bluuebunny/crossref_metadata_2025 huggingface dataset:
De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells
Authors: Babin Loélia , Darchen Alice , Robert Elie , Aid Zakia , Borry Rosalie , Soudais Claire , Piganeau Marion , De Cian Anne , Giovannangeli Carine , Bawa Olivia , Rigaud Charlotte , Scoazec Jean-Yves , Couronné Lucile , Veleanu Layla , Cieslak Agata , Asnafi Vahid , Sibon David , Lamant Laurence , Meggetto Fabienne , Mercher Thomas , Brunet Erika
Published: March 2022

Background

Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion.

Methods

We performed CRISPR/Cas9-mediated genome editing of the NPM-ALK chromosomal translocation in primary human activated T lymphocytes.

Results

Both CD4+ and CD8+ NPM-ALK-edited T lymphocytes showed rapid and reproducible competitive advantage in culture and led to in vivo disease development with nodal and extra-nodal features. Murine tumors displayed the phenotypic diversity observed in ALK+ ALCL patients, including CD4+ and CD8+ lymphomas. Assessment of transcriptome data from models and patients revealed global activation of the WNT signaling pathway, including both canonical and non-canonical pathways, during ALK+ ALCL lymphomagenesis. Specifically, we found that the WNT signaling cell surface receptor ROR2 represented a robust and genuine marker of all ALK+ ALCL patient tumor samples.

Conclusions

In this study, ab initio modeling of the ALK+ ALCL chromosomal translocation in mature T lymphocytes enabled the identification of new therapeutic targets. As ROR2 targeting approaches for other cancers are under development (including lung and ovarian tumors), our findings suggest that ALK+ ALCL cases with resistance to current therapies may also benefit from ROR2 targeting strategies.
Multifunctional photodynamic/photothermal nano-agents for the treatment of oral leukoplakia
Authors: Lin Lin , Song Chuanhui , Wei Zheng , Zou Huihui , Han Shengwei , Cao Zichen , Zhang Xinyu , Zhang Guorong , Ran Jianchuan , Cai Yu , Han Wei
Published: March 2022

Oral leukoplakia (OLK) has gained extensive attention because of the potential risk for malignant transformation. Photosensitizers (PSs) played an indispensable role in the photodynamic therapy (PDT) of OLK, but the poor light sensitivity greatly hampered its clinical application. Herein, a novel organic photosensitive ITIC-Th nanoparticles (ITIC-Th NPs) were developed for OLK photodynamic/photothermal therapy (PTT). ITIC-Th NPs present both high photothermal conversion efficiency (~ 38%) and suitable reactive oxygen species (ROS) generation ability under 660 nm laser irradiation, making them possess excellent PDT and PTT capability. In 4-nitroquinoline 1-oxide (4NQO)-induced oral precancerous animal models, ITIC-Th NPs effectively suppress the OLK's cancerization without apparent topical or systemic toxicity in vivo. This study offers a promising therapeutic strategy for PDT and PTT in OLK treatment, and this study is the first interdisciplinary research in the field of multimodal therapy for OLK.

Graphical Abstract
A drug-free nanozyme for mitigating oxidative stress and inflammatory bowel disease
Authors: Zeng Feng , Shi Yahong , Wu Chunni , Liang Jianming , Zhong Qixin , Briley Karen , Xu Bin , Huang Yongzhuo , Long Manmei , Wang Cong , Chen Jian , Tang Yonghua , Li Xinying , Jiang Mengda , Wang Luting , Xu Qin , Yang Liu , Chen Peng , Duan Shengzhong , Xie Jingyuan , Li Cong , Wu Yingwei
Published: March 2022

Inflammatory bowel disease (IBD) is an incurable disease of the gastrointestinal tract with a lack of effective therapeutic strategies. The proinflammatory microenvironment plays a significant role in both amplifying and sustaining inflammation during IBD progression. Herein, biocompatible drug-free ceria nanoparticles (CeNP-PEG) with regenerable scavenging activities against multiple reactive oxygen species (ROS) were developed. CeNP-PEG exerted therapeutic effect in dextran sulfate sodium (DSS)-induced colitis murine model, evidenced by corrected the disease activity index, restrained colon length shortening, improved intestinal permeability and restored the colonic epithelium disruption. CeNP-PEG ameliorated the proinflammatory microenvironment by persistently scavenging ROS, down-regulating the levels of multiple proinflammatory cytokines, restraining the proinflammatory profile of macrophages and Th1/Th17 response. The underlying mechanism may involve restraining the co-activation of NF-κB and JAK2/STAT3 pathways. In summary, this work demonstrates an effective strategy for IBD treatment by ameliorating the self-perpetuating proinflammatory microenvironment, which offers a new avenue in the treatment of inflammation-related diseases.

