqian , Deng Yan , Qi Yawen , liu Xuyan , Zhang Fengmei , Li Weimin
Published: October 2023

Previous NSCLC genomic studies were mostly based on the next-generation sequencing of short reads, which is an efficient approach for identifying single nucleotide variants and small indels but ineffective for identifying structural variants, especially large-scale insertions. Here, we studied 151 lung adenocarcinoma (LUAD) and 106 lung squamous cell carcinoma (LUSC) samples and paired blood samples using nanopore sequencing technology. We developed a rigorous computational pipeline and characterized the landscape of large-scale somatic insertions in NSCLC. Combining other omics data, we report three findings: 1. we identified an LUSC-enriched somatic simple repeat expansion shared by approximately 40% of LUSC patients that regulatesPTPRZ1gene expression through distal enhancers; 2. the somatic insertion of transposable elements (TEs) in NSCLC were mostly ‘complex TEs’ consisting of multiple TE elements; and 3. the insertion of short interspersed nuclear elements, especially from the Alu family in young lineages, is a frequent somatic mutation type that shapes the transcriptome of NSCLC through the expression of these elements.
Whole Genome Methylation Sequencing via Enzymatic Conversion (EM-seq): Protocol, Data Processing and Analysis
Authors: Olova Nelly N. , Andrews Simon
Published: October 2023

Whole genome bisulfite sequencing (WGBS) has been the gold standard technique for base resolution analysis of DNA methylation for the last 15 years. It has been, however, associated with technical biases, which lead to overall overestimation of global and regional methylation values, and significant artifacts in extreme cytosine-rich DNA sequence contexts. Enzymatic conversion of cytosine is the newest approach, set to replace entirely the use of the damaging bisulfite conversion of DNA. The EM-seq technique utilises TET2, T4-BGT and APOBEC in a two-step conversion process, where the modified cytosines are first protected by oxidation and glucosylation, followed by deamination of all unmodified cytosines to uracil. As a result, EM-seq is degradation-free and bias-free, requires low DNA input, and produces high library yields with longer reads, little batch variation, less duplication, uniform genomic coverage, accurate methylation over a larger number of captured CpGs, and no sequence-specific artifacts.
BRD2 and BRD3 genes independently evolved RNA structures to control unproductive splicing
Authors: Petrova Marina , Margasyuk Sergey , Vorobeva Margarita , Skvortsov Dmitry , Dontsova Olga , Pervouchine Dmitri D.
Published: October 2023

The mammalianBRD2andBRD3genes encode structurally related proteins from the bromodomain and extraterminal domain (BET) protein family. The expression ofBRD2is regulated by unproductive splicing upon inclusion of exon 3b, which is located in the region encoding a bromodomain. Bioinformatic analysis indicated thatBRD2exon 3b inclusion is controlled by a pair of conserved complementary regions (PCCR) located in the flanking introns. Furthermore, we identified a highly conserved element encoding a cryptic poison exon 5b and a previously unknown PCCR in the intron between exons 5 and 6 ofBRD3, however outside of the homologous bromodomain. Minigene mutagenesis and blockage of RNA structure by antisense oligonucleotides demonstrated that RNA structure controls the rate of inclusion of poison exons. The patterns ofBRD2andBRD3expression and splicing show downregulation upon inclusion of poison exons, which become skipped in response to transcription elongation slowdown, further confirming a role of PCCRs in unproductive splicing regulation. We conclude thatBRD2andBRD3independently acquired poison exons and RNA structures to dynamically control unproductive splicing. This study describes a convergent evolution of regulatory unproductive splicing mechanisms in these genes providing implications for selective modulation of their expression in therapeutic applications.
Fluorescent pH-sensing bandage for point-of-care wound diagnostics
Authors: Al-Hawat Marie-Lynn , Tricou Léo-Paul , Cherifi Katia , Lamontagne Stéphanie , Tran Minh , Ching Yie Ngu Amy , Manrique Gabriela , Guirguis Natalie , Israel Machuca-Parra Arturo , Matoori Simon
Published: October 2023

