bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing Effective Care in a University Population Based on National Vaccination Recommendations
Authors: Richards Julie , Brunacini Kevin , Stoll Nancy , Tepper Robyn
Published: December 2023

Vaccines are among the most cost-effective and successful medical interventions, saving approximately 2.3 million lives annually. Unfortunately, vaccination coverage for adults remains low, leading to unnecessary and costly health consequences. An initial chart review revealed that 95% (N = 20) of students were not up to date with vaccines. In a patient survey, 100% of students (N = 21) did not recall receiving useful vaccine information, but 66.7% reported it would be helpful (≥4 of 5 on the Likert scale). Strategies supporting effective care, an Institute of Medicine quality domain, were used to address these gaps. The aim was to increase effective care in university adult students for vaccines by 30% over 90 days. The quality improvement method of Plan-Do-Study-Act cycles was used to evaluate iterative tests of change. Examining contextual elements, team and patient feedback, aggregate data, and run charts informed tests of change over 4 cycles. Core interventions included enhanced screening, vaccine shared decision-making, provider checklists, and a team engagement plan. Greater than 83% (N = 152) of students were not up to date with vaccines as per national guidelines. Over 8 weeks, the team effectively referred students for 265 of the 274 vaccines they were eligible for—an accuracy rate of 95.3%. The aim score, a mean composite score reflecting all 3 interventions, increased from 49% to 95%. Effective care for vaccine uptake increased by 83.8%—far exceeding the goal. Campus health centers and other primary care settings could benefit from adopting a similar strategy that provides clear benefits to patients and the broader community while decreasing health care costs.
Predictors of Mortality Among Children and Adolescents Living With HIV on Antiretroviral Therapy in Western Kenya
Authors: Nyandiko Winstone , Enjema Njie Albertine , Mugo Richard , Apondi Edith , Sang Edwin , Mwangi Ann
Published: December 2023

Background:

Antiretroviral therapy (ART) has decreased HIV-attributable deaths; however, children and adolescents continue to have high HIV-associated mortality.

Setting:

We determined the predictors of death among children and young adolescents living with HIV (CALWH) who died while in care in Western Kenya.

Methods:

This retrospective case–control study used electronically abstracted data of 6234 CALWH who received care in Academic Model Providing Access to Healthcare HIV clinics in Western Kenya between January 2002 and November 2022. The cases comprised CALWH who were reported dead by November 2022, while the controls constituted of matched CALWH who were alive and in care. Independent predictors of mortality were determined using univariable and multivariable Cox proportional hazard regression models. Kaplan–Meier analysis ascertained survival.

Results:

Of the 6234 participants enrolled, slightly more than half were male (51.7%). The mean (SD) age at the start of ART was significantly lower in cases than in controls at 6.01 (4.37) and 6.62 (4.11) (P < 0.001), respectively. An age of 11 years or older at start of ART (adjusted Hazard Ratio [aHR]: 8.36 [3.60–19.40]), both parents being alive (aHR: 3.06 [1.67–5.60]), underweight (aHR: 1.82 [1.14–2.92]), and World Health Organization stages 3 (aHR: 2.63 [1.12–6.18]) and 4 (aHR: 2.20 [0.94–5.18]) increased mortality; while school attendance (aHR: 0.12 [0.06–0.21]), high CD4+ counts >350 cells/mm3 (aHR: 0.79 [0.48–1.29]), and low first viral load <1000 copies/mL (aHR: 0.24 [0.14–0.40]) were protective.

Conclusion:

Independent predictors of mortality were age 11 years or older at the start of ART, orphan status, underweight, and advanced HIV disease. Beyond the provision of universal ART, care accorded to CALWH necessitates optimization through tackling individual predictors of mortality.
Distinct SARS-CoV-2 populational immune backgrounds induce divergent RBD evolutionary preferences
Authors: Ma Wentai , Fu Haoyi , Jian Fanchong , Cao Yunlong , Li Mingkun
Published: December 2023

Immune evasion is a pivotal force shaping the evolution of viruses. Nonetheless, the extent to which virus evolution varies among populations with diverse immune backgrounds remains an unsolved mystery. Prior to the widespread SARS-CoV-2 infections in December 2022 and January 2023, the Chinese population possessed a markedly distinct (less potent) immune background due to its low infection rate, compared to countries experiencing multiple infection waves, presenting an unprecedented opportunity to investigate how the virus has evolved under different immune contexts. We compared the mutation spectrum and functional potential of BA.5.2.48, BF.7.14, and BA.5.2.49—variants prevalent in China—with their counterparts in other countries. We found that mutations in the RBD region in these lineages were more widely dispersed and evenly distributed across different epitopes. These mutations led to a higher ACE2 binding affinity and reduced potential for immune evasion compared to their counterparts in other countries. These findings suggest a milder immune pressure and less evident immune imprinting within the Chinese population. Despite the emergence of numerous immune-evading variants in China, none of them exhibited a transmission advantage. Instead, they were replaced by the imported XBB variant with stronger immune evasion since April 2023. Our findings demonstrated that the continuously changing immune background led to varying evolutionary pressures on SARS-CoV-2. Thus, in addition to the viral genome surveillance, immune background surveillance is also imperative for predicting forthcoming mutations and understanding how these variants spread in the population.
Clustering of RNA co-expression network identifies novel long non-coding RNA biomarkers in squamous cell carcinoma
Authors: Nissinen Liisa , Haalisto Josefiina , Riihilä Pilvi , Piipponen Minna , Kähäri Veli-Matti
Published: December 2023