Graphical Abstract
Biomimetic radiosensitizers unlock radiogenetics for local interstitial radiotherapy to activate systematic immune responses and resist tumor metastasis
Authors: Zhang Jiajia , Yang Mengdie , Fan Xin , Zhu Mengqin , Yin Yuzhen , Li Hongyan , Chen Jie , Qin Shanshan , Zhang Han , Zhang Kun , Yu Fei
Published: March 2022

Background

Similar to other local therapeutic methods, local interstitial radiotherapy (IRT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis.

Results

Mn-based IRT radiosensitizers consisting of 131I, MnO2 and bovine serum albumin (BSA) (131I-MnO2-BSA) were engineered. Such Mn-based IRT radiosensitizers successfully unlocked radiogenetics to magnify systematic immune responses of local IRT via remodeling hypoxic and immunosuppressive microenvironments and resist tumor metastasis. The MnO2 in 131I-MnO2-BSA caused decomposition of H2O2 enriched in tumors to generate O2 for alleviating hypoxic microenvironment and removing tumor resistances to IRT. Concurrently, hypoxia mitigation by such radiosensitizers-unlocked radiogenetics can effectively remodel immunosuppressive microenvironment associated with regulatory T (Treg) cells and tumor-associated macrophages (TAMs) infiltration inhibition to induce immunogenic cell death (ICD), which, along with hypoxia mitigation, activates systematic immune responses. More intriguingly, 131I-MnO2-BSA-enabled radiogenetics can upregulate PD-L1 expression, which allows anti-PD-L1-combined therapy to exert a robust antitumor effect on primary tumors and elicit memory effects to suppress metastatic tumors in both tumor models (4T1 and CT26).

Conclusions

IRT radiosensitizer-unlocked radiogenetics and the corresponding design principle provide a general pathway to address the insufficient systematic immune responses of local IRT.

Graphical Abstract
Health-related quality of life among older adults who experienced the Pohang earthquake in South Korea: A cross-sectional survey
Authors: Kim Eun-Mi , Kim Gwang Suk , Kim Heejung , Park Chang Gi , Lee Ogcheol , Pfefferbaum Betty
Published: March 2022

Background

Earthquakes are global natural disasters and can cause loss of property, livelihood and affect human health. A 5.4 magnitude earthquake, the Pohang earthquake, occurred in South Korea in 2017. In this study, based on a health-related quality of life (HRQOL) conceptual model, we examined the HRQOL and its associated factors among older adults who had experienced the earthquake.

Methods

A cross-sectional study was conducted with a quota sample of 312 older adults living in eight villages of a district that was the most damaged area during the Pohang earthquake. Data were collected from January 15–March 19, 2019, via face-to-face interviews using structured questionnaires. Structural equation modeling was performed to explore the associations among depression, posttraumatic stress symptoms, community resilience, social support, disaster preparedness, and HRQOL.

Results

The mean age of the participants was 77.93 ± 6.11 years. HRQOL scores were 49.85 ± 18.07 (physical health), 50.16 ± 18.75 (psychological health), 61.93 ± 19.20 (social relations), and 49.53 ± 16.37 (environment). The structural equation modeling analysis showed a good fit. Depression had direct (β =  − 2.21; p < 0.001), indirect (β =− 0.23; p < 0.001), and total effects on HRQOL (β =  − 2.44; p < 0.001). Community resilience (β = 6.05; p = 0.001) and social support (β = 0.12, p = 0.001) had direct and total effects on HRQOL. Disaster preparedness had indirect (β = 0.40; p = 0.001) and total (β = 0.69, p = 0.031) effects on HRQOL. In contrast, posttraumatic stress symptoms did not have significant effects on HRQOL.

Conclusions

Our findings indicated that lower depression, higher community resilience, social support, and disaster preparedness were associated with increased HRQOL. Thus, it is helpful to decrease depression and strengthen community resilience, social support, and disaster preparedness to promote HRQOL among older adults who have experienced earthquakes. These results can inform the development of HRQOL in socio-psychological improvement programs for older adults in community health centers and disaster-relief psychological support centers.
Pan-cancer analyses of pyroptosis with functional implications for prognosis and immunotherapy in cancer
Authors: Liu Aibin , Shen Lin , Li Na , Shen Liangfang , Li Zhanzhan
Published: March 2022

Background

Programmed cell death is an active and orderly form of cell death regulated by intracellular genes that plays an important role in the normal occurrence and development of the immune system, and pyroptosis has been found to be involved in tumorigenesis and development. However, compressive analysis and biological regulation of pyroptosis genes are lacking in cancers.

Methods

Using data from The Cancer Genome Atlas, we established a score level model to quantify the pyroptosis level in cancer. Multiomics bioinformatic analyses were performed to assess pyroptosis-related molecular features and the effect of pyroptosis on immunotherapy in cancer.

