bluuebunny/crossref_metadata_2025 huggingface dataset:
From spreading to embedding innovation in health care: Implications for theory and practice
Authors: Scarbrough Harry , Kyratsis Yiannis
Published: July 2021

Issue

In broad terms, current thinking and literature on the spread of innovations in health care presents it as the study of two unconnected processes—diffusion across adopting organizations and implementation within adopting organizations. Evidence from the health care environment and beyond, however, shows the significance and systemic nature of postadoption challenges in sustainably implementing innovations at scale. There is often only partial diffusion of innovative practices, initial adoption that is followed by abandonment, incomplete or tokenistic implementation, and localized innovation modifications that do not provide feedback to inform global innovation designs.

Critical Theoretical Analysis

Such important barriers to realizing the benefits of innovation question the validity of treating diffusion and implementation as unconnected spheres of activity. We argue that theorizing the spread of innovations should be refocused toward what we call embedding innovation—the question of how innovations are successfully implemented at scale. This involves making the experience of implementation a central concern for the system-level spread of innovations rather than a localized concern of adopting organizations.

Insight/Advance

To contribute to this shift in theoretical focus, we outline three mechanisms that connect the experience of implementing innovations locally to their diffusion globally within a health care system: learning, adapting, and institutionalizing. These mechanisms support the distribution of the embedding work for innovation across time and space.

Practical Implications

Applying this focus enables us to identify the self-limiting tensions within existing top-down and bottom-up approaches to spreading innovation. Furthermore, we outline new approaches to spreading innovation, which better exploit these embedding mechanisms.
Effect of Donor Age and Corneal Endothelial Cell Density on Non-utilization of Donor Corneal Tissues: A Study From Indian Eye Banks
Authors: Roy Aravind , Chaurasia Sunita , Fernandes Merle , Mohamed Ashik , Murthy Somasheila , Das Sujata
Published: July 2021

Purpose:

To study the causes of non-utilization of donor corneas and assess whether non-utilized tissues differ from utilized tissues with regard to age and endothelial cell density (ECD).

Methods:

Aretrospective, cross-sectional analyses of all donor corneas collected from a network of 4 eye banks of a tertiary eye care institute in India during a 1-year period (January to December 2019) was conducted. All donor corneas were assessed for tissue quality by slit lamp evaluation, donor age, and specular microscopy. The causes of non-utilization and effect of donor age and ECD on tissue utilization were studied.

Results:

A total of 10,969 corneas were harvested during the study period; 4618 (42.1%) tissues were discarded. The main causes of non-utilization were poor tissue quality accounting for 86.16% (n = 3979) of all discarded corneas. The mean donor age was 50.7 ± 2.9 years and 63.3 ± 2.3 years for used and discarded corneas, respectively (P < 0.0001). The mean ECD of donor tissues was significantly (P < 0.0001) higher in the utilization group (2787.3 ± 77.4 cells/mm2) than that in the non-utilization group (2394.4 ± 82.5 cells/mm2). Donor age and ECD and their interaction were significant (P < 0.001) predictors of tissue utilization rate.

Conclusions:

Donor age and ECD and their interaction were significantly associated with the rate of utilization of donor corneal tissues.
Testing the Use of Data Drawn from the Electronic Health Record to Compare Quality
Authors: Walsh Kathleen E. , Razzaghi Hanieh , Hartley David M. , Utidjian Levon , Alford Shannon , Darwar Rahul A. , Shenkman Elizabeth , Jonas Susannah , Goodick Mary , Finkelstein Jonathan , Ozonoff Al , Black L. Vandy , Shapiro Michael , Shaw Kathryn , McCafferty-Fernandez Jennifer , Marsolo Keith , Kelly Amy , Werk Lloyd N. , Smallwood Jordan , Bailey Charles
Published: July 2021

Introduction:

Health systems spend $1.5 billion annually reporting data on quality, but efficacy and utility for benchmarking are limited due, in part, to limitations of data sources. Our objective was to implement and evaluate measures of pediatric quality for three conditions using electronic health record (EHR)-derived data.

Methods:

PCORnet networks standardized EHR-derived data to a common data model. In 13 health systems from 2 networks for 2015, we implemented the National Quality Forum measures: % children with sickle cell anemia who received a transcranial Doppler; % children on antipsychotics who had metabolic screening; and % pediatric acute otitis media with amoxicillin prescribed. Manual chart review assessed measure accuracy.

Results:

Only 39% (N = 2,923) of 7,278 children on antipsychotics received metabolic screening (range: 20%–54%). If the measure indicated screening was performed, the chart agreed 88% of the time [95% confidence interval (CI): 81%–94%]; if it indicated screening was not done, the chart agreed 86% (95% CI: 78%–93%). Only 69% (N = 793) of 1,144 children received transcranial Doppler screening (range across sites: 49%–88%). If the measure indicated screening was performed, the chart agreed 98% of the time (95% CI: 94%–100%); if it indicated screening was not performed, the chart agreed 89% (95% CI: 82%–95%). For acute otitis media, chart review identified many qualifying cases missed by the National Quality Forum measure, which excluded a common diagnostic code.

