bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Attitudes Regarding Health Care Clinician Communication in Adolescents With Cystic Fibrosis
Authors: Woolley Joseph C. , Edmondson Shelby N. , Sathe Meghana N. , Rodriguez Francis Jenny K.
Published: May 2023

Background:

The quality of health care clinician (HCC) communication varies, yet few studies evaluate ways to improve communication among adolescents with cystic fibrosis (CF). We sought to characterize the attitudes of adolescents and young adults (AYA) with CF about HCC communication and describe the components important for high-quality communication.

Methods:

AYA with CF aged 12–20 years from a single large pediatric CF care center participated in a brief survey and semi-structured individual and group virtual interviews that were recorded, transcribed, coded, and analyzed with a combined deductive and inductive approach. Discrepancies were resolved by consensus.

Results:

Among the 39 survey respondents, most were White (77%), male (51%), and averaged 15.51 years (range 12–20 years). Many (40%) perceived their health status as “neutral” and over half (61%) were “very satisfied” with HCC communication. Overall, among the 17 interviews (averaged 53.6 min, range 31.5–74 min), participants reported a desire to be actively engaged in discussions about their health and included in the decision-making process with HCC to support adolescent autonomy and cultivate trust. Some factors detract (loss of control and fear of diagnosis), and others strengthen (transition to adult care and external motivators) adolescent autonomy. Some factors detract (perceived lack of interdisciplinary communication, statements of noncompliance, and being compared to others) and others strengthen (inherent trust and familiarity over time) the cultivation of trust.

Conclusions:

The development of adolescent autonomy and the cultivation and maintenance of trust between the patient and HCC are 2 essential components of quality communication that should inform future communication-focused interventions.
Improving Bowel Management in Children With Spina Bifida
Authors: Cohen Mitchell B. , Hopson Betsy , Swanson-Kimani Erin , Davis Drew , Rocque Brandon G.
Published: May 2023

Objectives:

In individuals with spina bifida (SB), bowel incontinence is associated with lower quality of life and lower likelihood of employment. In an effort to maximize bowel continence in children and adolescents, we created a bowel management assessment and follow-up protocol in a multidisciplinary clinic. Here we report the results of this protocol using quality-improvement methodology.

Methods:

Continence was defined as no unplanned bowel movements. Our protocol involved: (1) a standardized 4-item questionnaire about bowel continence and consistency; (2) if the patient was not achieving continence, an intervention starting with oral medication (stimulant and/or osmotic laxatives), and/or suppositories (glycerin or bisacodyl) followed by an escalation to trans-anal irrigation, or continence surgery; and (3) follow-up phone calls at regular intervals to monitor progress and make changes as needed. Results are summarized with descriptive statistics.

Results:

We screened 178 eligible patients in the SB clinic. Eighty-eight agreed to participate in the bowel management program. Of those who did not participate, the majority (68/90, 76%) were already achieving continence with their bowel regimen. Of children in the program, most (68/88, 77%) had a diagnosis of meningomyelocoele. At 1 year, the proportion of patients who were bowel accident free improved to 46% (vs 22% initially, P = 0.0007).

Conclusions:

A standardized bowel management protocol, primarily the use of suppositories and trans-anal irrigation to achieve social continence, as well as frequent telephone follow-up, can reduce bowel incontinence in children and adolescents with SB.
Comparing the effects of University of California Biomechanics Laboratory and custom-made semi-rigid insole on pedobarographic parameters in pediatric flexible flat foot
Authors: Suh Jee Hyun , Yoon Seo Yeon
Published: May 2023

Background:

Pediatric flexible flat foot (PFFF) is often associated with pain along the medial longitudinal arch and potential disability. There are several conservative treatment options for PFFF, ranging from intrinsic muscle exercises to orthosis, including University of California Biomechanics Laboratory (UCBL) and custom-made semi-rigid insoles.

Objective(s):

To investigate and compare the effect of UCBL and custom-made semi-rigid insoles on pedobarographic and radiologic parameters in PFFF.

Study Design:

This study prepared a retrospective chart review of 143 children diagnosed with PFFF between the age of 4 and 12 years.

Methods:

Data of twenty-seven children with PFFF who were prescribed foot orthoses between the age of 4 and 12 years were retrospectively reviewed. Medical charts were retrospectively reviewed, and pedobarographic and radiological parameters assessed before and 1 year after application of orthoses were reviewed.

Results:

The difference in the calcaneal pitch angle and the center of pressure excursion index (CPEI) were significantly improved in the custom-made semi-rigid insole group compared to that in the UCBL group. The contact area ratio of the midfoot and toe and CPEI at 1 year after wearing the insole was significantly improved in the custom-made semi-rigid insole group compared to that in the UCBL group. Moreover, the calcaneal pitch angle and CPEI were significantly improved 1 year after application of the insole in the custom-made semi-rigid insole group.