Long non-coding RNAs (lncRNAs) have been shown to play an important role in cancer progression. Cutaneous squamous cell carcinoma is the most common metastatic skin cancer with increasing incidence worldwide. The prognosis of the metastatic cSCC is poor, and currently there are no established biomarkers to predict metastatic risk nor specific therapeutic targets for advanced or metastatic cSCC. To elucidate the role of lncRNAs in cSCC, RNA sequencing of patient derived cSCC cell lines and normal human epidermal keratinocytes was performed. The correlation analysis of differentially expressed lncRNA and protein-coding genes revealed six distinct clusters. One of the upregulated clusters involved genes related to cell motility. Upregulation of the expression of lncRNAs involved in cSCC cell motility in cSCC and head and neck SCC (HNSCC) cells was confirmed by qRT-PCR. Upregulation ofHOTTIPandLINC00543was also noted in SCC tumorsin vivoand was associated with worse prognosis in HNSCC and lung SCC cohorts in the TCGA data, respectively. Altogether, these results reveal a novel set of lncRNAs involved in cSCC cell locomotion. These lncRNAs may serve as potential novel biomarkers or a biomarker panel and as putative therapeutic targets in locally advanced and metastatic cSCC.
Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion
Authors: Porter Hunter L. , Ansere Victor A. , Undi Ram Babu , Hoolehan Walker , Giles Cory B. , Brown Chase A. , Stanford David , Huycke Mark M. , Freeman Willard M. , Wren Jonathan D.
Published: December 2023

DNA methylation data has been used to make “epigenetic clocks” which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to “pseudomethylation” signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.
Chlamydial protease-like activating factor targets SLC7A11 for degradation to induce ferroptosis and facilitate dissemination
Authors: Chen Wentao , Su Xin , Pan Yuying , Xue Yaohua , Zeng Lihong , Xu Qingqing , Yu Xueying , Yin Xiaona , Zhou Han , Feng Zhanqin , Zhang Bao , Zhao Wei , Zheng Heping
Published: December 2023

Chlamydia trachomatis, the most prevalent bacterial agent of sexually transmitted infections, possesses remarkable capacities for dissemination within the host, leading to reproductive health complications. The release of progeny through the orchestrated lysis of host cells plays a crucial role inChlamydiadissemination, but the underlying molecular mechanisms remain largely elusive. Here, we uncovered a novel mechanism by whichChlamydiainduces host cells ferroptosis to facilitate its dissemination. This process involves the degradation of host protein SLC7A11 by the chlamydial protease-like activating factor (CPAF), resulting in glutathione depletion, oxidative damage, and subsequent host cell lysis characterized by lipid peroxidation. Infection with CPAF-deficient strain fails to induce host cells ferroptosis, leading to restricted progeny release. Importantly, inhibiting ferroptosis effectively limits the release ofChlamydiaprogeny, highlighting its potential as a therapeutic strategy for controllingChlamydiadissemination. These findings provide insights into the chlamydial conserved dissemination strategy and enhance understanding of its pathogenesis.
Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7
Authors: Niemelä Akseli , Koivuniemi Artturi
Published: December 2023

Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.
Correction of non-random mutational biases along a linear bacterial chromosome by the mismatch repair endonuclease NucS
Authors: Dagva Oyut , Thibessard Annabelle , Lorenzi Jean-Noël , Labat Victor , Piotrowski Emilie , Rouhier Nicolas , Myllykallio Hannu , Leblond Pierre , Bertrand Claire
Published: December 2023

The linear chromosome ofStreptomycesexhibits a highly compartmentalized structure with a conserved central region flanked by variable arms. As double strand break (DSB) repair mechanisms play a crucial role in shaping the genome plasticity ofStreptomyces, we investigated the role of EndoMS/NucS, a recently characterized endonuclease involved in a non-canonical Mismatch Repair (MMR) mechanism in archaea and actinobacteria, that singularly corrects mismatches by creating a DSB. We showed thatStreptomycesmutants lacking NucS display a marked colonial phenotype and a drastic increase in spontaneous mutation rate.In vitrobiochemical assays revealed that NucS cooperates with the replication clamp to efficiently cleave G/T, G/G and T/T mismatched DNA by producing DSBs. These findings are consistent with the transition-shifted mutational spectrum observed in the mutant strains and reveal that NucS-dependent MMR specific task is to eliminate G/T mismatches generated by the DNA polymerase during replication. Interestingly, our data unveil a crescent-shaped distribution of the transition frequency from the replication origin towards the chromosomal ends, shedding light on a possible link between NucS-mediated DSBs andStreptomycesgenome evolution.