Conclusions:

Measures of healthcare quality developed using EHR-derived data were valid and identified wide variation among network sites. This data can facilitate the identification and spread of best practices.
Standardized Headache Therapy in the Pediatric Emergency Department Using Improvement Methodology
Authors: Vukovic Adam A. , Hariharan Selena , Caruso Michelle C. , Zellner Sara M. , Kabbouche Marielle , Porter Stephen C. , Murtagh-Kurowski Eileen
Published: July 2021

Introduction:

Primary headache is a common cause of pediatric emergency department (PED) visits. Without published guidelines to direct treatment options, various strategies lacking evidence are often employed. This study aims to standardize primary headache treatment in the PED by promoting evidence-based therapies, reducing nonstandard abortive therapies, and introducing dihydroergotamine (DHE) into practice.

Methods:

A multidisciplinary team developed key drivers, created a clinical care algorithm, and updated electronic medical record order sets. Outcome measures included the percentage of patients receiving evidence-based therapies, nonstandard abortive therapies, DHE given after failed first-line therapies, and overall PED length of stay. Process measures included the percent of eligible patients with the order set usage and medications received within 90 minutes. Balancing measures included hospital admissions and returns to the PED within 72 hours. Annotated control charts depicted results over time.

Results:

We collected data from July 2017 to December 2019. The percent of patients receiving evidence-based therapies increased from 69% to 73%. The percent of patients receiving nonstandard abortive therapies decreased from 2.5% to 0.6%. The percent of patients receiving DHE after failed first-line therapies increased from 0% to 37.2%. No untoward effects on process or balancing measures occurred, with sustained improvement for 14 months.

Conclusion:

Standardization efforts for patients with primary headaches led to improved use of evidence-based therapies and reduced nonstandard abortive therapies. This methodology also led to improved DHE use for migraine headache resistant to first-line therapies. We accomplished these results without increasing length of stay, admission, or return visits.
Incidental Pituitary Adenoma on MIBI Parathyroid Imaging
Authors: Asiri Jaber Abdulwahab , Kulaybi Sami Ahmed , Daghas Fatimah Ahmed
Published: July 2021

A 77-year-old man with a case of hyperthyroidism with high parathyroid hormone (41 pmol/L), low vitamin D, and normal thyroid-stimulating hormone. The SPECT/CT fused images confirmed the evidence of retrotracheal hyperdense mass approximately 1.0 cm of diameter below the lower pole of the right thyroid lobe with increased uptake, highly suggestive of typical parathyroid adenoma. The most significant point is that there was an incidental finding: high focal uptake in the sellar/suprasellar region corresponding to heterogenous soft tissue lesion suspicious for pituitary adenoma. According to the previous scans, nuclear medicine, CT scan, and the MRI scan indicated pituitary adenoma.
FDG PET/CT in Sacroiliac IgG4 Disease
Authors: Elsobky Sherif , Dattani Vruti , Wagner Thomas , Mandumula Sri , Tavare Aniket
Published: July 2021

A 68-year-old woman with abdominal pain and a raised C-reactive protein was investigated with a CT of the abdomen. CT showed an irregular soft tissue mass anterior to the aorta, which was thought to be neoplastic. The patient underwent 18F-FDG PET/CT, which demonstrated hypermetabolic activity in this mass, as well as further foci of hypermetabolic activity in head and neck, sacroiliac joints, and pelvic floor muscles. A CT-guided biopsy of the sacroiliac joint was performed and revealed IgG4-related disease.
A quick protocol for the preparation of mouse retinal cryosections for immunohistochemistry
Authors: Yang Jialiang , Zou Tongdan , Yang Fang , Zhang Zilong , Sun Chen , Yang Zhenglin , Zhang Houbin
Published: July 2021

Immunohistochemistry (IHC) using mouse retinal cryosections is widely used to study the expression and intracellular localization of proteins in mouse retinas. Conventionally, the preparation of retinal cryosections from mice involves tissue fixation, cryoprotection, the removal of the cornea and lens, embedding and sectioning. The procedure takes 1–2 days to complete. Recently, we developed a new technique for the preparation of murine retinal cryosections by coating the sclera with a layer of Super Glue. This enables us to remove the cornea and extract the lens from the unfixed murine eye without causing the eyecup to collapse. In the present study, based on this new technique, we move a step forward to modify the conventional protocol. Unlike in the conventional protocol, in this method, we first coat the unfixed mouse eyeball on the sclera with Super Glue and then remove the cornea and lens. The eyecup is then fixed, cryoprotected and sectioned. This new protocol for the preparation of retinal cryosections reduces the time for the procedure to as little as 2 h. Importantly, the new protocol consistently improves the morphology of retinal sections as well as the image quality of IHC. Thus, this new quick protocol will be greatly beneficial to the community of visual sciences by expediting research progress and improving the results of IHC.
Ghrelin octanoylation by ghrelinO-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling
Authors: Davis Tasha R. , Pierce Mariah R. , Novak Sadie X. , Hougland James L.
Published: July 2021