Conclusions:

This result showed that the custom-made semi-rigid insole is more effective in improving the deviation of the center pressure curve and calcaneal pitch angle than the UCBL. The custom-made semi-rigid insole may help relieve foot instability during gait and improve the medial longitudinal arch in children with PFFF.
Panoramic Magnetic Resonance Imaging of the Breast With a Wearable Coil Vest
Authors: Obermann Michael , Nohava Lena , Frass-Kriegl Roberta , Soanca Onisim , Ginefri Jean-Christophe , Felblinger Jacques , Clauser Paola , Baltzer Pascal A.T. , Laistler Elmar
Published: May 2023

Background

Breast cancer, the most common malignant cancer in women worldwide, is typically diagnosed by x-ray mammography, which is an unpleasant procedure, has low sensitivity in women with dense breasts, and involves ionizing radiation. Breast magnetic resonance imaging (MRI) is the most sensitive imaging modality and works without ionizing radiation, but is currently constrained to the prone imaging position due to suboptimal hardware, therefore hampering the clinical workflow.

Objectives

The aim of this work is to improve image quality in breast MRI, to simplify the clinical workflow, shorten measurement time, and achieve consistency in breast shape with other procedures such as ultrasound, surgery, and radiation therapy.

Materials and Methods

To this end, we propose “panoramic breast MRI”—an approach combining a wearable radiofrequency coil for 3 T breast MRI (the “BraCoil”), acquisition in the supine position, and a panoramic visualization of the images. We demonstrate the potential of panoramic breast MRI in a pilot study on 12 healthy volunteers and 1 patient, and compare it to the state of the art.

Results

With the BraCoil, we demonstrate up to 3-fold signal-to-noise ratio compared with clinical standard coils and acceleration factors up to 6 × 4. Panoramic visualization of supine breast images reduces the number of slices to be viewed by a factor of 2–4.

Conclusions

Panoramic breast MRI allows for high-quality diagnostic imaging and facilitated correlation to other diagnostic and interventional procedures. The developed wearable radiofrequency coil in combination with dedicated image processing has the potential to improve patient comfort while enabling more time-efficient breast MRI compared with clinical coils.
Robotic Versus Conventional or Endoscopic Assisted Nipple Sparing Mastectomy and Immediate Prothesis Breast Reconstruction in the Management of Breast Cancer- A Prospectively Designed Multicenter Trial Comparing Clinical Outcomes, Medical Cost, and Patient-reported-outcomes (RCENSM-P)
Authors: Lai Hung-Wen , Chen Dar-Ren , Liu Liang-Chih , Chen Shou-Tung , Kuo Yao-Lung , Lin Shih-Lung , Wu Yao-Chung , Huang Tsung-Chun , Hung Chin-Sheng , Lin Ying-Jen , Tseng Hsin-Shun , Mok Chi Wei , Cheng Fiona Tsui-Fen
Published: May 2023

Objective:

To compare the clinical and patient-reported outcomes of minimal access and conventional nipple-sparing mastectomy (NSM). The secondary outcomes investigated included medical costs and oncological safety.

Summary Background Data:

Minimal-access NSM has been increasingly applied in the treatment of patients with breast cancer. However, prospective multi-center trials comparing Robotic-NSM(R-NSM) versus conventional-NSM(C-NSM) or endoscopic-NSM(E-NSM) are lacking.

Methods:

A prospectively designed three-arm multi-center, non-randomized trial(NCT04037852) was conducted from 1 October, 2019, to 31 Dec 2021, to compare R-NSM with C-NSM or E-NSM.

Results:

A total of 73 R-NSM, 74 C-NSM, and 84 E-NSM procedures were enrolled. The median wound length and operation time of C-NSM was (9 cm, 175 min), (4 cm, and 195 min) in R-NSM, and (4 cm and 222 min) in E-NSM. Complications were comparable between the groups. Better wound healing was observed in the minimal-access NSM group. The R-NSM procedure was 4000 and 2600 USD more expensive than C-NSM and E-NSM, respectively. Wound/scar and post-operative acute pain evaluation favored the use of minimal access NSM over C-NSM. Quality of life in terms of chronic breast/chest pain, mobility, and range of motion of the upper extremity showed no significant differences. The preliminary oncologic results showed no differences between the three groups.

Conclusion:

R-NSM or E-NSM is a safe alternative if compared with C-NSM in terms of peri-operative morbidities, especially with better wound healing. The advantage of minimal access groups was higher wound-related satisfaction. Higher costs remain one of the major limiting factors in the widespread adoption of R-NSM.
Challenges in prokaryote pangenomics
Authors: Tonkin-Hill Gerry , Corander Jukka , Parkhill Julian
Published: May 2023

Horizontal gene transfer (HGT) and the resulting patterns of gene gain and loss are a fundamental part of bacterial evolution. Investigating these patterns can help us to understand the role of selection in the evolution of bacterial pangenomes and how bacteria adapt to a new niche. Predicting the presence or absence of genes can be a highly error-prone process that can confound efforts to understand the dynamics of horizontal gene transfer. This review discusses both the challenges in accurately constructing a pangenome and the potential consequences errors can have on downstream analyses. We hope that by summarizing these issues researchers will be able to avoid potential pitfalls, leading to improved bacterial pangenome analyses.
xRead: a coverage-guided approach for scalable construction of read overlapping graph
Authors: Kong Tangchao , Liu Bo , Wang Yadong
Published: May 2023