Diabetic foot ulcers (DFUs) are a serious and prevalent complication of diabetes. Current diagnostic options are limited to macroscopic wound analysis such as wound size, depth, and infection. Molecular diagnostics promise to improve DFU diagnosis, staging, and assessment of treatment response. Here, we developed a rapid and easy-to-use fluorescent pH-sensing bandage for wound diagnostics. In a fluorescent dye screen, we identified pyranine as the lead compound due to its suitable pH-sensing properties in the clinically relevant pH range of 6 to 9. To minimize the release of this dye into the wound bed, we screened a library of ionic microparticles and found a strong adhesion of the anionic dye to a cationic polymeric microparticle. These dye-loaded microparticles showed a strong fluorescence response in the clinically relevant pH range of 6 to 9 and a dye release below 1% after one day in biological media. The dye-loaded microparticles were subsequently encapsulated in a calcium alginate hydrogel to minimize the interaction of the microparticles with the wound tissue. This pH-sensing diagnostic wound dressing was tested on full thickness dorsal wounds of mice, and a linear fluorescence response (R2= 0.9909) to clinically relevant pH values was observed. These findings encourage further development of this pH-sensing system for molecular diagnostics in DFUs.
Relating strain amplitude, strain threshold and bone formation rate to exogenous forcing frequency
Authors: Prasad Jitendra , Aruva Achsah Marlene , Shekhar Himanshu , Singh Sanjay , Singh Satwinder Jit
Published: October 2023

The literature supports the existence of a strain threshold, above which cortical bone adapts to exogenous mechanical loading by forming new bone. This strain threshold, however, varies with loading conditions, locations, waveforms, frequency etc. and there is a need to mathematically express the strain threshold in terms of these parameters. There have been several parametric, mathematical or numerical models in the literature for the cortical bone’s adaptation to mechanical loading, which may be already fitting some of the experimental data; however, they may not be easily and confidently derived from the first principles. To fill the gap, this work has attempted to derive the corresponding bone formation rate (BFR) rather from the first principles, namely using the energy principles. The derived model has been compared to the existing parametric models and validated with respect to the diverse experimental data available in the literature. The developed model is able to not only predict the BFR, but also helps to understand the nature and possible mathematical form of the strain threshold for cortical bone’s adaptation to mechanical loading.
Transthalamic input to higher-order cortex selectively conveys state information
Authors: Neske Garrett T. , Cardin Jessica A.
Published: October 2023

Communication among different neocortical areas is largely thought to be mediated by long-range synaptic interactions between cortical neurons, with the thalamus providing only an initial relay of information from the sensory periphery. Higher-order thalamic nuclei receive strong synaptic inputs from the cortex and send robust projections back to other cortical areas, providing a distinct and potentially critical route for cortico-cortical communication. However, the relative contributions of corticocortical and thalamocortical inputs to higher-order cortical function remain unclear. Using imaging of cortical neurons and projection axon terminals in combination with optogenetic manipulations, we find that the higher-order visual thalamus of mice conveys a specialized stream of information to higher-order visual cortex. Whereas corticocortical projections from lower cortical areas convey robust visual information, higher-order thalamocortical projections convey strong behavioral state information. Together, these findings suggest a key role for higher-order thalamus in providing contextual signals that flexibly modulate sensory processing in higher-order cortex.
Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression
Authors: Sun Xiaoxiao , Doose Jayce , Faller Josef , McIntosh James R. , Saber Golbarg T. , Huffman Sarah , Pantazatos Spiro P. , Yuan Han , Goldman Robin I. , Brown Truman R. , George Mark S. , Sajda Paul
Published: October 2023

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient’s individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.
PolymorphismQ223Rof the leptin receptor (LEPR) - a possible relationship with adaptation to non-tropical climate in Yakuts
Authors: Pavlova N.I. , Bochurov A.A. , Alekseev V.A. , Krylov A.V. , Sydykova L.A. , Kurtanov Kh.A.
Published: October 2023

Obesity is an energy imbalance that occurs due to a lack of energy intake and consumption. We studied the variability of theQ223Rpolymorphism of theLEPRgene in the Yakut population and the relationship with body mass index (BMI) and abdominal obesity in a sample of Yakuts (n=336), consisting of individuals with obesity (n=185) and normal weight (n=151). For genotyping, we used the classical methods of PCR-RFLP analysis. A comparative analysis of the obtained data on the frequencies of alleles and genotypes with data on other populations of the world was also carried out. The G variant allele frequency was 79.5% in normal weight patients and 82.7% in obese patients. Genotype analysis showed a high frequency of genotypes GG - 64.2% and GA - 30.5% in the group with normal BMI and GG - 69.7% and GA - 25.9% in the group with high BMI. There was no significant difference in the frequency of alleles and genotypes of theQ223Rpolymorphism between the groups. It was established that the frequency of the G allele of the Yakuts (79.5%) with the populations of East Asia (86.9%). When analyzing the average anthropometric values, depending on the genotype, a statistically significant difference in waist circumference was found in persons with abdominal obesity (p = 0.03), so it was greater in carriers of the heterozygous AG genotype than in carriers of the GG genotype.