The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelinO-acyltransferase (GOAT), a member of the membrane-boundO-acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.
On an integrable multi-component Camassa–Holm system arising from Möbius geometry
Authors: Kang Jing , Liu Xiaochuan , Qu Changzheng
Published: July 2021

In this paper, we mainly study the geometric background, integrability and peaked solutions of a

(
1
+
n
)

-component Camassa–Holm (CH) system and some related multi-component integrable systems. Firstly, we show this system arises from the invariant curve flows in the Möbius geometry and serves as the dual integrable counterpart of a geometrical

(
1
+
n
)

-component Korteweg–de Vries system in the sense of tri-Hamiltonian duality. Moreover, we obtain an integrable two-component modified CH system using a generalized Miura transformation. Finally, we provide a necessary condition, under which the dual integrable systems can inherit the Bäcklund correspondence from the original ones.
The anti-predation benefit of flash displays is related to the distance at which the prey initiates its escape
Authors: Loeffler-Henry Karl , Kang Changku , Sherratt Thomas N.
Published: July 2021

Flash behaviour is widespread in the animal kingdom and describes the exposure of a hidden conspicuous signal as an animal flees from predators. Recent studies have demonstrated that the signal can enhance survivorship by leading pursuing predators into assuming the flasher is also conspicuous at rest. Naturally, this illusion will work best if potential predators are ignorant of the flasher's resting appearance, which could be achieved if the prey flees while the predator is relatively far away. To test this hypothesis, we compared the survival of flashing and non-flashing computer-generated prey with different flight initiation distances (FIDs) using humans as model predators. This experiment found that flash displays confer a survivorship advantage only to those prey with a long FID. A complementary phylogenetic analysis of Australian bird species supports these results: after controlling for body size, species with putative flashing signals had longer FIDs than those without. Species with putative flashing signals also tended to be larger, as demonstrated in other taxa. The anti-predation benefit of flash displays is therefore related to the nature of escape behaviour. Since birds with hidden signals tend to flee at a distance, the flash display here is unlikely to function by startling would-be predators.
Multicellularity and sex helped shape the Tree of Life
Authors: Chen Lian , Wiens John J.
Published: July 2021

Across the Tree of Life, there are dramatic differences in species numbers among groups. However, the factors that explain the differences among the deepest branches have remained unknown. We tested whether multicellularity and sexual reproduction might explain these patterns, since the most species-rich groups share these traits. We found that groups with multicellularity and sexual reproduction have accelerated rates of species proliferation (diversification), and that multicellularity has a stronger effect than sexual reproduction. Patterns of species richness among clades are then strongly related to these differences in diversification rates. Taken together, these results help explain patterns of biodiversity among groups of organisms at the very broadest scales. They may also help explain the mysterious preponderance of sexual reproduction among species (the ‘paradox of sex’) by showing that organisms with sexual reproduction proliferate more rapidly.
High blood uric acid is associated with reduced risks of mild cognitive impairment among older adults in China: a 9-year prospective cohort study
Authors: Chen Chen , Li Xueqin , Lv Yuebin , Yin Zhaoxue , Zhao Feng , Liu Yingchun , Li Chengcheng , Ji Saisai , Zhou Jinhui , Wei Yuan , Cao Xingqi , Wang Jiaonan , Gu Heng , Lu Feng , Liu Zuyun , Shi Xiaoming
Published: July 2021

Background

It remains unsolved that whether blood uric acid (UA) is a neuroprotective or neurotoxic agent. This study aimed to evaluate the longitudinal association of blood UA with mild cognitive impairment (MCI) among older adults in China.

Methods

A total of 3103 older adults (aged 65+ years) free of MCI at baseline were included from the Healthy Aging and Biomarkers Cohort Study (HABCS). Blood UA level was determined by the uricase colorimetry assay and analyzed as categorical (by quartile) variables. Global cognition was assessed using the Mini-Mental State Examination four times between 2008 and 2017, with a score below 24 being considered as MCI. Cox proportional hazards models were used to examine the associations.

Results

During a 9-year follow-up, 486 (15.7%) participants developed MCI. After adjustment for all covariates, higher UA had a dose-response association with a lower risk of MCI (allPfor trend< 0.05). Participants in the highest UA quartile group had a reduced risk (hazard ratio [HR], 0.73; 95% [CI]: 0.55-0.96) of MCI, compared with those in the lowest quartile group. The associations were still robust even when considering death as a competing risk. Subgroup analyses revealed that these associations were statistically significant in younger older adults (65-79 years) and those without hyperuricemia.