Results

In the present study, we performed a comprehensive analysis of pyroptosis and its regulator genes in cancers. Most pyroptosis genes were aberrantly expressed in different types of cancer, attributed to the CAN frequency and differences in DNA methylation levels. We established a pyroptosis level model and found that pyroptosis had dual roles across cancers, while the pyroptosis levels were different among multiple cancers and were significantly associated with clinical prognosis. The dual role of pyroptosis was also shown to affect immunotherapeutic efficacy in several cancers. Multiple pyroptosis genes showed close associations with drug sensitivity across cancers and may be considered therapeutic targets in cancer.

Conclusions

Our comprehensive analyses provide new insight into the functions of pyroptosis in the initiation, development, progression and treatment of cancers, suggesting corresponding prognostic and therapeutic utility.
Mix-and-match: an improved, fast and accessible protocol for hypocotyl micrografting of Arabidopsis seedlings with systemic ACC responses as a case study
Authors: Vanderstraeten L. , Sanchez-Muñoz R. , Depaepe T. , Auwelaert F. , Van Der Straeten D.
Published: March 2022

Background

Grafting is a technique widely used in horticulture that also has been applied in agriculture. In plant physiology, grafting facilitates the elucidation of mechanisms underlying growth and developmental processes, through the construction of chimeric plants with organs of different genotypes. Despite its small size, the model species Arabidopsis thaliana is very amenable for grafting, which can be useful to investigate transport of nutrients, amino acids or secondary metabolites between different tissues, or to investigate developmental processes depending on root-to-shoot communication, such as shoot branching, root and shoot plasticity upon shade avoidance, or disease resistance. Nevertheless, grafting protocols are usually technically challenging and training is required to achieve a reasonable success rate. Additionally, specialized tools and equipment are often needed, such as chips to accommodate the grafted plantlets or collars to maintain the contact between root and shoot.

Results

In this methodology paper, we provide a fast, easy, accessible, and specialized equipment-free protocol that enables high success ratios. Critical steps and notes are detailed, easing the implementation of the procedure for non-trained researchers. An example of the protocol application by three independent non-trained researchers shows that this method allows to achieve a 90–100% of grafting efficiency after 6 days post-grafting recovery. In addition, the grafting of Col-0 with the acs8x mutant, depleted in 1-aminocyclopropane-1-carboxylic acid (ACC), the biosynthetic precursor of the phytohormone ethylene, provides an example of the application of this optimized protocol, showing the suitability of the process to study long-distance transport processes.

Conclusions

We present an optimized protocol for hypocotyl grafting of 4-day-old Arabidopsis thaliana seedlings. The combination of conditions yields a grafting success of 90–100% and provides an easy and accessible methodology, reducing the time frame, and without the necessity of acquiring specialized equipment. The presented protocol is simple, fast and highly efficient, easing the inclusion of hypocotyl grafting assays in any research project. In addition, the description of the protocol is detailed to a level ensuring that even non-trained researchers, are sufficiently prepared to adopt the grafting methodology.
Surgical management of upper limb lipoma arborescens: a systematic review
Authors: Kalifis Georgios , Maffulli Nicola , Migliorini Filippo , Marín Fermín Theodorakys , Hovsepian Jean Michel , Stefanou Nikolaos , Hantes Michael
Published: March 2022

Background

Lipoma arborescens (LA) is a rare benign synovial tumour characterized by the proliferation of mature adipocytes within the synovial cells. Given its rarity, current evidence is mainly based on case reports and case series, and no guidelines are available. The present study investigated the current surgical management and related outcomes of LA in the upper limb.

Methods

This systematic review was conducted following the PRISMA guidelines. PubMed, Scopus, and Virtual Health Library were accessed in September 2021. Clinical studies evaluating patients with LA undergoing surgical treatment were considered eligible for this systematic review. Only studies which reported data on LA located in the upper limb with histopathological confirmation were considered. Articles that reported data from nonsurgical management were not considered.

Results

A total of 21 studies reporting 22 lesions in 21 patients were assessed. The mean age of the patients was 48.48 years (range 22–77). Most studies evaluated the restoration of range of motion and symptom resolution for the functional outcome assessment. Open or arthroscopic excision and synovectomy were the most common surgical procedures for LA. The concomitant lesions were treated in a single-stage procedure. All patients had satisfactory outcomes after open or arthroscopic excision and synovectomy without recurrence at a mean follow-up of 21.14 months (range 2–60). One patient developed postoperative cellulitis (4.55%).