In conclusion, our study demonstrates that SNPQ223R(LEPR) is possible and has some effect on anthropometric parameters in the Yakut population, but differs from studies conducted on samples of European ethnicity. It can be assumed that the accumulation of the G allele of theQ223Rpolymorphism (LEPR) in the Yakut population, as well as in the populations of East Asia, is probably the result of metabolic adaptation to living conditions in a non-tropical climate.
Therapeutic journey of patients affected by stroke: cohort study
Authors: Santos de Mendonça Marcirene , de Paula Caio Lopes Pinheiro , Santos Douglas dos , da Silva Marcelo Nunes , Júlia Oliveira Ramos Maria , de Magalhães Soares Pinheiro Fernanda Gomes
Published: October 2023

The therapeutic journey of patients affected by a stroke cause health impacts and deaths. Stroke is an acute neurological dysfunction, classified as hemorrhagic or ischemic. This study aimed to compare the therapeutic journey in the access of patients affected by stroke in hospitals in the Brazilian Northeast.

Prospective cohort study, carried in all public hospitals that had a neuroimaging service in the State of Sergipe. The collection instrument sought sociodemographic characterization and timeline. The data were exported to the R Core Team 2022 software. After being coded and tabulated, they were analyzed using descriptive statistics. The hypothesis of independence was tested using Pearson Chi-Square and Fisher Exact tests.

A total of 159 patients cared for in the hinterland region of the State and 91 in the capital city (Aracaju) participated in the study, with a median age of 66 years old (SD:55.5-75) in the capital and with a median age of 72 years old (SD:60-82) in the hinterland. There was a predominance in females, 76.6% and 64.1%, respectively. It was found a higher incidence of the ischemic stroke (IS) (p<0.002). The decision time between the onset of signs and symptoms and the decision to call up transportation, it was observed that patients with IS cared for in the hinterland take three times longer (p=0.002). Regarding the time between the stroke detection and the CT scan, it was five times longer for those from the hinterland (p<0.001) in cases of IS. In cases of HS, the time was 1.4 longer for those from the hinterland. Concerning the neurological evaluation, in cases of IS and HS, the rates found were 76.6%vs78.3% in the hinterland, while 100% of patients were evaluated for both types of stroke episodes in the capital city (p<0.001).

The therapeutic journey of patients cared for in the hinterland of the State has a longer period of time.
Persistent Inequities in Intravenous Thrombolysis for Acute Ischemic Stroke in the United States: Results from the Nationwide Inpatient Sample
Authors: Sun Philip , Zheng Ling , Lin Michelle , Cen Steven , Hammond Gmerice , Maddox Karen E. Joynt , Kim-Tenser May , Sanossian Nerses , Mack William , Towfighi Amytis
Published: October 2023

Background

Despite its approval for use in acute ischemic stroke (AIS) >25 years ago, intravenous thrombolysis (IVT) remains underutilized, with inequities by age, sex, race/ethnicity, and geography. Little is known about IVT rates by insurance status. We aimed to assess temporal trends in the inequities in IVT use.

Methods

We assessed trends from 2002 to 2015 in IVT for AIS in the Nationwide Inpatient Sample by sex, age, race/ethnicity, hospital location/teaching status, and insurance, using survey-weighted logistic regression, adjusting for sociodemographics, comorbidities, and hospital characteristics. We calculated odds ratios for IVT for each category in 2002-2008 (Period 1) and 2009-2015 (Period 2).

Results

Among AIS patients (weighted N=6,694,081), IVT increased from 1.0% in 2002 to 6.8% in 2015 (adjusted annual relative ratio (AARR) 1.15, 95% CI 1.14-1.16). Individuals ≥85 years had the most pronounced increase from 2002 to 2015 (AARR 1.18, 1.17-1.19), but were less likely to receive IVT compared to those aged 18-44 years in both Period 1 (adjusted odds ratio (aOR) 0.23, 0.21-0.26) and Period 2 (aOR 0.36, 0.34-0.38). Women were less likely than men to receive IVT, but the disparity narrowed over time (Period 1 aOR 0.81, 0.78-0.84, Period 2 aOR 0.94, 0.92-0.97). Inequities in IVT by race/ethnicity resolved for Hispanic individuals in Period 2 but not for Black individuals (Period 2 aOR 0.81, 0.78-0.85). The disparity in IVT for Medicare patients, compared to privately insured patients, lessened over time (Period 1 aOR 0.59, 0.56-0.52, Period 2 aOR 0.75, 0.72-0.77). Patients treated in rural hospitals were less likely to receive IVT than those treated in urban hospitals; a more dramatic increase in urban areas widened the inequity (Period 2 urban non-teaching vs. rural aOR 2.58, 2.33-2.85, urban teaching vs. rural aOR 3.90, 3.55-4.28).