Conclusions

High blood UA level is associated with reduced risks of MCI among Chinese older adults, highlighting the potential of managing UA in daily life for maintaining late-life cognition.
Influence of Novel Coronavirus COVID – 19 and HIV: A Scoping Review of Hospital Course and Symptomatology
Authors: Sheikh Mona , Nagpal Shavy , Zaidi Madiha , Vijayan Rupalakshmi , Matos Wanessa , Ngaba Neguemadji Nagardig , Akano Lordstrong , Jahan Samia , Shah Shazia Q. , Go Camille Celeste , Thevuthasan Sindhu , Michel George
Published: July 2021

Background

An outbreak of novel coronavirus (SARS- CoV-2) was observed on December 2019 in Wuhan, China which led to a global pandemic declared in March 2020. As a consequence, it imposed delirious consequences in patients with underlying co – morbid conditions that make them immunocompromised. The purpose of this paper is to provide an in - depth review of influence of COVID – 19 in patients with underlying HIV in terms of mortality and hospitalization.

Authors also aim to provide a thorough risk analysis of hospitalization, ICU admission and mortality of PLWH and COVID-19. The secondary objective was to analyze the CD4+ count variations and outcome of COVID - 19 and to correlate if ART provided a protective role. Authors also aim to provide an evaluation of typical clinical presentation of COVID-19 in PLWH. ART is found to show activity against SARS-CoV-2 in vitro, and there is some similarity in the structure of HIV-1 gp41 and S2 proteins of SARS-CoV since they both belong to +ssRNA type.

Methods

We conducted a literature review using search engines namely, Cochrane, PubMed and Google Scholar. The following keywords were targeted: “COVID-19,” “SARS-CoV-2,” and “HIV.” We included case reports, case series, and cohort (retrospective and prospective) studies. We excluded clinical trials and review articles. We came across 23 articles that met the inclusion criteria. PRISMA guidelines were followed for study acquisition (Fig. 9).

Results

From the 23 studies, we found a total of 651 PLWH with confirmed COVID-19 (549, 91, and 11 in cohorts, case series, and case reports, respectively). The overall risk of hospital admission from pooled data of the 23 reviewed articles was 69.13% (450/651), ICU admission was 12.90% (84/651) in total infected patients, and 18.67% (84/450) among hospitalized patients. The overall case fatality rate from the 23 reviewed articles was 11.21 (73/651).A weak positive correlation was found between CD4+ counts and hospital admissions in case series and case reports, while the weak negative correlation was found in cohorts. For mortality, there was a negative weak association in the cohorts and in case series, while a weak positive was seen in case reports (Fig.7). We assessed the presenting symptoms of PLWH with COVID-19, and our review demonstrated this group does not greatly differ from the rest of the population, as their common presenting symptoms were cough, fever, and SOB.

Conclusion

Our results indicated that there was a high rate of hospitalization, ICU admission, and mortality among patients living with HIV and COVID-19. PLWH needs to be noted as a high-risk group for COVID-19 complications and severity. We recommend that PLWH be closely monitored by their physicians and strictly adhere to antiretroviral therapy and standard universal COVID-19 precautions.
Are culturally vibrant communities healthier? Relationships between performing arts activity and health outcomes in the 500 largest US cities
Authors: McCrary J. Matt , Großbach Michael , Altenmüller Eckart
Published: July 2021

Aims

Recent reviews have demonstrated broad links between performing arts participation (e.g. music-making; dancing; acting) and receptive engagement (e.g. listening to music; attending a dance/theatre performance)and improved health, including reduced disease and mortality risk. However, no investigations to date have interrogated the links between community-level performing arts activity (i.e. participation + receptive engagement) and health outcomes – i.e. do the performing arts help create healthy communities? This study aims to address this question by examining links between performing arts activity and health outcomes across 500 cities in the United States.

Methods

Secondary analysis of demographic, health outcome, performing arts activity (estimated by annual performing arts revenue), and preventive/unhealthy behaviour data for 500 large cities in the United States – data extracted from the US Centers for Disease Control 500 Cities Project, Dun & Bradstreet Hoovers Database, and US Census. Links between performing arts activity and 12 health/disease outcomes were evaluated using a series of hierarchical beta regression models which progressively controlled for demographic variables and preventive/unhealthy behaviour prevalence.

Results

The 500 analysed US cities comprise 33.4% of the total US population and 84,010 performing arts businesses (total annual revenue $27.84 billion). No significant associations were found between performing arts activity and nine of twelve health outcomes in fully adjusted models (p≥.17). Statistically significant relationships (p<.01) between increased performing arts activity and increased prevalence of chronic kidney disease, coronary heart disease, and stroke were determined to be clinically equivocal.