The development of long-read sequencing is promising to high-quality and comprehensive de novo assembly for various species around the world. However, it is still challenging for genome assemblers to well-handle thousands of genomes, tens of gigabase level genome sizes and terabase level datasets simultaneously and efficiently, which is a bottleneck to large de novo sequencing studies. A major cause is the read overlapping graph construction that state-of-the-art tools usually have to cost terabyte-level RAM space and tens of days for that of large genomes. Such lower performance and scalability are not suited to handle the numerous samples to be sequenced. Herein, we propose xRead, an iterative overlapping graph approach that achieves high performance, scalability and yield simultaneously. Under the guidance of its novel read coverage-based model, xRead uses heuristic alignment skeleton approach to implement incremental graph construction with highly controllable RAM space and faster speed. For example, it enables to process the 1.28 TbA. mexicanumdataset with less than 64GB RAM and obviously lower time-cost. Moreover, the benchmarks on the datasets from various-sized genomes suggest that it achieves higher accuracy in overlap detection without loss of sensitivity which also guarantees the quality of the produced graphs. Overall, xRead is suited to handle numbers of datasets from large genomes, especially with limited computational resources, which may play important roles in many de novo sequencing studies.
Heterospecific physical interference modulates the reproductive attributes of a ladybird beetle
Authors: Sariq Mohd , Omkar  , Mishra Geetanjali
Published: May 2023

Propylea dissectaandCheilomenes sexmaculata(Coleoptera: Coccinellidae), are similar sized, co-ocurring aphidophagous insects that share common resources. We conducted the current study to observe the phenomenon of reproductive interference and effect of presence of heterospecific adults (C. sexmaculata) on the reproductive output ofP. dissecta. For this, we used two reciprocal mating combinations of heterospecifics. The first heterospecific combination usedP. dissectamales withC. sexmaculatafemales and the second heterospecific mating combination usedP. dissectafemales withC. sexmaculatamales. To further examine the effect ofC. sexmaculatamale onP. dissectafemale, we used mixed mating treatments (C. sexmaculatamale with conspecific pair ofP. dissecta). Our results suggested that (1) in the first heterospecific mating combination, mating did not commence betweenP. dissectamaleC. sexmaculatafemale, while in the second heterospecific mating combination, mating was recorded betweenP. dissectafemale andC. sexmaculatamale, (2)C. sexmaculatamale interferes the conspecific mating inP. dissectathrough multiple mating attempts which resulted in reduced fitness and reproductive success ofP. dissecta. Overall, we illustrated the negative effects of reproductive interference caused byC. sexmaculataon the reproductive output (fecundity and egg viability) ofP. dissecta.
THE POSSIBILITY OF AN EXTENSION OF CATARACT TREATMENT BEYOND EYE SURGERY: A NOVEL NON-INVASIVE PHOTOBLEACHING OF THE HUMAN LENS BY LED
Authors: Smith S Desmond , Dhillon Bal
Published: May 2023

As discussed below cataract is the world-leading cause of blindness and impaired vision with only eye surgery as a treatment. There is major requirement for an alternative which this research has provided via Genetically Modified pigs with natural cataract making live animal experiments of LED photobleaching successful monitored by fluorescence spectra. The latter were shown by EBS as spectrally identical in pigs and humans. EBS developed a miniature fluorescence spectrometer via tunable interference filters with fluorescence excited by an LED. A second LED in the blue/violet region provided a 20mW treatment beam which was shown to reverse the fluorescence signal and dramatically improve the transmission of pigs’ eyes. These results led to permission for early Human Trials. The results were judged by independent optometrists by LOCS and fluorescence in pigs and in Human Trials by LOCS and Visual Acuity. Adequate positive results have led to full length Human Trials being conducted in four European countries. Prospects of worldwide application have been therefore indicated.
Improving few-shot learning-based protein engineering with evolutionary sampling
Authors: Jawaid M. Zaki , Yeo Robin W. , Gautam Aayushma , Gainous T. Blair , Hart Daniel O. , Daley Timothy P.
Published: May 2023

Designing novel functional proteins remains a slow and expensive process due to a variety of protein engineering challenges; in particular, the number of protein variants that can be experimentally tested in a given assay pales in comparison to the vastness of the overall sequence space, resulting in low hit rates and expensive wet lab testing cycles. In this paper, we propose a few-shot learning approach to novel protein design that aims to accelerate the expensive wet lab testing cycle and is capable of leveraging a training dataset that is both small and skewed (≈ 105datapoints, < 1% positive hits). Our approach is composed of two parts: a semi-supervised transfer learning approach to generate a discrete fitness landscape for a desired protein function and a novel evolutionary Monte Carlo Markov Chain sampling algorithm to more efficiently explore the fitness landscape. We demonstrate the performance of our approach by experimentally screening predicted high fitness gene activators, resulting in a dramatically improved hit rate compared to existing methods. Our method can be easily adapted to other protein engineering and design problems, particularly where the cost associated with obtaining labeled data is significantly high. We have provided open source code for our method athttps://github.com/SuperSecretBioTech/evolutionary_monte_carlo_search.
High Frequencies of Antiviral Effector Memory TEMCells and Memory B Cells Mobilized into Herpes Infected Vaginal Mucosa Associated With Protection Against Genital Herpes
Authors: Dhanushkodi Nisha Rajeswari , Prakash Swayam , Quadiri Afshana , Zayou Latifa , Singer Mahmoud , Takashi Nakayama , Vahed Hawa , BenMohamed Lbachir
Published: May 2023