GRAPHICAL ABSTRACT
Cell type-specific adaptation of the SARS-CoV-2 spike
Authors: Carrascosa-Sàez Marc , Marqués María-Carmen ,   The IBV-Covid19-Pipeline, Geller Ron , Elena Santiago F. , Rahmeh Amal , Dufloo Jérémy , Sanjuán Rafael
Published: December 2023

SARS-CoV-2 can infect various human tissues and cell types, principally via interaction with its cognate receptor ACE2. However, how the virus evolves in different cellular environments is poorly understood. Here, we used experimental evolution to study the adaptation of the SARS-CoV-2 spike to four human cell lines expressing different levels of key entry factors. After 20 passages, cell type-specific phenotypic changes were observed. Selected spike mutations were identified and functionally characterized in terms of entry efficiency, ACE2 affinity, spike processing, TMPRSS2 usage, entry pathway and syncytia formation. We found that the effects of these mutations varied across cell types. Interestingly, two spike mutations (L48S and A372T) that emerged in cells expressing low ACE2 levels increased receptor affinity, syncytia induction, and entry efficiency under low-ACE2 conditions. Our results demonstrate specific adaptation of the SARS-CoV-2 spike to different cell types and have implications for understanding SARS-CoV-2 tissue tropism and evolution.
Seasonal variation in D2/3 dopamine receptor availability in the human brain
Authors: Sun Lihua , Malén Tuulia , Tuisku Jouni , Kaasinen Valtteri , Hietala Jarmo A. , Rinne Juha , Nuutila Pirjo , Nummenmaa Lauri
Published: December 2023

Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmicin vivodopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. Here, based on historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. We found that daylength at the time of scanning was negatively correlated with availability of this type of receptors in the striatum. Likely, seasonally varying D2/3 receptor signaling also underlies the seasonality of mood, feeding, and motivational processes.

Significance of the study

Brainin vivoneurotransmitter signaling demonstrates seasonal patterns. The dopamine D2/3 receptor, with both pre- and postsynaptic expressions, has been targeted by major antipsychotic and antiparkinsonian pharmaceuticals. The current study, based on a large dataset of healthy brain PET images quantifying these receptors, shows that dark seasons are associated with increased receptor availability in the striatum. Considering the previous findings of increased dopamine synthesis and lowered number of transporters, findings may suggest elevated presynaptic control of dopamine release and increased dopamine receptor sensitivity during dark seasons. The rhythmic D2/3 receptor availability may be a mechanism underlying seasonality in mood, feeding, and motivational processes.
Reduced palatability, fast flight, and tails: Decoding the defence arsenal of Eudaminae skipper butterflies in a Neotropical locality
Authors: Linke Daniel , Mejia Jacqueline Hernandez , Navarro Valery N. P. Eche , Salinas Sánchez Letty , Ribeiro Pedro de Gusmão , Elias Marianne , Matos-Maraví Pável
Published: December 2023

Prey often relies on multiple defences to avoid predators, such as difficulty of capture, attack deflection, or unpleasant taste. Eudaminae skipper butterflies rely on behavioural (fast flight) and mechanical defences (hindwing tails), but other defences like unpalatability (consumption deterrence), and the interaction among defences, have not been assessed.

We test the palatability of 12 abundant Eudaminae species from a Neotropical locality, using training and feeding experiments with domestic chicks. Further, we approximate the difficulty of capture explained by flight speed and quantified by wing loading. To test how multiple defences are associated and explained by body size and habitat preference, we perform phylogenetic Bayesian regression analyses.

We found a broad range of palatability in Eudaminae, within and among species. Palatability was negatively correlated with wing loading, indicating that butterflies with higher flight speed tend to have lower palatability.

The presence or absence of tails did not explain the level of butterfly palatability, showing that attack deflection and consumption deterrence are not mutually exclusive defences. Habitat preference (open or forested environments) did not explain the level of palatability in Eudaminae, but it seems that butterflies with high wing loading (fast flight) tended to occupy semi-closed (e.g., hilltops) or closed habitats (e.g., secondary forest).