Conclusion

From 2002 through 2015, IVT for AIS increased among adults. Despite encouraging trends, only 1 in 15 AIS patients received IVT and persistent inequities remained for Black individuals, women, government-insured, and those treated in rural areas, highlighting the need for intensified efforts at addressing inequities.
Engineered Active Zymogen of Microbial Transglutaminase
Authors: Ariyoshi Ryutaro , Matsuzaki Takashi , Sato Ryo , Minamihata Kosuke , Hayashi Kounosuke , Wakabayashi Rie , Goto Masahiro , Kamiya Noriho
Published: October 2023

Microbial transglutaminase (MTG) has shown to be a powerful biocatalytic glue for site-specific crosslinking of a range of biomolecules and synthetic molecules, those handled with an MTG-reactive moiety. The preparation of active recombinant MTG requires the posttranslational proteolytic digestion of propeptide working as an intramolecular chaperon to assist the correct folding of MTG zymogen (MTGz) in the biosynthesis. Herein, we propose anengineered activezymogen of MTG (EzMTG) that is expressed as soluble form in the hostE. colicytosol and exhibits the cross-linking activity without limited proteolysis. Based on the 3D structure of MTGz and serendipitous findings, saturated mutagenesis of K10 or Y12 in propeptide domain leads to generate several active MTGz mutants. In particular, K10D/Y12G mutant exhibited the catalytic activity comparable with a mature form. However, the expression level was low possibly due to the reduction of chaperone activity and/or the promiscuous substrate specificity of MTG, which is potentially harmful to the host cells. By contrast, soluble K10R/Y12A mutant is expressed in the cytosol of hostE. coliand exhibited unique substrate-dependent reactivity toward peptidyl substrates. The quantitative analysis of the binding affinity of mutated propeptide to the active site suggested the trade-off relationship of EzMTGs between the binding affinity and the catalytic activity. Our proof-of-concept study provides insights into the design of a new biocatalyst by using the zymogen as a scaffold and will convey a potential route to the high-throughput screening of MTG mutants for bioconjugation applications.
Triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors
Authors: Wang Jimin , Batista Victor S. , Bunick Christopher G.
Published: October 2023

Deucravacitinib, 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, is a highly selective inhibitor of protein tyrosine kinase 2 (TYK2) that targets the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. The structural basis for its selectivity and allosteric inhibition remains poorly understood. Here, we investigate the inhibition mechanism through analysis of available structures relevant to the STAT pathway, including crystal structures of the truncated TYK2 FERM-SH2 domain bound to the IFNα type I receptor (IFNαR1) and the truncated TYK2 JH2-JH1 domain. Our computational analysis provides a mechanistic hypothesis for the relatively rapid interferon-induced gene expression mediated by TYK2 relative to other cytokines. We find that deucravacitinib inhibits TYK2 kinase in three distinct states: the autoinhibited state and two activated states for autophosphorylation and phosphorylation of downstream protein substrates. Its binding to the TYK2 pseudokinase domain in the autoinhibited state restricts the essential dynamics of the TYK2 kinase domain required for kinase activity. Furthermore, it binds competitively with ATP in the pseudokinase domain, and also directly prevents formation of the active state of TYK2 through steric clashes.
CaMKIIα and CaMKIIβ hub domains adopt distinct oligomeric states and stabilities
Authors: Özden Can , MacManus Sara , Adafia Ruth , Samkutty Alfred , Ocampo Ana Torres , Garman Scott C. , Stratton Margaret M.
Published: October 2023

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multidomain serine/threonine kinase that plays important roles in the brain, heart, muscle tissue, and eggs/sperm. The N-terminal kinase and regulatory domain is connected by a flexible linker to the C-terminal hub domain. The hub domain drives the oligomeric organization of CaMKII, assembling the kinase domains into high local concentration. Previous structural studies have shown multiple stoichiometries of the holoenzyme as well as the hub domain alone. Here we report a comprehensive study of the hub domain stoichiometry and stability in solution. We solved two crystal structures of the CaMKIIβ hub domain that show 14mer (3.1 Å) and 16mer (3.4 Å) assemblies. Both crystal structures were determined from crystals grown in the same drop, which suggests that CaMKII oligomers with different stoichiometries likely coexist. To further interrogate hub stability, we employed mass photometry and temperature denaturation studies of CaMKIIβ and α hubs, which highlight major differences between these highly similar domains. We created a dimeric CaMKIIβ hub unit using rational mutagenesis, which is significantly less stable than the oligomer. Both hub domains populate an intermediate during unfolding. We found that multiple CaMKIIβ hub stoichiometries are present in solution and that larger oligomers are more stable. CaMKIIα had a narrower distribution of molecular weight and was distinctly more stable than CaMKIIβ.
Lateral entorhinal cortex subpopulations represent experiential epochs surrounding reward
Authors: Issa John B. , Radvansky Brad A. , Xuan Feng , Dombeck Daniel A.
Published: October 2023