Conclusions

This study contributes to a growing body of conflicting epidemiologic evidence regarding the impact of the performing arts on health/disease and mortality outcomes, evaluated using a range of disparate methodologies. A consensus, psychometrically rigorous approach is required to address this prevailing uncertainty in future epidemiologic studies examining effects of performing arts activities both within and across countries and communities.
Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention
Authors: Mayer Bryan T. , deCamp Allan C. , Huang Yunda , Schiffer Joshua T. , Gottardo Raphael , Gilbert Peter B. , Reeves Daniel B.
Published: July 2021

Broadly neutralizing antibodies are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As learned from effective ART, HIV viral diversity necessitates combination antibody cocktails. Here, we demonstrate how to optimally choose the ratio within combinations based on the constraint of a total dose size. Optimization in terms of prevention efficacy outcome requires a model that synthesizes 1) antibody pharmacokinetics (PK), 2) a mapping between concentration and neutralization against a genetically diverse pathogen (e.g., distributions of viral IC50 or IC80), 3) a protection correlate to translate in vitro potency to clinical protection, and 4) an in vivo interaction model for how drugs work together. We find that there is not a general solution, and the optimal dose ratio likely will be different if antibodies cooperate versus if both products must be simultaneously present. Optimization requires trade-offs between potency and longevity; using an in silico case-study, we show a cocktail can outperform a bi-specific antibody (a single drug with 2 merged antibodies) with superior potency but worse longevity. In another practical case study, we perform a triple antibody optimization of VRC07, 3BNC117, and 10-1074 bNAb variants using empirical PK and a pre-clinical correlate of protection derived from animal challenge studies. Here, a 2:1:1 dose emphasizing VRC07 would optimally balance protection while achieving practical dosing and given conservative judgements about prior data. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.
Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer’s disease-associated genetic variants
Authors: He Liang , Loika Yury , Kulminski Alexander M.
Published: July 2021

Elucidating regulatory effects of Alzheimer’s disease (AD)-associated genetic variants is critical for unraveling their causal pathways and understanding the pathology. However, their cell-type-specific regulatory mechanisms in the brain remain largely unclear. Here, we conducted an analysis of allele-specific expression quantitative trait loci (aseQTLs) for 33 AD-associated variants in four brain regions and seven cell types using ~3000 bulk RNA-seq samples and >0.25 million single nuclei. We develop a flexible framework using a hierarchical Poisson mixed model unifying samples in both allelic and genotype-level expression data. We identified 24 AD-associated variants (~73%) that are allele-specific eQTLs (aseQTLs) in at least one brain region. Multiple aseQTLs are region-dependent or exon-specific, such as rs2093760 with CR1, rs7982 with CLU, and rs3865444 with CD33. Notably, the APOE ε4 variant reduces APOE expression across all regions, even in healthy controls. In pinpointing the cell types responsible for the observed region-level aseQTLs, we found rs2093760 as an aseQTL of CR1 in oligodendrocytes but not in microglia. Many AD-associated variants are aseQTLs in microglia or monocytes of immune-related genes, including HLA-DQB1, HLA-DQA2, CD33, FCER1G, MS4A6A, SPI1, and BIN1, highlighting the regulatory role of AD-associated variants in the immune response. These findings provide further insights into potential causal pathways and cell types mediating the effects of the AD-associated variants.
Age- and episodic memory-related differences in task-based functional connectivity in women and men
Authors: Subramaniapillai Sivaniya , Rajagopal Sricharana , Ankudowich Elizabeth , Pasvanis Stamatoula , Misic Bratislav , Rajah M.Natasha
Published: July 2021

Aging is associated with episodic memory decline and changes in functional brain connectivity. Understanding whether and how biological sex influences age- and memory performance-related functional connectivity has important theoretical and clinical implications for our understanding of brain and cognitive aging. Yet, little is known about the effect of sex on neurocognitive aging. Here, we scanned 161 healthy adults between 19-76 yrs of age in an event-related functional magnetic resonance imaging (fMRI) study of face-location spatial context memory. Adults were scanned while performing easy and difficult versions of the task at both encoding and retrieval. We used multivariate whole-brain partial least squares (PLS) connectivity to test the hypothesis that there are sex differences in age- and episodic memory performance-related functional connectivity. We examined how individual differences in age and retrieval accuracy correlated with task-related connectivity. We then repeated this analysis after disaggregating the data by self-reported sex. We found that increased encoding and retrieval-related connectivity within the dorsal attention network (DAN), and between DAN and frontoparietal network (FPN) and visual networks, was positively correlated to retrieval accuracy and negatively correlated with age in both sexes. We also observed sex differences in age- and performance-related functional connectivity: i) greater between-network integration was apparent at both levels of task difficulty in women only, and ii) increased DAN-DMN connectivity with age was observed in men and was correlated with poorer memory performance. Therefore, the neural correlates of age-related episodic memory decline differ in women and men and has important theoretical and clinical implications for the cognitive neuroscience of memory, aging and dementia prevention.
Analysis of long and short enhancers in melanoma cell states
Authors: Mauduit David , Minnoye Liesbeth , Taskiran Ibrahim Ihsan , de Waegeneer Maxime , Christiaens Valerie , Hulselmans Gert , Demeulemeester Jonas , Wouters Jasper , Aerts Stein
Published: July 2021