Finally, the level of unpalatability in Eudaminae is size dependent, larger butterflies are less palatable, perhaps due to their more likely detectability/preference by predators. Altogether, our findings shed light on the contexts favouring the prevalence of single vs. multiple defensive strategies in prey.
PD-L1 blockade immunotherapy rewires cancer emergency myelopoiesis
Authors: Boumpas Athina , Papaioannou Antonis , Bousounis Pavlos , Grigoriou Maria , Bergo Veronica , Papafragkos Iosif , Tasis Athanasios , Iskas Michael , Boon Louis , Makridakis Manousos , Vlachou Antonia , Gavriilaki Eleni , Hatzioannou Aikaterini , Mitroulis Ioannis , Trompouki Eirini , Verginis Panayotis
Published: December 2023

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (αPDL1) in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice shifting towards an inflammatory state. Functionally, transplantation of HSPCs isolated from αPDL1-treated tumor-bearing mice exhibited resistance to cancer-associated myelopoiesis as evident by the generation of reduced frequencies of myeloid-derived suppressor cells (MDSCs) compared to cells from control-treated mice. Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis.
Comparative roles of caudate and putamen in the serial order of behavior: Effects of striatal glutamate receptor blockade on variable versus fixed spatial self-ordered sequencing in marmosets
Authors: Gould Stacey Anne , Hodgson Amy , Clarke Hannah F. , Robbins Trevor W. , Roberts Angela C.
Published: December 2023

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. Lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intra-striatal CNQX microinfusions, we demonstrate that caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited a greater impairment. We demonstrate that continuous perseverative errors in the variable array were caused by putamen infusions, likely due to interference with the putamen’s established role in monitoring motor feedback. Caudate infusions, on the other hand caused recurrent perseveration, with deficits possibly reflecting interference with the caudate’s established role in spatial working memory and goal-directed planning. In contrast to the variable array, whilst both caudate and putamen are needed for fixed array responding, combined effects were not additive, suggesting possible competing roles. Infusions in either region led to continuous perseveration when infused individually, but not when infused simultaneously. Caudate infusions did not cause recurrent perseveration in the fixed array; instead, this was caused by putamen infusions. The results overall are consistent with a role of caudate in planning and flexible responding, but putamen in more rigid habitual or automatic responding.

Significance Statement

This investigation employing local intra-striatal infusions into caudate nucleus and/or putamen of the New World marmoset reveals important roles for these regions in variable and fixed spatial self-ordered sequencing. Here, we directly implicate subcortical output regions of the lateral prefrontal cortex in self-ordered sequencing behavior. The ability to self-order sequences, as well as more broadly to plan, organize information, and respond flexibly, is impaired in many neurological diseases and psychiatric disorders. By understanding the basic neural circuitry underlying these cognitive abilities, we may better understand how to rectify them in people with deficits across a plethora of disorders.
Pancreatic Schwann cell reprogramming supports cancer-associated neuronal remodeling
Authors: Rangel-Sosa Martha M. , Mann Fanny , Chauvet Sophie
Published: December 2023

The peripheral nervous system is a key regulator of cancer progression. In pancreatic ductal adenocarcinoma (PDAC), the sympathetic branch of the autonomic nervous system inhibits cancer development. This inhibition is associated with extensive sympathetic nerve sprouting in early pancreatic cancer precursor lesions. However, the underlying mechanisms behind this process remain unclear. This study aimed to investigate the roles of pancreatic Schwann cells in the structural plasticity of sympathetic neurons. We examined the changes in the number and distribution of Schwann cells in a transgenic mouse model of PDAC and in a model of metaplastic pancreatic lesions induced by chronic inflammation. Schwann cells proliferated and expanded simultaneously with new sympathetic nerve sprouts in metaplastic/neoplastic pancreatic lesions. Sparse genetic labeling showed that individual Schwann cells in these lesions had a more elongated and branched structure than those under physiological conditions. Schwann cells overexpressed proinflammatory and neurotrophic factors, including glial cell-derived neurotrophic factor (GDNF). Sympathetic neurons upregulated the GDNF receptor and promoted cell growth in response to GDNFin vitro. Selective genetic deletion ofGdnfin Schwann cells completely blocked sympathetic nerve sprouting in metaplastic pancreatic lesionsin vivo. This study demonstrated that pancreatic Schwann cells underwent adaptive reprogramming during early cancer development, supporting a protective antitumor neuronal response. These finding could help to develop new strategies to modulate cancer associated neural plasticity.

MAIN POINTS

Non-myelinating pancreatic Schwann cells associate with sympathetic axon terminals supplying the pancreas.

Pancreatic Schwann cells proliferate and undergo adaptive reprogramming in response to chronic inflammation and the development of pancreatic cancer.