During goal-directed navigation, “what” information, which describes the experiences occurring in periods surrounding a reward, can be combined with spatial “where” information to guide behavior and form episodic memories1,2. This integrative process is thought to occur in the hippocampus3, which receives spatial information from the medial entorhinal cortex (MEC)4; however, the source of the “what” information and how it is represented is largely unknown. Here, by establishing a novel imaging method, we show that the lateral entorhinal cortex (LEC) of mice represents key experiential epochs during a reward-based navigation task. We discover a population of neurons that signals goal approach and a separate population of neurons that signals goal departure. A third population of neurons signals reward consumption. When reward location is moved, these populations immediately shift their respective representations of each experiential epoch relative to reward, while optogenetic inhibition of LEC disrupts learning of the new reward location. Together, these results indicate the LEC provides a stable code of experiential epochs surrounding and including reward consumption, providing reward-centric information to contextualize the spatial information carried by the MEC. Such parallel representations are well-suited for generating episodic memories of rewarding experiences and guiding flexible and efficient goal-directed navigation5–7.
The neural basis of swap errors in working memory
Authors: Alleman Matteo , Panichello Matthew , Buschman Timothy J. , Johnston W. Jeffrey
Published: October 2023

When making decisions in a cluttered world, humans and other animals often have to hold multiple items in memory at once – such as the different items on a shopping list. Psychophysical experiments in humans and other animals have shown remembered stimuli can sometimes become confused, with participants reporting chimeric stimuli composed of features from different stimuli. In particular, subjects will often make “swap errors” where they misattribute a feature from one object as belonging to another object. While swap errors have been described behaviorally, their neural mechanisms are unknown. Here, we elucidate these neural mechanisms through trial-by-trial analysis of neural population recordings from posterior and frontal brain regions while monkeys perform two multi-stimulus working memory tasks. In these tasks, monkeys were cued to report the color of an item that either was previously shown at a corresponding location (requiring selection from working memory) or will be shown at the corresponding location (requiring attention to a position). Animals made swap errors in both tasks. In the neural data, we find evidence that the neural correlates of swap errors emerged when correctly remembered information is selected incorrectly from working memory. This led to a representation of the distractor color as if it were the target color, underlying the eventual swap error. We did not find consistent evidence that swap errors arose from misinterpretation of the cue or errors during encoding or storage in working memory. These results suggest an alternative to established views on the neural origins of swap errors, and highlight selection from and manipulation in working memory as crucial – yet surprisingly brittle – neural processes.
Novel inheritedCDX2variant segregating in a family with diverse congenital malformations of the genitourinary system
Authors: Ramadesikan Swetha , Colwell Caitlyn M. , Supinger Rachel , Hunter Jesse , Thomas Jessica , Varga Elizabeth , Mardis Elaine R. , Wood Richard J. , Koboldt Daniel C.
Published: October 2023

Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants inCDX2with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations inCDX2.CDX2encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role ofCDX2in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.
The active degree of written questions in the Macau Legislative Assembly: a qualitative comparative analysis (QCA)
Authors: Tang Chunlin , Liu Sike , Deng Si
Published: October 2023

Purpose

This study intends to explore the configuration that affects the active degree of written questions in the Macau Legislative Assembly.

Design/methodology/approach

This study takes the members elected by the sixth Legislative Assembly of Macau as samples and uses the fuzzy set qualitative comparative analysis method. Five conditional factors are discussed, including multiple concurrent factors and complex causal mechanisms, which lead to the difference in the active degree of written questions.

Findings

The main conclusions are as follows: (1) Not Serving in the government is a necessary condition for a high active degree of the written question, and (2) The driving mechanism of a high active degree of written question can be divided into two paths. Among them, direct election into the Legislative Assembly is the crucial factor.

Originality/value

Traditional research mainly uses quantitative research methods. This study uses qualitative comparative analysis (QCA), which is a hybrid method designed to bridge the qualitative (case-oriented) and quantitative (variable-oriented) research gap.
HSBC: Facilitating Trade Finance Through Blockchain
Authors: Sahay Arvind , Tiwari Tara
Published: October 2023