Conclusion

Open and arthroscopic excision combined with synovectomy should be considered the standard treatment option of upper limb LA. Concomitant pathologies can be addressed in a one-stage procedure. Although LA was recognized as a clinical entity decades ago, there is a lack of evidence based guidelines and long term outcome data are unavailable.
CRISPR-Cas gene editing technology and its application prospect in medicinal plants
Authors: Guo Miaoxian , Chen Hongyu , Dong Shuting , Zhang Zheng , Luo Hongmei
Published: March 2022

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas gene editing technology has opened a new era of genome interrogation and genome engineering because of its ease operation and high efficiency. An increasing number of plant species have been subjected to site-directed gene editing through this technology. However, the application of CRISPR-Cas technology to medicinal plants is still in the early stages. Here, we review the research history, structural characteristics, working mechanism and the latest derivatives of CRISPR-Cas technology, and discussed their application in medicinal plants for the first time. Furthermore, we creatively put forward the development direction of CRISPR technology applied to medicinal plant gene editing. The aim is to provide a reference for the application of this technology to genome functional studies, synthetic biology, genetic improvement, and germplasm innovation of medicinal plants. CRISPR-Cas is expected to revolutionize medicinal plant biotechnology in the near future.
Molecular environment and atypical function: What do we know about enzymes associated with Mucopolysaccharidoses?
Authors: Kong Weijing , Lu Cheng , Ding Yingxue , Meng Yan
Published: March 2022

Mucopolysaccharidoses are a group of lysosomal storage disorders caused by deficiency of enzymes involved in glycosaminoglycans degradation. Relationship between mucopolysaccharidoses and related enzymes has been clarified clearly. Based on such relationship, lots of therapies have been commercialized or are in the process of research and development. However, many potential treatments failed, because those treatments did not demonstrate expected efficacy or safety data. Molecular environment of enzyme, which is essential for their expression and activity, is fundamental for efficacy of therapy. In addition to enzyme activities, mucopolysaccharidoses-related enzymes have other atypical functions, such as regulation, which may cause side effects. This review tried to discuss molecular environment and atypical function of enzymes that are associated with mucopolysaccharidoses, which is very important for the efficacy and safety of potential therapies.
An international comparative analysis of public reimbursement of orphan drugs in Canadian provinces compared to European countries
Authors: Ward Leanne Marie , Chambers Alexandra , Mechichi Emine , Wong-Rieger Durhane , Campbell Craig
Published: March 2022

Background

The Canadian government has committed to developing a national strategy for drugs for rare diseases starting in 2022. Considering this announcement, we conducted a comparative analysis to examine patient access to therapies for rare disease in Canada relative to Europe and the U.S.

Methods

Given its similarity to the Canadian health care system, we used Europe as the reference point to analyze all of the therapies with an orphan drug designation approved by the European Medicine Agency (EMA) from 1 January 2015 to 31 March 2020. We then contrasted access to these drugs in Canada (Health Canada) and the U.S. (Food and Drug Administration, FDA). We focused on: (1) the number of therapies for rare diseases entering the Canadian market; (2) the percentage of these therapies that are publicly available to Canadians; and (3) the timelines for patients to access these therapies in Canada.

Results

Sixty-three approved therapies with an orphan drug designation from the EMA were identified. Fifty-three (84%) of these drugs had also been submitted to the FDA for approval, and 41 (65%) were submitted to Health Canada for approval. In Europe, Germany, Denmark, and the U.K. had the highest percentage of publicly reimbursed orphan drugs (84%, 70%, 68%, respectively). In comparison, Ontario (32%), Quebec (25%), and Alberta (25%) had the highest percentage of drugs reimbursed among the Canadian provinces. The shortest median duration (in months) from EMA approval to jurisdictional decision on reimbursement was in Austria (3.2), followed by Germany (4.1), and Finland (6.0). In Canada, the shortest median duration (in months) from regulatory approval to reimbursement was in British Columbia (17.3), Quebec (19.6) and Manitoba (19.6), while the longest duration was in P.E.I (38.5), followed by Nova Scotia (25.9), and Newfoundland (25.1).

Conclusions

Our comparative analysis found that relative to the EU Canadians had less frequent and timely access to therapies for rare diseases. This highlights the need for a rare disease strategy in Canada that allows for clear identification and transparent tracking of the pathway for rare disease drugs, and ultimately optimizes the number of patients with access to these therapies.
Host-microbiome protein-protein interactions capture disease-relevant pathways
Authors: Zhou Hao , Beltrán Juan Felipe , Brito Ilana Lauren
Published: March 2022

Background

Host-microbe interactions are crucial for normal physiological and immune system development and are implicated in a variety of diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D). Despite large-scale case-control studies aimed at identifying microbial taxa or genes involved in pathogeneses, the mechanisms linking them to disease have thus far remained elusive.

Results

To identify potential pathways through which human-associated bacteria impact host health, we leverage publicly-available interspecies protein-protein interaction (PPI) data to find clusters of microbiome-derived proteins with high sequence identity to known human-protein interactors. We observe differential targeting of putative human-interacting bacterial genes in nine independent metagenomic studies, finding evidence that the microbiome broadly targets human proteins involved in immune, oncogenic, apoptotic, and endocrine signaling pathways in relation to IBD, CRC, obesity, and T2D diagnoses.