Glial cell line-derived neurotrophic factor expression in reprogrammed pancreatic Schwann cells promotes Schwann cell expansion and sympathetic axon sprouting in pancreatic cancer precursor lesions.
THE WIP6 TRANSCRIPTION FACTORTOO MANY LATERALSSPECIFIES VEIN TYPE IN C4AND C3GRASS LEAVES
Authors: Vlad Daniela , Zaidem Maricris , Perico Chiara , Sedelnikova Olga , Bhattacharya Samik , Langdale Jane A.
Published: December 2023

Grass leaves are invariantly strap shaped with an elongated distal blade and a proximal sheath that wraps around the stem. Underpinning this uniform shape is a scaffold of leaf veins, most of which extend in parallel lines along the proximo-distal leaf axis. Differences between species are apparent both in the types of veins that develop and in the spacing between them across the medio-lateral leaf axis. A prominent engineering goal is to increase vein density and the proportion of bundle sheath cells surrounding the veins in leaves of C3photosynthesizing species such as rice, in order to facilitate introduction of the more efficient C4photosynthetic pathway. Here we discover that the WIP6 zinc finger transcription factor TOO MANY LATERALS (TML) specifies vein rank in both maize (C4) and rice (C3), species with distinct venation patterns. Loss of functiontmlmutations lead to the development of large lateral veins in positions normally occupied by smaller intermediate veins. The spatial localization ofTMLtranscripts in wild-type leaves is consistent with a role in suppressing lateral vein formation in procambial cells that develop intermediate veins, specifically the class of intermediate veins that extend from the leaf blade into the leaf sheath. Attempts to manipulate TML function in rice were unsuccessful because transgene expression was silenced, suggesting that precise spatial and temporal regulation ofTMLexpression is essential during the regeneration of shoot tissue from callus. Given that transcriptome analysis demonstrated altered profiles of genes associated with cytokinin and auxin signaling in loss of function maize mutants, the necessity for tight regulation ofTMLgene expression could be an indirect consequence of hormonal inbalances as opposed to ectopic activity of a specific downstream target. Importantly, however, loss of function mutants in rice display increased vascular and bundle sheath cell occupancy in the leaf. Collectively this work provides an understanding of how vein rank is specified in grass leaves and a first step towards an anatomical chassis for C4engineering in rice.
Allosteric Modulation of Fluorescence Revealed by Hydrogen Bond Dynamics in a Genetically Encoded Maltose Biosensor
Authors: Berksoz Melike , Atilgan Canan
Published: December 2023

Genetically encoded fluorescent biosensors (GEFBs) proved to be reliable tracers for many metabolites and cellular processes. In the simplest case, a fluorescent protein (FP) is genetically fused to a sensing protein which undergoes a conformational change upon ligand binding. This drives a rearrangement in the chromophore environment and changes the spectral properties of the FP. Structural determinants of successful biosensors are revealed only in hindsight when the crystal structures of both ligand-bound and ligand-free forms are available. This makes the development of new biosensors for desired analytes a long trial-and-error process. In the current study, we conducted µs-long all atom molecular dynamics (MD) simulations of a maltose biosensor in both theapo(dark) andholo(bright) forms. We performed detailed hydrogen bond occupancy analyses to shed light on the mechanism of ligand induced conformational change in the sensor protein and its allosteric effect on the chromophore environment. We find that two strong indicators for distinguishing bright and dark states of biosensors are due to substantial changes in hydrogen bond dynamics in the system and solvent accessibility of the chromophore.
Identifying Developmental Changes in Functional Brain Connectivity Associated with Cognitive Functioning in Children and Adolescents with ADHD
Authors: Pho B , Stevenson RA , Mohzenszadeh Y , Stojanoski B
Published: December 2023

Children and adolescents diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) often show deficits in various measures of higher-level cognition, such as, memory and executive functioning. Poorer high-level cognitive functioning in children with ADDH has been associated with differences in functional connectivity across the brain, including the frontoparietal network. However, little is known about the developmental changes to cortical functional connectivity profiles associated with higher-order cognitive abilities in this cohort. To characterize changes in the functional brain connectivity profiles related to higher-order cognitive functioning, we analyzed a large dataset(n=479) from the publicly available Healthy Brain Network which included fMRI data collected while children and adolescents between the ages of 6 and 16 watched a short movie-clip. The cohort was divided into two groups, neurotypical youth (n=106), and children and adolescents with ADHD (n=373). We applied machine learning models to functional connectivity profiles generated from the fMRI data to identify patterns of network connectivity that differentially predict cognitive abilities in our cohort of interest. We found, using out-of-sample cross validation, models using functional connectivity profiles in response to movie-watching successfully predicted IQ, visual spatial, verbal comprehension, and fluid reasoning in children ages 6 to 11, but not in adolescents with ADHD. The models identified connections with the default mode, memory retrieval, and dorsal attention networks as driving prediction during early and middle childhood, but connections with the somatomotor, cingulo-opercular, and frontoparietal networks were more important in middle childhood. This work demonstrated that computational models applied to neuroimaging data in response to naturalistic stimuli can identify distinct neural mechanisms associated with cognitive abilities at different developmental stages in children and adolescents with ADHD.
Pangenome comparison ofBacteroides fragilisgenomospecies unveil genetic diversity and ecological insights
Authors: Oles Renee E. , Terrazas Marvic Carrillo , Loomis Luke R. , Hsu Chia-Yun , Tribelhorn Caitlin , Ferre Pedro Belda , Ea Allison , Bryant MacKenzie , Young Jocelyn , Carrow Hannah C. , Sandborn William J. , Dulai Parambir , Sivagnanam Mamata , Pride David , Knight Rob , Chu Hiutung
Published: December 2023