Understanding how enhancers drive cell type specificity and efficiently identifying them is essential for the development of innovative therapeutic strategies. In melanoma, the melanocytic (MEL) and the mesenchymal-like (MES) states present themselves with different responses to therapy, making the identification of specific enhancers highly relevant. Using massively parallel reporter assay (MPRA) in a panel of patient-derived melanoma lines (MM lines), we set to identify and decipher melanoma enhancers by first focusing on regions with state specific H3K27 acetylation close to differentially expressed genes. A more in-depth evaluation of those regions was then pursued by investigating the activity of ATAC-seq peaks found therein along with a full tiling of the acetylated regions with 190 bp sequences. Activity was observed in more than 60% of the selected regions and we were able to precisely locate the active regions within ATAC-seq peaks. Comparison of sequence content with activity, using the deep learning model DeepMEL2, revealed that AP-1 alone is responsible for the MES enhancer activity, while SOX and MITF both influence MEL enhancer activity with SOX being required to achieve high levels of activity. Overall, our MPRA assays shed light on the relationship between long and short sequences in terms of their sequence content, enhancer activity, and specificity as reporters across melanoma cell states.
Mutated in Colorectal Cancer (MCC) is a centrosomal protein that relocalizes to the ncMTOC during intestinal cell differentiation
Authors: Tomaz Lucian B. , Liu Bernard A. , Ong Sheena L. M. , Tan Ee Kim , Meroshini M. , Tolwinski Nicholas S. , Williams Christopher S. , Gingras Anne-Claude , Leushacke Marc , Dunn N. Ray
Published: July 2021

Mutated in Colorectal Cancer (MCC) encodes a coiled-coil protein implicated, as its name suggests, in the pathogenesis of hereditary human colon cancer. To date, however, the contributions of MCC to intestinal homeostasis remain unclear. Here, we examine the subcellular localization of MCC, both at the mRNA and protein levels, in the adult intestinal epithelium. Our findings reveal that Mcc transcripts are restricted to proliferating crypt cells, including Lgr5+ stem cells, and that Mcc protein is distinctly associated with the centrosome in these cells. Upon intestinal cellular differentiation, Mcc is redeployed to the non-centrosomal microtubule organizing center (ncMTOC) at the apical domain of villus cells. Using intestinal organoids, we show that the shuttling of the Mcc protein depends on phosphorylation by Casein Kinases 1δ/ε, which are critical modulators of WNT signaling. Together, our findings support a putative role for MCC in establishing and maintaining the cellular architecture of the intestinal epithelium as a component of both the centrosome and ncMTOC.
Complete Mitochondrial and Plastid DNA Sequences of the Freshwater Green Microalga Medakamo hakoo
Authors: Takusagawa Mari , Kato Shoichi , Matsunaga Sachihiro , Maruyama Shinichiro , Tsujimoto-Inui Yayoi , Nozaki Hisayoshi , Yagisawa Fumi , Ohnuma Mio , Kuroiwa Haruko , Kuroiwa Tsuneyoshi , Misumi Osami
Published: July 2021

Here we report the complete organellar genome sequences of Medakamo hakoo, a green alga identified in freshwater in Japan. It has 90.8-kb plastid and 36.5-kb mitochondrial genomes containing 80 and 33 putative protein coding genes, respectively, representing the smallest organellar genome among currently known core Trebouxiophyceae.
m6A is required for resolving progenitor identity during planarian stem cell differentiation
Authors: Dagan Yael , Yesharim Yarden , Bonneau Ashley R. , Schwartz Schraga , Reddien Peter W. , Wurtzel Omri
Published: July 2021

Regeneration requires accurate production of missing cell lineages. Cell production is driven by changes to gene expression, which is shaped by multiple layers of regulation. Here, we find that the ubiquitous mRNA base-modification, m6A, is required for proper cell fate choice and cellular maturation in planarian stem cells (neoblasts). We mapped m6A-enriched regions in 7,600 planarian genes, and found that perturbation of the m6A pathway resulted in progressive deterioration of tissues and death. Using single cell RNA sequencing of >20,000 cells following perturbation of the pathway, we discovered that m6A negatively regulates transcription of histone variants, and that inhibition of the pathway resulted in accumulation of undifferentiated cells throughout the animal in an abnormal transcriptional state. Analysis of >1000 planarian gene expression datasets revealed that the inhibition of the chromatin modifying complex NuRD had almost indistinguishable consequences, unraveling an unappreciated link between m6A and chromatin modifications. Our findings reveal that m6A is critical for planarian stem cell homeostasis and gene regulation in regeneration.
Barcode Fusion Genetics-Protein-fragment Complementation Assay (BFG-PCA): tools and resources that expand the potential for binary protein interaction discovery
Authors: Evans-Yamamoto Daniel , Rouleau François D. , Nanda Piyush , Makanae Koji , Liu Yin , Després Philippe C. , Matsuo Hitoshi , Seki Motoaki , Dube Alexandre K. , Ascencio Diana , Yachie Nozomu , Landry Christian R.
Published: July 2021