Vaginal mucosa-resident anti-viral effector memory B- and T cells appeared to play a crucial role in protection against genital herpes. However, how to mobilize such protective immune cells into the vaginal tissue close to infected epithelial cells remains to be determined. In the present study, we investigate whether and how, CCL28, a major mucosal-associated chemokine, mobilizes effector memory B- and T cells in leading to protecting mucosal surfaces from herpes infection and disease. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). We found the presence of significant frequencies of HSV-specific memory CCR10+CD44+CD8+T cells, expressing high levels of CCR10 receptor, in herpes-infected asymptomatic (ASYMP) women compared to symptomatic (SYMP) women. A significant amount of the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP B6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+TEMcells and memory CCR10+B220+CD27+B cells in the VM of HSV-infected asymptomatic mice. In contrast, compared to wild-type (WT) B6 mice, the CCL28 knockout (CCL28(-/-)) mice: (i) Appeared more susceptible to intravaginal infection and re-infection with HSV-2; (ii) Exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+TEMcells and of memory CD27+B220+B cells in the infected VM. The results imply a critical role of the CCL28/CCR10 chemokine axis in the mobilization of anti-viral memory B and T cells within the VM to protect against genital herpes infection and disease.
Interleukin-16/STAT6 recruits CBP/p300 to upregulate TIMP-3 and promote atherosclerotic plaque stability
Authors: He Hui , Ding Meng , Zhu Yuan , Jiang Tianyu , Dong Doudou , Xu Xiaoting , Ou Hailong
Published: May 2023

Background

Atherosclerotic plaque rupture increases the risk of ischemic heart disease and stroke and commonly causes sudden death. High levels of circulating or intraplaque interleukin 16 (IL-16) are clinically associated with a reduced incidence of cardiovascular events. Here, we investigated the effects of IL-16 on plaque phenotypic modification and identified the molecules involved in smooth muscle cells (SMCs).

Methods

We deleted IL-16 in ApoE-/- mice to generate IL16-/-ApoE-/- mice, and the double mutant was used for plaque phenotype analysis after a 24-week high-fat diet. RNA sequencing was performed to identify the changes in cellular processes and molecule expression in response to IL-16 defects. Affinity purification-mass spectrometry was used to identify the STAT6 binding protein. Bone marrow transplantation was used to investigate the effects of hematopoietic IL-16 deficiency or reconstitution on plaque stability.

Results

IL-16 deficiency reduced collagen deposition and increased the necrotic core area in the plaques of the brachiocephalic artery and aortic root lesions. Intraplaque TIMP-3 levels were found to be decreased in association with an increase in the proteolytic activity of MMPsinIL16-/-ApoE-/- mice. Next, we demonstrated that IL-16 activates the CD4/JAK2/STAT6 pathway and that STAT6 directly binds the TIMP-3 promoter in SMCs. Furthermore, IL-16 treatment increased the interaction of cAMP-response element binding protein (CBP)/p300 with STAT6, which promoted STAT6 acetylation and increased histone H3 acetylation in the TIMP-3 promoter. Inhibition of CBP/p300 resulted in decreased acetylation of STAT6 and TIMP-3 promoter histone H3 and TIMP-3 expression, suggesting a requirement for CBP/p300 as a coactivator. Finally, we found that hematopoietic-derived IL-16 from ApoE-/- mice or overexpression of TIMP-3 successfully attenuated plaque instability in IL16-/-ApoE-/- mice.

Conclusions

IL-6 upregulates TIMP-3 expression and remodels the intraplaque extracellular matrix toward a stable phenotype, suggesting IL-16 as a potential target for intervening in atherosclerosis at later stages.
Genome-wide association study of REM sleep behavior disorder in Parkinson’s disease
Authors: Sosero Yuri L. , Heilbron Karl , Fontanillas Pierre , Norcliffe-Kaufmann Lucy , Yu Eric , Rudakou Uladzislau , Ruskey Jennifer A. , Freeman Kathryn , Asayesh Farnaz , Brolin Kajsa , Swanberg Maria , Morris Huw R , Wu Lesley , Real Raquel , Pihlstrøm Lasse , Tan Manuela , Gasser Thomas , Brockmann Kathrin , Liu Hui , Hu Michele T.M. , Grosset Donald G. , Lewis Simon J.G. , Kwok John B. , Pastor Pau , Alvarez Ignacio , Skorvanek Matej , Lackova Alexandra , Ostrozovicova Miriam , Rizig Mie ,   23andMe Research Team,   The International Parkinson’s Disease Genomics Consortium, Krohn Lynne , Gan-Or Ziv
Published: May 2023

Objective

REM sleep behavior disorder (RBD) is a prodromal synucleinopathy, reported in a subset of Parkinson’s disease (PD) patients, and associated with neuropsychiatric symptoms in PD. We aimed to compare the genetic background of PD patients with probable RBD (PD+RBD) and PD patients without probable RBD (PD-RBD). Furthermore, we examined genetic correlations and potential causal associations between multiple neuropsychiatric traits and PD+RBD.