Bacteroides fragilisis a Gram-negative commensal bacterium commonly found in the human colon that differentiates into two genomospecies termed division I and II. We leverage a comprehensive collection of 694B. fragiliswhole genome sequences and report differential gene abundance to further support the recent proposal that divisions I and II represent separate species. In division I strains, we identify an increased abundance of genes related to complex carbohydrate degradation, colonization, and host niche occupancy, confirming the role of division I strains as gut commensals. In contrast, division II strains display an increased prevalence of plant cell wall degradation genes and exhibit a distinct geographic distribution, primarily originating from Asian countries, suggesting dietary influences. Notably, division II strains have an increased abundance of genes linked to virulence, survival in toxic conditions, and antimicrobial resistance, consistent with a higher incidence of these strains in bloodstream infections. This study provides new evidence supporting a recent proposal for classifying divisions I and IIB. fragilisstrains as distinct species, and our comparative genomic analysis reveals their niche-specific roles.
Transposase-Assisted Tagmentation: An Economical and Scalable Strategy for Single-Worm Whole-Genome Sequencing
Authors: Wang Zi , Ke Jinyi , Guo Zhengyang , Wang Yang , Lei Kexin , Wang Shimin , Chen Guanghan , shen Zijie , Li Wei , Ou Guangshuo
Published: December 2023

AlphaMissense identifies 23 million human missense variants as likely pathogenic, but only 0.1% have been clinically classified. To experimentally validate these predictions, chemical mutagenesis presents a rapid, cost-effective method to produce billions of mutations in model organisms. However, the prohibitive costs and limitations in the throughput of whole-genome sequencing (WGS) technologies, crucial for variant identification, constrain its widespread application. Here, we introduce a Tn5 transposase-assisted tagmentation technique for conducting WGS inC. elegans,E. coli,S. cervisiae, andC. reinhardtii. This method, demands merely 20 minutes of hands-on time for a single worm or single-cell clones and incurs a cost below 10 US dollars. It effectively pinpoints causal mutations in mutants defective in cilia or neurotransmitter secretion and in mutants synthetically sterile with a variant analogous to the oncogenic BRAF(V600E) mutation. Integrated with chemical mutagenesis, our approach can generate and identify missense variants economically and efficiently, facilitating experimental investigations of missense variants in diverse species.
Genomic and Phenotypic Consequences of Bi-Directional Introgression Between Chinese and European Pig Breeds
Authors: Qiu Yibin , Liu Langqing , Huang Min , Ruan Donglin , Ding Rongrong , Zhang Zebin , Zheng Enqin , Wang Shiyuan , Deng Shaoxiong , Cheng Xinyan , Shi Jiaxin , Yang Yingshan , Zhou Fuchen , Huang Sixiu , Yang Huaqiang , Li Zicong , Cai Gengyuan , Yang Jie , Wu Zhenfang
Published: December 2023

Historically, Chinese indigenous pigs were introduced to Europe centuries ago with the aim of enhancing economically important traits in European breeds. In recent decades, there has been a reciprocal introduction of European commercial breeds to China for indigenous pig breeding. Our study investigated the genomes of 418 pigs, revealing a genomics landscape of bi-directional introgression patterns between Chinese and European pig populations. We noted a common occurrence of incomplete linkage disequilibrium between structural variations (SVs) and adjacent single-nucleotide polymorphisms (SNPs) in our population, suggesting that conventional SNP-based analyses might not adequately capture the effect of SVs. Therefore, we examine both the roles of population-level SNPs and SVs in bi-directional introgression patterns, and highlight a show case centered around theBMP2gene. We identified introgressed haplotypes and SVs originating from Southern Chinese indigenous pigs, dispersing widely across various European pig breeds. Concurrently, we noted that the introgressed European haplotypes and SVs have attained high frequencies in Northern Chinese indigenous breeds, likely contributing to improvements in body size. In summary, these findings underscore the significant role of introgression in shaping the genetic composition and phenotypic traits in modern pig breeds.
The dCMP deaminase DCTD and the E3 ligase TOPORS are central mediators of decitabine cytotoxicity
Authors: Carnie Christopher J. , Götz Maximilian J. , Palma-Chaundler Chloe S. , Weickert Pedro , Wanders Amy R. , Serrano-Benitez Almudena , Li Hao-Yi , Gupta Vipul , Blum Christian J. , Sczaniecka-Clift Matylda , Zagnoli-Vieira Guido , D’Alessandro Giuseppina , Richards Sean L. , Gueorguieva Nadia , Beli Petra , Stingele Julian , Jackson Stephen P.
Published: December 2023