Barcode fusion genetics (BFG) utilizes deep sequencing to improve the throughput of protein-protein interaction (PPI) screening in pools. BFG has been implemented in Yeast two-hybrid (Y2H) screens (BFG-Y2H). While Y2H requires test protein pairs to localize in the nucleus for reporter reconstruction, Dihydrofolate Reductase Protein-Fragment Complementation Assay (DHFR-PCA) allows proteins to localize in broader subcellular contexts and proves to be largely orthogonal to Y2H. Here, we implemented BFG to DHFR-PCA (BFG-PCA). This plasmid-based system can leverage ORF collections across model organisms to perform comparative analysis, unlike the original DHFR-PCA that requires yeast genomic integration. The scalability and quality of BFG-PCA were demonstrated by screening human and yeast interactions for >11,000 protein pairs. BFG-PCA showed high-sensitivity and high-specificity for capturing known interactions for both species. BFG-Y2H and BFG-PCA capture distinct sets of PPIs, which can partially be explained based on the domain orientation of the reporter tags. BFG-PCA is a high-throughput protein interaction technology to interrogate binary PPIs that exploits clone collections from any species of interest, expanding the scope of PPI assays.
Tannins and gut health in broilers: Effects of a blend of chestnut and quebracho tannins on gut health and performance of broiler chickens
Authors: Redondo Enzo A. , Redondo Leandro M. , Bruzzone Octavio A. , Diaz-Carrasco Juan M. , Cabral Claudio , Garces Victorino , Liñeiro Maximo , Fernandez-Miyakawa Mariano E.
Published: July 2021

Consumer demands and increased regulations on the use of antimicrobials in farm animals accentuated the need to develop strategies to replace antimicrobial growth promoters (AGPs) in food-producing animals. The present study evaluates the productive and gut health outcomes during the implementation of AGPs free programs based on the inclusion of a tannin blend compared with AGPs based program under commercial conditions. In the first trial, 6 farms were randomly assigned to AGP or tannin-based programs. In a second trial, both programs were applied simultaneously in one farm and the results were studied over 1 year. Although productive results from both trials were similar among treatments, evaluations of gut health indicators show improvements in the tannins treated flocks. Frequency and severity of intestinal gross lesions were reduced in jejunum (42% vs 23%; p<0.05 – 1.37 vs. 0.73; p<0.01, respectively) and ileum (25% vs. 10%; p<0.0.5 – 1.05 vs. 0.58; p<0.01) in tannins treated birds. Results from 16S studies, show that cecal microbiota diversity was not differentially affected by AGPs or tannins, but changes in the relative abundance of certain taxa were described, including Lactobacillus and Bifidobacterium groups. Additional evaluations using an in vivo model for C. perfringens necrotic enteritis showed that tannins treated birds had reduced incidence of gross lesions in jejunum (43.75 vs. 74.19%; p<0.01) and ileum (18.75% vs. 45.16%; p<0.05) compared with control. These results suggest that AGPs can be replaced by tannins feed additives, and contribute in the implementation of antimicrobial-free programs in broilers without affecting health or performance.
Structural insights into tick-borne encephalitis virus neutralization and animal protection by a therapeutic antibody
Authors: Baykov Ivan K. , Chojnowski Grzegorz , Pachl Petr , Matveev Andrey L. , Moor Nina A. , Emelianova Lyudmila A. , Rezacova Pavlina M. , Lamzin Victor S. , Tikunova Nina V.
Published: July 2021

Tick-borne encephalitis virus (TBEV) causes about 5-6 thousand cases annually, while there is still no effective treatment for this virus. To fill this gap, a high-affinity chimeric anti-TBEV antibody ch14D5 has previously been constructed, and high protective activity in a murine TBEV model has been shown for this antibody. However, the mechanism of action of this antibody and the recognized epitope have not been known yet. In this study, it is shown by X-ray crystallography that this antibody recognizes a unique epitope on the lateral ridge of the D3 domain of glycoprotein E, which is readily accessible for binding. The orientation of this antibody relative to the virion surface makes bivalent binding possible, which facilitates the cross-linking of glycoprotein E molecules and thus blocking of surface rearrangements required for infection. Since the antibody tightly binds to this protein even at pH ∼ 5.0, it locks the virion in an acidic environment inside the late endosomes or phagosomes and, therefore, effectively blocks the fusion of the viral and endosomal/phagosomal membranes. We believe that this is why the ch14D5 antibody does not induce an antibody-dependent enhancement of infectionin vivo, which is critical in the development of antibody-based therapeutic agents. In addition, the structure of the antibody-glycoprotein E interface can be used for the rational design of this antibody for enhancing its properties.
Symmetry and simplicity spontaneously emerge from the algorithmic nature of evolution
Authors: Johnston Iain G , Dingle Kamaludin , Greenbury Sam F. , Camargo Chico Q. , Doye Jonathan P. K. , Ahnert Sebastian E. , Louis Ard A.
Published: July 2021