Conclusions

This host-centric analysis provides a mechanistic hypothesis-generating platform and extensively adds human functional annotation to commensal bacterial proteins.
LIBERATE: a study protocol for midodrine for the early liberation from vasopressor support in the intensive care unit (LIBERATE): protocol for a randomized controlled trial
Authors: Opgenorth Dawn , Baig Nadia , Fiest Kirsten , Karvellas Constantine , Kutsogiannis Jim , Lau Vincent , Macintyre Erika , Senaratne Janek , Slemko Jocelyn , Sligl Wendy , Wang Xiaoming , Bagshaw Sean M. , Rewa Oleksa G.
Published: March 2022

Background

Intravenous (IV) vasopressors to support hemodynamics are a primary indication for intensive care unit (ICU) admission. Utilization of oral vasopressor therapy may offer an alternative to IV vasopressor therapy in the ICU, thus decreasing the need for ICU admission. Oral vasopressors, such as midodrine, have been used for hemodynamic support in non-critically ill patients, but their evaluation in critically ill patients to potentially spare IV vasopressor therapy has been limited.

Methods

The LIBERATE study will be a multicenter, parallel-group, blinded, randomized placebo-controlled trial. It will recruit adult (i.e., age ≥ 18 years) critically ill patients receiving stable or decreasing doses of IV vasopressors. Eligible patients will be randomized to receive either midodrine 10 mg administered enterally every 8 h or placebo until 24 h post-discontinuation of IV vasopressors. The primary outcome will be ICU length of stay. Secondary outcomes include all-cause mortality at 90 days, hospital length of stay, length of IV vasopressor support, re-initiation of IV vasopressors, rates of ICU readmission, and occurrence of AEs. Health economic outcomes including ICU, hospital and healthcare costs, and cost-effectiveness will be evaluated. Pre-planned subgroup analyses include age, sex, frailty, severity of illness, etiology of shock, and comorbid conditions.

Discussion

LIBERATE will rigorously evaluate the effect of oral midodrine on duration of ICU stay and IV vasopressor support in critically ill patients.

Trial registration

ClinicalTrials.gov NCT05058612. Registered on September 28, 2021
Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial
Authors: Gagnon David J. , Ryzhov Sergey V. , May Meghan A. , Riker Richard R. , Geller Bram , May Teresa L. , Bockian Sarah , deKay Joanne T. , Eldridge Ashley , Van der Kloot Thomas , Lerwick Patricia , Lord Christine , Lucas F. Lee , Mailloux Patrick , McCrum Barbara , Searight Meghan , Wirth Joel , Zuckerman Jonathan , Sawyer Douglas , Seder David B.
Published: March 2022

Background

Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality.

Methods

The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and Clostridioides difficile-associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years.

Discussion

The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome.

Trial registration

ClinicalTrials.gov NCT04999592. Registered on August 10, 2021.
d-Lactic acid production from agricultural residues by membrane integrated continuous fermentation coupled with B vitamin supplementation
Authors: Ma Kedong , Cui Yubo , Zhao Ke , Yang Yuxuan , Wang Yidan , Hu Guoquan , He Mingxiong
Published: March 2022

Background

d-Lactic acid played an important role in the establishment of PLA as a substitute for petrochemical plastics. But, so far, the d-lactic acid production was limited in only pilot scale, which was definitely unable to meet the fast growing market demand. To achieve industrial scale d-lactic acid production, the cost-associated problems such as high-cost feedstock, expensive nutrient sources and fermentation technology need to be resolved to establish an economical fermentation process.

Results

In the present study, the combined effect of B vitamin supplementation and membrane integrated continuous fermentation on d-lactic acid production from agricultural lignocellulosic biomass by Lactobacillus delbrueckii was investigated. The results indicated the specific addition of vitamins B1, B2, B3 and B5 (VB1, VB2, VB3 and VB5) could reduce the yeast extract (YE) addition from 10 to 3 g/l without obvious influence on fermentation efficiency. By employing cell recycling system in 350 h continuous fermentation with B vitamin supplementation, YE addition was further reduced to 0.5 g/l, which resulted in nutrient source cost reduction of 86%. A maximum d-lactate productivity of 18.56 g/l/h and optical purity of 99.5% were achieved and higher than most recent reports.

Conclusion

These findings suggested the novel fermentation strategy proposed could effectively reduce the production cost and improve fermentation efficiency, thus exhibiting great potential in promoting industrial scale d-lactic acid production from lignocellulosic biomass.