HSBC (The Hong Kong and Shanghai Banking Corporation Limited) Holdings Plc. is a part of various trade finance consortia which aimed to digitise the traditional paper-based trade finance process. It had successfully executed multiple trade finance pilots using a blockchain based platform Voltron and was launching its Contour blockchain trade finance platform as a service to its clients. The trade finance market was estimated to be USD 18 trillion on an annual basis and HSBC had a 12% share in the trade finance transactions worldwide. This case revolves around the challenges facing banks/consortia while porting the traditional trade finance process to the blockchain based system. The crux is how the banks form the consortia, implement blockchain and facilitate trading globally given that it is a new technology and will require bringing all the stakeholders involved in the trade finance value chain to the blockchain based platform. HSBC is facing some decision questions on the formation, governance and management of the consortium, on the interoperability between consortia and on how to price its services to its customers.
How can The Left-Out Store get it right?
Authors: Prasad S. Shyam , Desai Rajendra , Wadher Maitri
Published: October 2023

Learning outcomes

This case study will allow students to learn about effective segmentation and how to choose an appropriate segment, analyse the attractiveness of the target market by using five-forces analysis and explore business growth alternatives by using Ansoff’s growth matrix.

Case overview/synopsis

The Left-Out Store was an online shop that sold products exclusively for left-handers. Maitri Wadher, the proprietor of the store, being a left-handed person and driven by her childhood experiences, started the store to help left-handed people find products for their use. She started the online-only store in September 2018, and in October 2022, she found that, despite the COVID-19 pandemic having abated, her store had not grown as expected. How, then, should she push for growth? Was the niche segment substantial enough? Was her target market attractive? Should she penetrate the market or go for market development? What should she do?

Complexity academic level

PG level (MBA/PGDM).

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 8: Marketing.
If managers feel safe, budget control becomes enabling. Evidence from a large local government organization in Sweden
Authors: Johansson-Berg Tobias , Wennblom Gabriella
Published: October 2023

Purpose

The authors study how enabling perceptions (flexibility, reparability and internal and global transparency) of a budgetary control system are formed, and whether enabling perceptions empower lower-level managers and make them form less negative attitudes about red tape in the organization. This study research is warranted because of the lack of knowledge on how perceptual variation in flexibility, repairability and transparency of a control system within an organization, where managers experiencing the same control system design, can be explained.

Design/methodology/approach

Survey data with answers from 211 managers from a large local government organization in Sweden is analyzed with structural equation modeling.

Findings

The extent to which the budget system is perceived as having enabling qualities (being flexible, reparable and transparent) is explained by the safeness of the individual manager's psychological climate. This climate is characterized by trust and fairness perceptions in upper management. In turn, enabling perceptions positively affect a sense of psychological empowerment and reduces attitudes toward red tape in the organization.

Originality/value

The authors contribute by identifying an important factor explaining individual-level variability in enabling perceptions of control systems within organizations. Compared to previous research that has taken an interest in the organizational-level climate, the authors theorize about and investigate (parts of) the individual-level psychological climate as an explanation of within-system variability.
Design of UWB MIMO antenna using lean wearable textile substrate for reduced SAR
Authors: Perumalsamy Sasireka , G. Kavya , S. Rajkumar
Published: October 2023

Purpose

This paper aims to propose a two-element dual fed ultra-wideband (UWB) multiple input multiple output (MIMO) antenna system with no additional decoupling structures. The antenna operates from 3.1 to 10.6 GHz. The antenna finds its usage in on-body wearable device applications.

Design/methodology/approach

The antenna system measures 63.80 × 29.80 × 0.7 mm. The antenna radiating element is designed by using a modified dumbbell-shaped structure. Jean cloth material is used as substrate. The isolation improvement is achieved through spacing between two elements.

Findings

The proposed antenna has a very low mutual coupling of S21 < −20 dB and impedance matching of S11 < −10 dB. The radiation characteristics are stable in the antenna operating region. It provides as ECC < 0.01, diversity gain >9.9 dB. The antenna offers low average specific absorption rate (SAR) of 0.169 W/kg. The simulated and measured results are found to be in reasonable match.

Originality/value

The MIMO antenna is proposed for on-body communication, hence, a very thin jean cloth material is used as substrate. This negates the necessity of additional material usage in antenna design and the result range indicates good diversity performance and with a low SAR of 0.169 W/kg for on-body performance. This makes it a suitable candidate for textile antenna application.
Measuring the effects of electronic government services and corrupt practices on information exchange: a comparison of public and private hospitals
Authors: Shrivastava Utkarsh , Han Bernard , Daneshvar Kakhki Mohammad , Tarn J. Michael
Published: October 2023

Purpose

Health Information Exchange (HIE) is essential for the efficient and cost-effective delivery of health-care services. The provider’s administrative structure and external environment can substantially influence adopting technologies involving inter-organizational linkages, such as HIE. Using the theoretical lens of institutional theory, this study aims to compare how public and private hospitals' engagement in HIE is influenced by corruption and government online services or e-government usage.