Methods

We performed a genome-wide association study (GWAS) including 5,403 PD+RBD and 13,020 PD-RBD. To test for genetic correlations and potential causal associations between neuropsychiatric traits and PD+RBD, we used linkage disequilibrium score regression and Mendelian randomization.

Results

TheSNCAlocus was associated with PD+RBD compared to PD-RBD (rs10005233, OR=1.21, 95% CI=1.16-1.27,p=1.81e-15). Further examination of known genetic loci associated with PD from the most recent PD GWAS in Europeans and Asians identified additional variants associated with reduced risk for PD+RBD: two in theSNCAlocus (rs5019538-G, OR=0.85, 95% CI=0.81-0.89,p=2.46E-10; rs356182-G, OR=0.89, 95% CI=0.84-0.95,p=0.0001), and one in theLRRK2locus (rs34637584, p.G2019S, OR=0.41, 95% CI=0.28-0.61,p=1.04E-5). We found a potential genetic correlation between attention deficit hyperactivity disorder (ADHD) and PD+RBD, which was not statistically significant after correction for multiple comparisons. No causative association emerged between PD and neuropsychiatric traits.

Interpretation

Genetic variants contribute to the occurrence of RBD in PD, further distinguishing between the PD+RBD and PD-RBD subtypes. Understanding the mechanisms underlying these genetic associations could contribute to the development of subtype-specific treatments.
The Notch-Pdgfrβ axis suppresses brown adipocyte progenitor differentiation in early postnatal mice
Authors: Shi Zuoxiao , Xiong Shaolei , Hu Ruoci , Wang Zilai , Park Jooman , Qian Yanyu , Wang Jaden , Bhalla Pratibha , Velupally Nipun , Song Qing , Song Zhenyuan , Layden Brian T. , Jiang Yuwei
Published: May 2023

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here throughin vivolineage tracing, we observed that PDGFRβ+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRβ+ pericytes promotes brown adipogenesis through the downregulation of PDGFRβ. Furthermore, inhibition of Notch signaling in PDGFRβ+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFRβ axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.

Highlights

PDGFRβ+ pericytes act as an essential developmental brown APC.

TBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner.

Inhibiting Notch-Pdgfrβ axis promotes brown APC adipogenesis.

Enhanced postnatal brown adipogenesis improves metabolic health in adult stage.
Cross-Protection Induced by Highly Conserved Human B, CD4+,and CD8+T Cell Epitopes-Based Coronavirus Vaccine Against Severe Infection, Disease, and Death Caused by Multiple SARS-CoV-2 Variants of Concern
Authors: Prakash Swayam , Dhanushkodi Nisha R. , Zayou Latifa , Ibraim Izabela Coimbra , Quadiri Afshana , Coulon Pierre Gregoire , Tifrea Delia F , Suzler Berfin , Amin Mohamed , Chilukuri Amruth , Edwards Robert A , Vahed Hawa , Nesburn Anthony B , Kuppermann Baruch D , Ulmer Jeffrey B. , Gil Daniel , Jones Trevor M. , BenMohamed Lbachir
Published: May 2023

Background

The Coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of SARS-CoV-2 infections has decreased significantly; the long-term outlook of COVID-19 remains a serious cause of high death worldwide; with the mortality rate still surpassing even the worst mortality rates recorded for the influenza viruses. The continuous emergence of SARS-CoV-2 variants of concern (VOCs), including multiple heavily mutated Omicron sub-variants, have prolonged the COVID-19 pandemic and outlines the urgent need for a next-generation vaccine that will protect from multiple SARS-CoV-2 VOCs.

Methods

In the present study, we designed a multi-epitope-based Coronavirus vaccine that incorporated B, CD4+, and CD8+T cell epitopes conserved among all known SARS-CoV-2 VOCs and selectively recognized by CD8+and CD4+T-cells from asymptomatic COVID-19 patients irrespective of VOC infection. The safety, immunogenicity, and cross-protective immunity of this pan-Coronavirus vaccine were studied against six VOCs using an innovative triple transgenic h-ACE-2-HLA-A2/DR mouse model.

Results

The Pan-Coronavirus vaccine: (i) is safe; (ii) induces high frequencies of lung-resident functional CD8+and CD4+TEMand TRMcells; and (iii) provides robust protection against virus replication and COVID-19-related lung pathology and death caused by six SARS-CoV-2 VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma or P1 (B.1.1.28.1), Delta (lineage B.1.617.2) and Omicron (B.1.1.529).Conclusions: A multi-epitope pan-Coronavirus vaccine bearing conserved human B and T cell epitopes from structural and non-structural SARS-CoV-2 antigens induced cross-protective immunity that cleared the virus, and reduced COVID-19-related lung pathology and death caused by multiple SARS-CoV-2 VOCs.
Growth factor-free, peptide-functionalized gelatin hydrogel promotes arteriogenesis and attenuates tissue damage in a murine model of critical limb ischemia
Authors: Curry Corinne W. , Sturgeon Sarah M. , O’Grady Brian J. , Yates Alexis K. , Kjar Andrew , Paige Hayden A. , Mowery Lucas S. , Katdare Ketaki A. , Patel Riya V. , Mlouk Kate , Stiefbold Madison R. , Vafaie-Partin Sidney , Kawabata Atsuyuki , McKee Rachel M. , Lotridge Stephanie Moore- , Hawkes Adrienne , Kusunose Jiro , Gibson-Corley Katherine N. , Schmeckpeper Jeffrey , Schoenecker Jonathan G. , Caskey Charles F. , Lippmann Ethan S.
Published: May 2023

Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks orde novogrowth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these “GelCad” hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in bothex vivoandin vivoassays. In a murine femoral artery ligation model of CLI, delivery ofin situcrosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development.
POMBOX: a fission yeast toolkit for molecular and synthetic biology
Authors: Hebra Téo , Smrčková Helena , Elkatmis Büsra , Převorovský Martin , Pluskal Tomáš
Published: May 2023

Schizosaccharomyces pombeis a popular model organism in molecular biology and cell physiology. With its ease of genetic manipulation and growth, supported by in-depth functional annotation in the PomBase database and genome-wide metabolic models,S. pombeis an attractive option for synthetic biology applications. However,S. pombecurrently lacks modular tools for generating genetic circuits with more than one transcriptional unit. We have developed a toolkit to address this issue. Adapted from the MoClo- YTK plasmid kit forSaccharomyces cerevisiaeand using the same Golden Gate grammar, our POMBOX toolkit is designed to facilitate the fast, efficient and modular construction of genetic circuits inS. pombe. It allows for interoperability when working with DNA sequences that are functional in bothS. cerevisiaeandS. pombe(e.g. protein tag, antibiotic resistance cassette, coding sequences). Moreover, POMBOX enables the modular assembly of multi-gene pathways and increases possible pathway length from 6 to 12 transcriptional units. We also adapted the stable integration vector homology arms to Golden Gate assembly and tested the genomic integration success rate depending on different sequence sizes, from four to twenty-four kilobases. We included fourteenS. pombepromoters that we characterized for two fluorescent proteins, in both minimal defined media (EMM2) and complex media (YES). Then we tested sixS. cerevisiaeand six synthetic terminators inS. pombe. Finally, we used the POMBOX kit for a synthetic biology application in metabolic engineering and expressed plant enzymes inS. pombeto produce specialized metabolite precursors, namely methylxanthine, amorpha-4,11-diene and cinnamic acid from the purine, mevalonate and amino acid pathways.
Experimental evolution of hybrid populations to identify Dobzhansky-Muller incompatibility loci
Authors: Szabo Nicole , Cutter Asher D.
Published: May 2023

Epistatic interactions between loci that reduce fitness in inter-species hybrids, Dobzhansky-Muller incompatibilities (DMIs), contribute genetically to the inviability and infertility within hybrid populations. It remains a challenge, however, to identify the loci that contribute to DMIs as causes of reproductive isolation between species. Here, we assess through forward simulation the power of evolve and resequence experimental evolution of hybrid populations to map DMI loci. We document conditions under which such a mapping strategy may be most feasible and demonstrate how mapping power is sensitive to biologically relevant parameters such as one-way versus two-way incompatibility type, selection strength, recombination rate, and dominance interactions. We also assess the influence of parameters under direct control of an experimenter, including duration of experimental evolution and number of replicate populations. We conclude that an evolve and re-sequence strategy for mapping DMI loci, and other cases of epistasis, can be a viable option under some circumstances for study systems with short generation times likeCaenorhabditisnematodes.
CA3 circuit model compressing sequential information in theta oscillation and replay
Authors: Kuroki Satoshi , Mizuseki Kenji
Published: May 2023

The hippocampus compresses the sequential information in a theta oscillation cycle and short-term sequential activities during sharp-wave ripple while sleeping or resting; these processes are known as theta sequence and replay, respectively. The theta sequence is based on theta phase precession patterns of individual neurons. However, how these sequential neuronal activities are generated and how they store information about the outside environment remains unknown. We developed a hippocampal cornu ammonis (CA)3 computational model based on the biological CA3 circuit’s anatomical and electrophysiological evidence to address these. The model comprises theta rhythm inhibition, place input, and CA3-CA3 plastic recurrent connection. The model could compress the sequence of the external inputs and reproduce theta phase precession and replay, learn additional sequences, and reorganize previously learned sequences. A gradual increase in synaptic inputs, controlled by interactions between theta-paced inhibition and place inputs, explained the mechanism for sequence acquisition. This model highlights the crucial role of plasticity in the CA3 recurrent connection and theta oscillational dynamics, and hypothesizes how the CA3 circuit acquires, compresses, and replays sequential information.
Tempered IL-2 Signals Program PD-1 Checkpoint Blockade-Responsive Stem-like Exhausted T Cells During Priming
Authors: Kalia Vandana , Reed Jim , Khanna Asheema , Toumi Ryma , Xiao Hanxi , Pulliam Thomas , Deo Rucha , Nghiem Paul , Sarkar Surojit
Published: May 2023