Graphical Abstract
Screening for odorant receptor genes expressed in Aedes aegypti involved in host-seeking, blood-feeding and oviposition behaviors
Authors: Ni Meng , Zhao Teng , Lv Hui-xin , Li Man-jin , Xing Dan , Zhao Tong-yan , Li Chun-xiao
Published: March 2022

Background

Aedes aegyptiis one of the most important vectors of zoonotic diseases worldwide, and its survival and reproductive processes depend heavily on its olfactory system. In this study, the expression levels of all odorant receptor (OR) genes ofAe. aegyptiwere explored during different physiological periods to identify olfactory genes that may be associated with mosquito blood-feeding and the search for oviposition sites.

Methods

Four experimental groups, consisting ofAe. aegyptimales, pre-blood-feeding females, post-blood-feeding females and post-oviposition females, were established. A total of 114 pairs of primers targeting all messenger RNA encoded by OR genes were designed based on the whole genome ofAe. aegypti. The expression of OR genes was evaluated by real-time fluorescence quantitative PCR for relative quantification and the comparison of differences between groups.

Results

A total of 53 differentially expressed OR genes were identified between males and females inAe. aegyptiantennae. Also, eight, eight and 13 differentially expressed OR genes were identified in pre- versus post-blood-feeding females, in pre- versus post-oviposition females and in post-blood-feeding versus post-oviposition females, respectively. In addition, 16 OR genes were significantly differentially expressed in multiple physiological periods of the mosquitoes.

Conclusions

A large number of ORs with significant intergroup differences and high expression levels were screened in this study. Some of these genes are reported for the first time, providing possible targets for the development of mosquito control pathways based on the olfactory system.

Graphical Abstract
Amniotic suspension allograft improves pain and function in a rat meniscal tear-induced osteoarthritis model
Authors: Kimmerling Kelly A. , Gomoll Andreas H. , Farr Jack , Mowry Katie C.
Published: March 2022

Background

Osteoarthritis is a degenerative disease of the knee that affects 250 million people worldwide. Due to the rising incidence of knee replacement and revision surgery, there is a need for a nonsurgical treatment to reduce pain and improve function in patients with knee osteoarthritis. Placental-derived allografts, such as an amniotic suspension allograft (ASA), provide growth factors and cytokines that could potentially modulate the inflammatory environment of osteoarthritis. The purpose of this study was to evaluate the efficacy of ASA in a rat medial meniscal tear (MMT) induced osteoarthritis model through histology, microCT, synovial fluid biomarkers, and behavioral testing.

Methods

Rats underwent MMT surgery at day − 7; at day 0, rats were injected with either ASA, vehicle control, or fibroblast growth factor-18 (FGF18). Behavioral testing, including gait analysis, pain threshold, incapacitance, and knee swelling were evaluated in-life, along with histology, microCT analysis of cartilage, and synovial fluid testing post-sacrifice. One MMT cohort was sacrificed at day 10, the other at day 21. A third cohort acted as a safety arm and did not receive MMT surgery; these rats were injected with either vehicle control or ASA and evaluated at day 3 and day 21.

Results

Behavioral testing showed a significant improvement in pain threshold, incapacitance, and gait following an injection of ASA. MicroCT showed significant improvements in cartilage thickness and attenuation at day 10 only, and histology showed no detrimental effects compared to the vehicle control at day 21. Synovial fluid analysis showed a significant increase in anti-inflammatory IL-10. The safety cohort showed no significant differences except for an increase in synovitis at day 21, which could be evidence of a xenogeneic response in this model.

Conclusions

In this study, an injection of ASA was well tolerated with no adverse events. Improvements in pain and function, along with cartilage properties at day 10, were observed. Increases in anti-inflammatory cytokines was also seen, along with no significant cartilage degeneration at day 21 compared to the vehicle control. This study provides evidence for the use of ASA as a nonsurgical treatment for knee OA.
DeSIDE-DDI: interpretable prediction of drug-drug interactions using drug-induced gene expressions
Authors: Kim Eunyoung , Nam Hojung
Published: March 2022

Adverse drug-drug interaction (DDI) is a major concern to polypharmacy due to its unexpected adverse side effects and must be identified at an early stage of drug discovery and development. Many computational methods have been proposed for this purpose, but most require specific types of information, or they have less concern in interpretation on underlying genes. We propose a deep learning-based framework for DDI prediction with drug-induced gene expression signatures so that the model can provide the expression level of interpretability for DDIs. The model engineers dynamic drug features using a gating mechanism that mimics the co-administration effects by imposing attention to genes. Also, each side-effect is projected into a latent space through translating embedding. As a result, the model achieved an AUC of 0.889 and an AUPR of 0.915 in unseen interaction prediction, which is competitively very accurate and outperforms other state-of-the-art methods. Furthermore, it can predict potential DDIs with new compounds not used in training. In conclusion, using drug-induced gene expression signatures followed by gating and translating embedding can increase DDI prediction accuracy while providing model interpretability. The source code is available on GitHub (https://github.com/GIST-CSBL/DeSIDE-DDI).
Use of GC-IMS for detection of volatile organic compounds to identify mixed bacterial culture medium
Authors: Lu Yanyi , Zeng Lin , Li Min , Yan Bowen , Gao Dandan , Zhou Bangfu , Lu Weiping , He Qinghua
Published: March 2022