The nucleoside decitabine (5-aza-dC) is used to treat several hematological cancers. Upon triphosphorylation and incorporation into DNA, 5-aza-dC induces covalent DNMT1 DNA-protein crosslinks (DPCs) and DNA hypomethylation. However, 5-aza-dC treatment success varies, and relapse is common. Using genome-scale CRISPR/Cas9 screens, we map factors determining 5-aza-dC susceptibility. Unexpectedly, we find that loss of the dCMP deaminase DCTD causes 5-aza-dC resistance, suggesting that 5-aza-dUMP generation underlies most 5-aza-dC cytotoxicity in wild-type cells. Combining results from a subsequent genetic screen in DCTD-deficient cells with identification of the proximal proteome of DNMT1-DPCs, we uncover the ubiquitin/SUMO1 E3 ligase, TOPORS, as a new DPC repair factor. TOPORS is recruited to DNMT1-DPCs in a SUMO-dependent manner and promotes their degradation. Our study suggests that 5-aza-dC-induced DPCs cause cytotoxicity when DPC repair is compromised, while cytotoxicity in wild-type cells arises from perturbed nucleotide metabolism and lays the foundations for the development of predictive biomarkers for decitabine treatment.
Adipose gene expression profiles and their associations with adaptations in Northern Finncattle, Mirandesa cattle, Yakutian cattle and Holstein cattle
Authors: Ruvinskiy Daniil , Amaral Andreia , Weldenegodguad Melak , Honkatukia Mervi , Lindeberg Heli , Peippo Jaana , Soppela Päivi , Stammler Florian , Uimari Pekka , Ginja Catarina , Kantanen Juha , Pokharel Kisun
Published: December 2023

Background

The drastic change in global climate has led to in-depth studies of the genetic resources of native cattle adapted to challenging environments. Native cattle breed data may harbor unique variants that will enable the generation of new tools to improve the adaptation potential of commercial cattle breeds. Adipose tissues are key factors in the regulation of metabolism and energy balance and are crucial for the molecular switches needed to adapt to rapid environmental and nutritional changes. The transcriptome landscape of four adipose tissues was used in this study to investigate the effect of the environment on the gene expression profiles of three local breeds, Yakutian cattle (Sakha Republic), Northern Finncattle (Finland), Mirandesa cattle (Portugal) and commercial Holstein cattle.

Results

A total of 26 animals (12 cows, 14 bulls) yielded 81 samples of perirenal adipose tissue (n=26), metacarpal adipose tissue (n=26), tailhead adipose tissue (n=26) and prescapular adipose tissue (n=3). More than 17,000 genes were expressed in our dataset. Principal component analysis of the normalized expression profiles revealed a differential expression profile of the metacarpal adipose tissue. We found that the genes upregulated in the metacarpal adipose tissue of Yakutian cattle, such asNR4A3,TEKT3, andFGGY, were associated with energy metabolism and response to cold temperatures. In Mirandesa cattle, the upregulated genes in perirenal adipose tissue were related to immune response and inflammation (AVPR2, CCN1, andIL6), while in Northern Finncattle, the upregulated genes appeared to be involved in various physiological processes, including energy metabolism (IGFBP2). According to the sex-based comparisons, the most interesting result was the upregulation of theTPRG1 genein three tissues of Yakutian cattle females, suggesting that adaptation is related to feed efficiency.

Conclusions

The highest number of differentially expressed genes was found between Yakutian cattle and Holstein, several of which were associated with immunity in Yakutian cattle, indicating potential differences in disease resistance and immunity between the two breeds. This study highlights the vast difference in gene expression profiles in adipose tissues between breeds from different climatic environments, most likely highlighting selective pressure and the potential significance of the uniquely important regulatory functions of metacarpal adipose tissue.
Kind minds: using the ‘compassionate kitbag’ in a compassion focused therapy group for adults with intellectual disabilities
Authors: Busfield Andy , Peters Charlotte , McKenzie Karen
Published: December 2023

Purpose

This paper aims to describe and evaluate the impact of a compassion-focused therapy (CFT) group for adults with intellectual disabilities (ID).

Design/methodology/approach

People with ID are commonly subjected to stigmatising experiences that can contribute to feelings of shame. CFT targets shame and self-criticism by helping people to cultivate self-compassion. There is evidence to suggest that CFT can be meaningfully adapted for people with ID. Qualitative and quantitative data were collected using a mixed-methods design, aiming to gain a rich evaluation of the CFT group. Eight adults with ID were referred by their local community psychology team. An 11-week group protocol was based on materials from previous research. The protocol included the development of a “compassion box”, aiming to make CFT concepts more concrete and tangible. Questionnaires measuring psychological distress, self-compassion and negative social comparisons were completed pre- and post-group. Feedback from participants and carers were collated and facilitators’ observations were recorded.