Stem-like progenitor exhausted CD8 T cells are critical for maintaining long-term resistance during chronic infections and cancer, and represent an important checkpoint blockade immunotherapy target for functional reinvigoration and disease control. Hence, there is vigorous interest in understanding the ontogenesis of TCF-1Histem-like exhausted CD8 T cells, and in defining the signals that promote their development. Here, we show that virus-specific TCF1HiGzmBLoCD8 T cells develop during early stages of chronic viral infection, and are progressively deprogrammed from the stem-like lineage towards terminal differentiation by strong IL-2 signals. In vivo fate-tracking studies show that strong T cell-intrinsic IL-2 signals through the high affinity heterotrimeric IL-2Rα/β/γ receptor drive skewed development of terminally differentiated TCF-1LoGzmBHicells, which largely die in chronic antigenic environment. In contrast, tempered IL-2 signals through the intermediate affinity IL-2Rβ/γ heterodimer, or delayed priming in diminished IL-2 milieu support preferential development of TCF-1Histem-like exhausted CD8 T cells, capable of long-term persistence and potent responsiveness to PD-1 therapy in later stages of chronic viral infection. In human tumors as well, single cell RNA-seq analyses of tumor infiltrating lymphocytes from melanoma, human papillomavirus+ head and neck cancer and lung cancer patients revealed an inverse relationship between IL-2 signaling signature and T cell stemness. Moreover, melanoma patients with enriched IL-2 signaling signature showed poor responses to checkpoint blockade immunotherapy. Collectively, these findings bear relevance to clinical immunotherapies of chronic viral infections and cancers, and support exogenous IL-2 signal manipulation prior to therapy as a strategy for augmenting long-term clinical outcomes.

ONE SENTENCE SUMMARY

Programming of exhausted T cell fates by differential IL-2
Perinatal-lethal nonimmune fetal hydrops attributed toMECOM-associated bone marrow failure
Authors: Dash Camille A. , Madden Jill A. , Cummings Christy , Rose Melissa , Wilson Sheria D. , Mori Mari , Agrawal Pankaj B. , Chaudhari Bimal P. , Wojcik Monica H.
Published: May 2023

Pathogenic variants inMECOM, a gene critical to the self-renewal and proliferation of hematopoietic stem cells, are known to cause a rare bone marrow failure syndrome associated with amegakaryocytic thrombocytopenia and bilateral radioulnar synostosis known as RUSAT2. However, the spectrum of disease seen with causal variants inMECOMis broad, ranging from mildly affected adults to fetal loss. We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived. In both cases, genomic sequencing revealed de novo variants inMECOMconsidered to be responsible for their severe presentations. These cases add to the growing body of literature that describeMECOM-associated disease, particularlyMECOMas a cause of fetal hydrops due to bone marrow failure in utero. Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, asMECOMis absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation.
Crystal structures and kinetic studies of a laboratory evolved aldehyde reductase explain the dramatic shift of its new substrate specificity
Authors: Sridhar Shruthi , Zavarise Alberto , Kiema Tiila-Riikka , Dalwani Subhadra , Eriksson Tor , Hajee Yannick , Reddy Enugala Thilak , Wierenga Rik K. , Widersten Mikael
Published: May 2023

The Fe2+-dependent E. coli enzyme FucO catalyzes the reversible interconversion of short-chain (S)-lactaldehyde and (S)-1,2-propanediol, using NADH and NAD+ as cofactors, respectively. Laboratory-directed evolution experiments have been carried out previously using phenylacetaldehyde as the substrate for screening catalytic activity with bulky substrates, which are very poorly reduced by wild-type FucO. These experiments identified the N151G/L259V double mutant (dubbed DA1472) as the most active variant with this substrate via a two-step evolutionary pathway, in which each step consisted of one point mutation. Here the crystal structures of DA1472 and its parent D93 (L259V) are reported, showing that these amino acid substitutions provide more space in the active site, though they do not cause changes in the main-chain conformation. The catalytic activity of DA1472 with the physiological substrate (S)-lactaldehyde and a series of substituted phenylacetaldehyde derivatives were systematically quantified and compared with that of wild-type as well as with the corresponding point-mutation variants (N151G and L259V). There is a 9000-fold increase in activity, when expressed as k
cat/K
M values, for DA1472 compared with wild-type FucO for the phenylacetaldehyde substrate. The crystal structure of DA1472 complexed with a non-reactive analog of this substrate (3,4-dimethoxyphenylacetamide) suggests the mode of binding of the bulky group of the new substrate. These combined structure–function studies therefore explain the dramatic increase in catalytic activity of the DA1472 variant for bulky aldehyde substrates. The structure comparisons also suggest why the active site in which Fe2+ is replaced by Zn2+ is not able to support catalysis.
Vocational training support and innovation at SMEs
Authors: Hlasny Vladimir
Published: May 2023

Purpose

While the value of human capital for technological innovation is well acknowledged, literature on the role of vocational training in corporate innovation is notably scarce. The purpose of this study is to assess the effect of government support for small and medium-sized enterprise (SME) competencies on Korean firms’ innovation. The author investigates SMEs’ patent applications (supported by the government to varying degrees) while accounting for firms’ market position, ownership and management structure, as well as prior changes in firms’ technologies, products, processes and other characteristics. Alternative hypotheses about management motivation – the “lazy manager”, “career concerns” and “special East Asian institutional constraints” hypotheses – are also evaluated.