In order to explore the possibility to identify common wound infection bacteria in mixed culture with gas chromatograph-ion migration spectroscopy (GC-IMS), the headspace gas of single and mixed cultures of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa were detected and analyzed by GC-IMS system. The bacteria were cultured in thioglycolate medium tubes then transferred to the sampling bottles (indirect method), or directly cultured in the sampling bottles (direct method) to allow accumulation of volatile compounds and facilitate automation. The specific microorganism volatile organic compounds (mVOCs) of the three bacteria were obtained. Some of them have been known to certain substance, for example, ethanol, isoamyl acetate, Phenylacetaldehyde, 2-heptanone etc., while others have not. Principal component analysis (PCA) showed that a higher separability can be achieved with direct method than indirect method. This work indicated that it is possible to identify compound bacteria by detecting specific mVOCs with GC-IMS, and the specific mVOCs should be medium-dependent.
Climate trend analysis for a semi-arid Borana zone in southern Ethiopia during 1981–2018
Authors: Worku Mitiku Adisu , Feyisa Gudina Legese , Beketie Kassahun Ture
Published: March 2022

Background

Understanding the climate variability at local scale could help suggest local adaptation responses to manage climate associated risks. This paper analyzed the variability and trend of climate in semi-arid Borana zone of southern Ethiopia over the period 1981–2018 using Mann–Kendall (MK) test, Sen’s Slope Estimator (SEE) and inverse distance weighted (IDW) interpolation technique. Gridded (4 km * 4 km) climate data (daily precipitation, daily maximum temperature (Tmax) and minimum temperature (Tmin)) were collected from National Meteorology Agency (NMA) of Ethiopia.

Results

The results revealed the study area received a mean monthly precipitation of 39.19 mm and a monthly mean Tmax and Tmin of 29.66 °C and 16.31 °C were observed respectively. Rainfall shows a significant increasing trend during August, October and November and extremely variable during December, January and February where CV > 100%. Tmax shows a significant warming trend during August but January, February, August and October exhibited similar trend for Tmin. Rainfall and Tmin shows a significant trend during Meher and no trend for the rest of the seasons. Mean annual rainfall shows a significant increase where no trend observed for both Tmax and Tmin at this timescale. Decadal rainfall and Tmin exhibited no trend but Tmax show significant warming trend during 2001–2010 decade. Better rainfall and cooler temperature were observed in the north central, northeastern and northwestern whereas the southeastern and southwestern regions were drier and warmer.

Conclusion

Rainfall is highly variable than temperature both at temporal and spatial scales in Borana. The intensity of rainfall decreases from the northeastern and northwestern parts towards the southwest while temperature increased from the north central parts towards the southwest for Tmax and the southeast for Tmin. The effect of topography is substantial for the local scale variability observed in the study area. Internal variability is observed at temporal and spatial scales and therefore any adaptation responses to local climate variability should consider the microscale climate.
Extensive metagenomic analysis of the porcine gut resistome to identify indicators reflecting antimicrobial resistance
Authors: Zhou Yunyan , Fu Hao , Yang Hui , Wu Jinyuan , Chen Zhe , Jiang Hui , Liu Min , Liu Qin , Huang Lusheng , Gao Jun , Chen Congying
Published: March 2022

Background

Antimicrobial resistance (AMR) has been regarded as a major threat to global health. Pigs are considered an important source of antimicrobial resistance genes (ARGs). However, there is still a lack of large-scale quantitative data on the distribution of ARGs in the pig production industry. The bacterial species integrated ARGs in the gut microbiome have not been clarified.

Results

In the present study, we used deep metagenomic sequencing data of 451 samples from 425 pigs including wild boars, Tibetan pigs, and commercial or cross-bred experimental pigs under different rearing modes, to comprehensively survey the diversity and distribution of ARGs and detect the bacteria integrated in these ARGs. We identified a total of 1295 open reading frames (ORFs) recognized as antimicrobial resistance protein-coding genes. The ORFs were clustered into 349 unique types of ARGs, and these could be further classified into 69 drug resistance classes. Tetracycline resistance was most enriched in pig feces. Pigs raised on commercial farms had a significantly higher AMR level than pigs under semi-free ranging conditions or wild boars. We tracked the changes in the composition of ARGs at different growth stages and gut locations. There were 30 drug resistance classes showing significantly different abundances in pigs between 25 and 240 days of age. The richness of ARGs and 41 drug resistance classes were significantly different between cecum lumen and feces in pigs from commercial farms, but not in wild boars. We identified 24 bacterial species that existed in almost all tested samples (core bacteria) and were integrated 128 ARGs in their genomes. However, only nine ARGs of these 128 ARGs were core ARGs, suggesting that most of the ARGs in these bacterial species might be acquired rather than constitutive. We selected three subsets of ARGs as indicators for evaluating the pollution level of ARGs in samples with high accuracy (r = 0.73~0.89).