Engineers routinely design systems to be modular and symmetric in order to increase robustness to perturbations and to facilitate alterations at a later date. Biological structures also frequently exhibit modularity and symmetry, but the origin of such trends is much less well understood. It can be tempting to assume – by analogy to engineering design – that symmetry and modularity arise from natural selection. But evolution, unlike engineers, cannot plan ahead, and so these traits must also afford some immediate selective advantage which is hard to reconcile with the breadth of systems where symmetry is observed. Here we introduce an alternative non-adaptive hypothesis based on an algorithmic picture of evolution. It suggests that symmetric structures preferentially arise not just due to natural selection, but also because they require less specific information to encode, and are therefore much more likely to appear as phenotypic variation through random mutations. Arguments from algorithmic information theory can formalise this intuition, leading to the prediction that many genotype-phenotype maps are exponentially biased towards phenotypes with low descriptional complexity. A preference for symmetry is a special case of this bias towards compressible descriptions. We test these predictions with extensive biological data, showing that that protein complexes, RNA secondary structures, and a model gene-regulatory network all exhibit the expected exponential bias towards simpler (and more symmetric) phenotypes. Lower descriptional complexity also correlates with higher mutational robustness, which may aid the evolution of complex modular assemblies of multiple components.
Integrative analysis of the salt stress response in cyanobacteria
Authors: Klähn Stephan , Mikkat Stefan , Riediger Matthias , Georg Jens , Hess Wolfgang R. , Hagemann Martin
Published: July 2021

Microorganisms evolved specific acclimation strategies to thrive in environments of high or fluctuating salinities. Here, salt acclimation in the model cyanobacteriumSynechocystissp. PCC 6803 was analyzed by integrating transcriptomic, proteomic and metabolomic data. A dynamic reorganization of the transcriptome and proteome occurred during the first hours after salt shock, e.g. involving the upregulation of genes to activate compatible solute biochemistry balancing osmotic pressure. The massive accumulation of glucosylglycerol then had a measurable impact on the overall carbon and nitrogen metabolism. In addition, we observed the coordinated induction of putative regulatory RNAs and of several proteins known for their involvement in other stress responses. Overall, salt-induced changes in the proteome and transcriptome showed good correlations, especially among the stably up-regulated proteins and their transcripts. We define an extended salt stimulon comprising proteins directly or indirectly related to compatible solute metabolism, ion and water movements, and a distinct set of regulatory RNAs involved in post-transcriptional regulation. Our comprehensive data set provides the basis for engineering cyanobacterial salt tolerance and to further understand its regulation.
LrpCBA pilus proteins of gut-dwelling Ligilactobacillus ruminis: crystallization and X-ray diffraction analysis
Authors: Prajapati Amar , Palva Airi , von Ossowski Ingemar , Krishnan Vengadesan
Published: July 2021

Adhesion to host surfaces for bacterial survival and colonization involves a variety of molecular mechanisms. Ligilactobacillus ruminis, a strict anaerobe and gut autochthonous (indigenous) commensal, relies on sortase-dependent pili (LrpCBA) for adherence to the intestinal inner walls, thereby withstanding luminal content flow. Here, the LrpCBA pilus is a promiscuous binder to gut collagen, fibronectin and epithelial cells. Structurally, the LrpCBA pilus displays a representative hetero-oligomeric arrangement and consists of three types of pilin subunit, each with its own location and function, i.e. tip LrpC for adhesion, basal LrpB for anchoring and backbone LrpA for length. To provide further structural insights into the assembly, anchoring and functional mechanisms of sortase-dependent pili, each of the L. ruminis pilus proteins was produced recombinantly for crystallization and X-ray diffraction analysis. Crystals of LrpC, LrpB, LrpA and truncated LrpA generated by limited proteolysis were obtained and diffracted to resolutions of 3.0, 1.5, 2.2 and 1.4 Å, respectively. Anomalous data were also collected from crystals of selenomethionine-substituted LrpC and an iodide derivative of truncated LrpA. Successful strategies for protein production, crystallization and derivatization are reported.
Supply chain resilience in the face of uncertainty: how horizontal and vertical collaboration can help?
Authors: Lotfi Maryam , Larmour Abby
Published: July 2021

Purpose

The COVID-19 outbreak highlights that many supply chains are exposed to unforeseen disruptions, that risks are unavoidable, and that the international nature of supply chains can seriously disrupt normal operations. Therefore, the need for Supply Chain Resilience (SCRES) is more imperative than ever. Furthermore, collaboration in supply chains may have benefitted the response to the COVID-19 outbreak. The aim of this research is to gain a deeper understanding of how collaboration with both types of horizontal and vertical collaboration in the supply chain affects its resilience.

Design/methodology/approach

A thematic analysis of the literature is used to investigate the concepts of both vertical and horizontal collaboration and supply chain resilience separately, then integrating identified themes to understand the relationship between them through a thematic map.

Findings

The thematic analysis indicates that the more firms collaborate in the supply chain, the more resilient they will be. Furthermore, both horizontal and vertical collaboration between supply chain partners will enhance resilience. This relationship is positively moderated by governance in the partnership and negatively moderated by competition in the partnership.

Originality/value

This is one of the first papers to provide in-depth insights into how collaboration, with both types of horizontal and vertical collaboration, affects supply chain resilience. Neither of previous articles provide an understanding of how both types of collaboration enables supply chain resilience.