Design/methodology/approach

Censored and count data analysis methods are used on a panel of 595 Korean firms covering 2005–2015 from the Korean Human Capital Corporate Survey, Intellectual Property Office and National Investment Commission. A regression discontinuity estimator accounts for potential endogeneity because of support for vocational training at firms.

Findings

Firms receiving training support are more innovative than firms without support, but latent effects may play a role. The regression-discontinuity model suggests that firms that succeeded only marginally in obtaining support had higher innovative output than non-recipients near the eligibility threshold.

Originality/value

The findings of this study establish that government support had the intended effect on SMEs’ technological capacity. This cannot be discounted as a simple crowding-out effect. The author also establishes that management–ownership separation within firms was conducive to innovation, that product competition had an inverse U-shaped effect and that management–ownership separation had a substitutable relationship with competition in overcoming managers’ effort avoidance. The findings support the “lazy manager” hypothesis over the “career concerns” and the “special East Asian institutional constraints” hypotheses.
Uniformly convergent computational method for singularly perturbed time delayed parabolic differential-difference equations
Authors: Mohapatra Jugal , Priyadarshana Sushree , Raji Reddy Narahari
Published: May 2023

Purpose

The purpose of this work is to introduce an efficient, global second-order accurate and parameter-uniform numerical approximation for singularly perturbed parabolic differential-difference equations having a large lag in time.

Design/methodology/approach

The small delay and advance terms in spatial direction are handled with Taylor's series approximation. The Crank–Nicholson scheme on a uniform mesh is applied in the temporal direction. The derivative terms in space are treated with a hybrid scheme comprising the midpoint upwind and the central difference scheme at appropriate domains, on two layer-resolving meshes namely, the Shishkin mesh and the Bakhvalov–Shishkin mesh. The computational effectiveness of the scheme is enhanced by the use of the Thomas algorithm which takes less computational time compared to the usual Gauss elimination.

Findings

The proposed scheme is proved to be second-order accurate in time and to be almost second-order (up to a logarithmic factor) uniformly convergent in space, using the Shishkin mesh. Again, by the use of the Bakhvalov–Shishkin mesh, the presence of a logarithmic effect in the spatial-order accuracy is prevented. The detailed analysis of the convergence of the fully discrete scheme is thoroughly discussed.

Research limitations/implications

The use of second-order approximations in both space and time directions makes the complete finite difference scheme a robust approximation for the considered class of model problems.

Originality/value

To validate the theoretical findings, numerical simulations on two different examples are provided. The advantage of using the proposed scheme over some existing schemes in the literature is proved by the comparison of the corresponding maximum absolute errors and rates of convergence.
Innovation comes with responsibility: a dual moderation model of taking charge and innovative job performance
Authors: Liu Pingqing , Yuan Yunyun , Yang Lifeng , Liu Bin , Xu Shuang
Published: May 2023

Purpose

The aim of this study is to examine the relationships between taking charge, bootlegging innovation and innovative job performance, and to explore the moderating roles of felt responsibility for constructive change (FRCC) and creative self-efficacy (CSE).

Design/methodology/approach

Data for this research was collected from 503 employees working in a chain company. Through a longitudinal study design, a three-wave survey with 397 valid data provided support for the proposed theoretical model.

Findings

The results maintain a positive association between taking charge, bootlegging innovation and innovative job performance, indicating the mediating effect of bootlegging innovation. Additionally, both the FRCC and CSE facilitate the indirect effect of taking charge on innovative job performance through bootlegging innovation. Furthermore, the integrated moderated mediation model analysis suggested that FRCC is more vital in improving employees' innovative job performance.

Originality/value

This research aims to break the black box between taking charge and innovative job performance, which has been relatively unexplored. Drawing from self-determination theory (SDT) and the proactive motivation model, the authors verify the bridge-building role of bootlegging innovation and the dual-facilitating effects of FRCC and CSE while employees conduct taking charge. This study’s results provide new insight for managers to foster, encourage and support employees' proactive behavior.
Innovation and export: evidence from manufacturing SMEs in a developing economy
Authors: Duc Tran Cong , Tien Thanh Pham , The Duy Duong
Published: May 2023

Purpose

Innovation allows firms to gain or maintain their competitive advantages in both domestic and international markets. However, the findings on the association between innovation and export vary depending on countries, samples, time, variables and methods used for empirical analysis. The purpose of this study is to examine the influence of different types of innovation on export in small- and medium-sized enterprises (SMEs) in a developing economy in the context of global integration.

Design/methodology/approach

For empirical analysis, the authors use a sample of manufacturing SMEs in Vietnam in 2013 and 2015. Because the firms do not engage in innovation at random in the research sample, the authors use propensity score matching to account for self-selection bias. The authors also use different matching estimators to ensure robust results.

Findings

Innovation activities are found to be positively associated with the probability of engaging in export activities. The effects are mainly contributed by the adoption of new technology or process.

Practical implications

This research underscores the importance of public interventions and policies designed to promote innovation and export in the SMEs.

Originality/value

To the best of the authors’ knowledge, this research is one of the early attempts to examine the association between different types of innovation and export in SMEs in a developing economy.