Findings

Questionnaire findings were mixed, and some participants found the measures difficult to understand. Participants’ qualitative feedback and facilitators’ observations suggested that the group created feelings of safety and connectedness whilst facilitating engagement and action with shame and self-criticism. Several participants highlighted the usefulness of the ‘”compassion box”, although some barriers were noted.

Originality/value

This paper provides a rich description of how group CFT can be adapted to meet the needs of adults with ID and is the first study of its kind, to the best of the authors’ knowledge, to evaluate the incorporation of the “compassion box”.
Family incivility and organisational citizenship behaviour: roles of negative rumination, workplace friendship and optimism
Authors: Kuriakose Vijay , Bishwas Sumant Kumar
Published: December 2023

Purpose

This study aims to understand the relationship between family incivility and employees' organisational citizenship behaviour. It also explores the mediating role of negative rumination and the moderating roles of workplace friendship and optimism.

Design/methodology/approach

To test the hypothesised relationships, 381 responses were collected from employees at two-time points. The hypothesised relationships were tested using process macros.

Findings

The results indicated that family incivility is negatively related to organisational citizenship behaviour and increases negative rumination. The study also established the mediating role of negative rumination in the relationship between family incivility and organisational citizenship behaviour. The study also supported the buffering role of workplace friendship and optimism in the relationship between family incivility and negative rumination.

Research limitations/implications

The study findings extend the understanding of how a non-work stressor can influence employee behaviour in the organisation. The study findings provide valuable directions to mitigate family incivility's adverse effects and extend the existing body of knowledge.

Originality/value

The study is unique as it links family events to work outcomes. Only a few scholarly attempts were undertaken to understand the effect of family incivility on employees' work behaviours. By explaining the mechanism and conditions, the study has a unique value to the scholarship.
Designing innovation in urban hotels through guest experience data on interior design
Authors: Gavilan Diana , A. Al-shboul Omar Adeeb
Published: December 2023

Purpose

This paper aims to identify potential avenues for innovation in urban hotel management by analyzing self-reported data from visitors regarding their experience with interior design.

Design/methodology/approach

A qualitative exploratory computer-assisted content analysis was conducted to identify the impact of interior design on the guest experience. Leximancer 4.0 software analyzed 2,562 reviews from urban hotels collected through a reservation website.

Findings

The findings reveal that data reported by guests on interior design play a crucial role in shaping guest experiences, both positively and negatively. The esthetic appeal of interior design is shown to impact resting and comfort, affecting overall performance significantly. The study also highlights how different star categories of hotels and variations in visitors' purposes for their stay lead to distinct guest experiences and different opportunities to innovate.

Research limitations/implications

The study’s results provide evidence for researchers and practitioners of the potential of the guest-reported interior design experience as a valuable source for fostering innovation. In addition, in the hotel industry, innovation may eventually be attained through interior design renovation.

Practical implications

Self-reported data from guests on interior design is an effective tool for innovation. Making interior design a priority throughout the establishment and ongoing management of a hotel is crucial. By integrating interior design, not only can potential negative experiences be avoided, but greater guest satisfaction can also be achieved during their stay, promoting memorable experiences that align with the hotel category and customer expectations.

Social implications

This research emphasizes the importance of interior design as a catalyst for innovation and improved social experiences in the hospitality industry. Innovation in interior design can improve hotel performance in several dimensions, including attracting more visitors to the hotel and the area, increasing tourism revenue for local businesses and contributing to the broader societal goal of reducing environmental impact and promoting sustainability.

Originality/value

This article adopts a guest-centered methodology to provide valuable insights for hotel managers to leverage interior design as a tool for innovation in the hospitality industry after showing that interior design enhances guests' experiences, comfort and hotel differentiation.
Estimating public and private sectors' union wage effects in Ghana: is there a disparity?
Authors: Owusu-Afriyie John , Baffour Priscilla Twumasi , Baah-Boateng William
Published: December 2023

Purpose

This study seeks to estimate union wage effect in the public and private sectors of Ghana, respectively. It also seeks to ascertain whether the union wage effect in the two sectors varies.

Design/methodology/approach

The authors use data from the Ghana Living Standards Survey 6 (GLSS 6, 2012/2013) and Ghana Labour Force Survey (GLFS, 2015). In terms of estimation technique, the authors employ the Blinder–Oaxaca decomposition technique to estimate union wage effect in public and private sectors, respectively.

Findings

The findings indicate that union wage effect in the public sector is positive and higher relative to that of the private sector.

Practical implications

The findings imply that strict enforcement of Section 82 of Labour Act 2003 (Act 651) will curb the political influence of public sector unions over their employer (Government).

Originality/value

This research paper has not been presented to any journal for publication and it is the authors' original work.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-01-2023-0045