Design/methodology/approach

The study uses the positivist research design of secondary data analysis to test the six hypotheses proposed. Data from multiple third-party reliable sources, including the European Commission and World Bank, are combined into the final dataset consisting of observations from 1,442 hospitals across 30 countries in Europe. A multilevel modeling approach is used to associate country and hospital-level variables and test the hypothesis.

Findings

The study finds that, on average, a 10% increase in corruption leads to a 6.3% decrease, while a 10% increase in e-government leads to a 7% increase in the probability of HIE engagement for a hospital. The negative impact of corruption on average is 18% more in public than private hospitals, while the positive impact of e-government is 75% stronger in public in comparison to private hospitals. The study also finds that HIE engagements in health systems with predominantly public hospitals are more sensitive to corruption and e-government.

Originality/value

To the best of the authors’ knowledge, the study is one of the first to use the institutional view to test the influence of government actions and public providers' concentration on HIE engagement. The comparison of public and private institutions enriches our understanding of promoters and inhibitors of HIE.
International Differences in Profitability*
Authors: Bloch Harry , Zhou Yixiao
Published: October 2023

We examine the global distribution of company profitability over the 30 years from 1989 to 2018 focusing on the international dimension. We find the international component of profitability differences first declines and then rises. Regression analysis of time‐series data shows that transitory shocks to international profitability differences mostly dissipate over a few years, although there is evidence of persistent profitability differences for many countries. Dividing the sample to accommodate a structural break, the rate of dissipation declines between 1989–2002 and 2003–2018 subperiods. The extent of persistent differences also declines, suggesting convergence of international differences in profitability may have reached its limit.
Transcatheter arterial embolisation for the relief of shoulder and elbow chronic joint pain refractory to conventional treatment: Systematic review
Authors: Aly Mohamed , Fashina Chelsea , Hagiga Ahmed , Hafez Ahmed , Di Mascio Livio
Published: October 2023

Angiogenesis and accompanying nerve fibres might cause unsettling joint pain. Studies have suggested that transcatheter arterial embolisation (TAE) of these abnormal neovessels could relieve pain and symptoms in patients with upper limb joint pain refractory to conventional treatment. This study aims to investigate the efficacy and safety of TAE in treating chronic pain of shoulder and elbow joints that have been resistant to other treatments. Using six databases, a systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. The primary outcome involved changes in the visual analogue scale (VAS) after TAE; while secondary outcomes involved comparing other parameters where relevant. Average VAS decreased from baseline, then at 1 day, 1 week, 1 month, 3 months, 4 months, 6 months, 1 year, 2 years and 44 months (7.5 at baseline vs. 4.7, 4.3, 3.4, 2.1, 2.5, 1.2, 0.7, 1.1 and 0.1, respectively). Average Quick‐DASH scores decreased from baseline, then at 1, 3 and 6 months (61.3 at baseline vs. 30.6, 19.3 and 6.9, respectively). Minor adverse events were reported in 27/143 (18.9%) patients, where they resolved spontaneously or with oral analgesia. TAE is a possible treatment option for refractory shoulder and elbow joint pain; however, randomised controlled trials are still required.
Discovery and structural characterization of a thermostable bacterial monoamine oxidase
Authors: Santema Lars L. , Basile Lorenzo , Binda Claudia , Fraaije Marco W.
Published: October 2023

Monoamine oxidases (MAOs) are pivotal regulators of neurotransmitters in mammals, while microbial MAOs have been shown to be valuable biocatalysts for enantioselective synthesis of pharmaceutical compounds or precursors thereof. To extend the knowledge of how MAOs function at the molecular level and in order to provide more biocatalytic tools, we set out to identify and study a robust bacterial variant: a MAO from the thermophile Thermoanaerobacterales bacterium (MAOTb). MAOTb is highly thermostable with melting temperatures above 73 °C and is well expressed in Escherichia coli. Substrate screening revealed that the oxidase is most efficient with n‐alkylamines with n‐heptylamine being the best substrate. Presteady‐state kinetic analysis shows that reduced MAOTb rapidly reacts with molecular oxygen, confirming that it is a bona fide oxidase. The crystal structure of MAOTb was resolved at 1.5 Å and showed an exceptionally high similarity with the two human MAOs, MAO A and MAO B. The active site of MAOTb resembles mostly the architecture of human MAO A, including the cysteinyl protein–FAD linkage. Yet, the bacterial MAO lacks a C‐terminal extension found in human MAOs, which explains why it is expressed and purified as a soluble protein, while the mammalian counterparts are anchored to the membrane through an α‐helix. MAOTb also displays a slightly different active site access tunnel, which may explain the specificity toward long aliphatic amines. Being an easy‐to‐express, thermostable enzyme, for which a high‐resolution structure was elucidated, this bacterial MAO may develop into a valuable biocatalyst for synthetic chemistry or biosensing.
Effects of simultaneous and sequential mixed fermentation of non‐Saccharomyces strains and a Saccharomyces cerevisiae strain on the fermentation process and volatile compounds of Mijiu
Authors: Li Rou , Xu Yan , Wang Dong
Published: October 2023

The combined use of non‐Saccharomyces yeasts and Saccharomyces cerevisiae in mixed fermentation is considering as a potential way to improve the flavour characteristics of Mijiu (a traditional rice wine in China). In this study, we investigated the effects of mixed fermentation, including simultaneous and sequential inoculation fermentation, of typical non‐Saccharomyces yeast strains (Saccharomycopsis fibuligera; Candida glabrata) and an S. cerevisiae strain on the fermentation process and volatile compounds of Mijiu. The results showed that the fermentation rate of Mijiu was improved by the simultaneous inoculation fermentation of different non‐Saccharomyces yeasts and S. cerevisiae. However, the increase of volatile compounds in the simultaneous inoculation fermentation depended on non‐Saccharomyces yeast species, although the positive contribution of non‐Saccharomyces yeasts to volatile compounds of Mijiu was confirmed in their pure fermentation. The sequential inoculation fermentation significantly enhanced the content or complexity of volatile compounds of Mijiu but with low‐fermentation rate. This could be attributed to the change of the number of non‐Saccharomyces yeast cells during the mixed fermentation possibly caused by the inhibition of S. cerevisiae with high concentration on non‐Saccharomyces yeasts. Our work provided useful information on the mixed inoculation fermentation strategy combining suitable non‐Saccharomyces yeasts and S. cerevisiae for improving the fermentation rate and the aroma quality of Mijiu.
Improving gelling properties of fish gelatin by γ‐polyglutamic acid with four different molecular weights
Authors: Shu Sheng , Sha Xiao‐Mei , Hu Zi‐Zi , Ma Qing‐Ling , Qiao Juan‐Juan , Fang Ting , Jiang Wen‐Li , Tu Zong‐Cai
Published: October 2023

This work investigated gelling properties and structural characteristics of fish gelatin (FG) modified by four different molecular weights of γ‐polyglutamic acid (γ‐PGA) with 700, 1000, 2000 and 3000 kDa, respectively. Gelation‐melting transition temperature and gel strength increased with the increase of molecular weight in γ‐PGA. Especially, γ‐PGA in 3000 kDa made gel strength, gelation and melting temperatures reaching to 628.08 g (P < 0.05), 22.30 °C and 30.17 °C (P < 0.05), respectively. Non‐covalent interactions existed in FG and γ‐PGA. Such as, new hydrogen bonds were generated between them. Moreover, γ‐PGA with increased molecular weight enhanced three‐stranded helical structure and microscopic meshwork of FG. Finally, a schematic model was described to illustrate the interaction between FG and γ‐PGA in different molecular weights. On the whole, γ‐PGA with high molecular weight significantly improved gelling properties of FG, and could be a potential modifier of FG in the future.
Geography's Human Resources over the Past Half‐Century*
Authors: Pandit Kavita
Published: October 2023

This article examines trends over the past five decades in three human resource issues in geography: the production of new geographers; the size and diversity of the membership of the Association of American Geographers (AAG); and the topical specializations of geographers. The number of geography degrees awarded increased rapidly in the 1950s and 1960s, followed by a modest decline as baby boomers exited their college years. The number surged again in the 1990s, however, and it seems to have stabilized in recent years. AAG membership trends followed a similar trajectory and membership is currently poised to set a new record. The participation of women in the discipline has increased steadily over the past half‐century, but geography still lags the social and physical sciences in the share of women receiving bachelor's degrees. The participation of geographers from ethnic minority groups continues to be very low. The number of AAG specialty groups has doubled since their inception in 1978, and geographic information science (GIS) now occupies a prominent position within the discipline. Challenges in the coming years include increasing the diversity in geography, reducing the turnover in AAG membership, preparing for the imminent retirement of a large cohort of baby‐boom geographers, and reconnecting with nonacademic geographers.
Horizontal transmission of Metarhizium brunneum conidia from sporulating cadavers to Agriotes obscurus adults
Authors: Janmaat Alida F. , Hinz Chris , Kabaluk Todd , Cory Jenny S.
Published: October 2023

The application of fungal entomopathogens, such as Metarhizium brunneum, has the potential to continue to impact targeted host populations through secondary cycling. In the present study, we examined the horizontal transmission of M. brunneum conidia from conspecific mycosed cadavers or soil on which the cadavers sporulated to Agriotes obscurus beetles. Close contact between the susceptible hosts and sporulating cadavers or contaminated soil was required for increased mortality of hosts and subsequent production of mycosed cadavers.