Conclusions

This study provides a primary overview of ARG profiles in various farms under different rearing modes, and the data serve as a reference for optimizing the use of antimicrobials and evaluating the risk of pollution by ARGs in pig farms.
Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease
Authors: Chignon Arnaud , Mathieu Samuel , Rufiange Anne , Argaud Déborah , Voisine Pierre , Bossé Yohan , Arsenault Benoit J. , Thériault Sébastien , Mathieu Patrick
Published: March 2022

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.
Assessing preoperative hope and expectations related to functional neurosurgery: a new questionnaire
Authors: Radomska Michalina , Flores Alves dos Santos João , Weber Kerstin , Baertschi Marc , Burkhard Pierre R. , Herrmann François , Belayachi Sanaâ , Favez Nicolas , Canuto Alessandra
Published: March 2022

Background

Despite successful functional neurosurgery, patients suffering from epilepsy or Parkinson’s disease may experience postoperative psychological distress and social maladjustments. Difficulties in coping with postoperative changes, even positive ones, have shown to be related to patients’ presurgery cognitive representations (i.e., expectations, hope). The aim of this study was to develop an instrument assessing various key features of surgery outcomes’ representations, namely the Preoperative Hope and Expectations Questionnaire (PHEQ).

Methods

Participants were patients (n= 50) diagnosed with Parkinson’s disease (n= 25) or epilepsy (n= 25), candidates for functional neurosurgery (i.e., Deep brain stimulation, anterior temporal lobectomy). Two to three weeks before the planned surgery, they were administrated items assessing their actual state, preoperative expectations, and hope regarding surgery outcomes. They also completed measures assessing optimism, quality of life and mood.

Results

Exploratory analysis resulted in a 14-item version of the PHEQ composed of two factors (abstract representations, including psychological well-being andconcrete representations, such as direct surgery outcomes). The PHEQ demonstrated high internal consistency and good convergent validity. Patients were more prone to express postoperative improvements in terms of hope rather than expectations. They generally focused on concrete rather than abstract features, although patients with Parkinson’s disease had higher abstract future-oriented representations.

Conclusions

The PHEQ presents satisfactory psychometric properties and may be considered as a reliable instrument for research and clinical practice.
Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer's disease
Authors: Chen Hsiang-Han , Eteleeb Abdallah , Wang Ciyang , Fernandez Maria Victoria , Budde John P. , Bergmann Kristy , Norton Joanne , Wang Fengxian , Ebl Curtis , Morris John C. , Perrin Richard J. , Bateman Randall J. , McDade Eric , Xiong Chengjie , Goate Alison , Farlow Martin , Chhatwal Jasmeer , Schofield Peter R. , Chui Helena , Harari Oscar , Cruchaga Carlos , Ibanez Laura ,   Dominantly Inherited Alzheimer Network
Published: March 2022

Background

Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations inAPP,PSEN1, andPSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD.

Methods

We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts forPSEN1,PSEN2andAPPgenes. Only circPSEN1passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performedin-silicofunctional analyses using the Circular RNA interactome website and DIANA mirPath software.

Results

Our results show significant differences in gene counts of circPSEN1in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23—ADADvsCO: log2FC = 0.794,p = 1.63 × 10–04, ADADvsAD: log2FC = 0.602,p = 8.22 × 10–04). The high gene counts are contributed by two circPSEN1species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linearPSEN1gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1levels do not seem to be specific toPSEN1mutation carriers; the counts are also elevated in APP andPSEN2mutation carriers.In-silicofunctional analyses suggest that circPSEN1is involved in several pathways such as axon guidance (p = 3.39 × 10–07), hippo signaling pathway (p = 7.38 × 10–07), lysine degradation (p = 2.48 × 10–05) or Wnt signaling pathway (p = 5.58 × 10–04) among other KEGG pathways. Additionally, circPSEN1counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70.

Conclusions

Our findings show the differential expression of circPSEN1is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of ourin-silicoanalyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.
An ontological data model for points of interest (POI) in a cultural heritage site
Authors: Ranjgar Babak , Sadeghi-Niaraki Abolghasem , Shakeri Maryam , Choi Soo-Mi
Published: March 2022

Cultural heritage (CH) reflects on the history of a society and its traditions and it is treated as the nation’s memory and identity. Digitizing and web, beside its benefits, brought some challenges in disseminating and retrieving CH information, which has heterogeneous content varying widely in type and properties yet encompassing rich semantic links. Semantic web technologies, especially ontologies, provide a common understanding inside a domain that helps sharing knowledge and interoperability. They can be very helpful in data modeling for a better information retrieval compared to relational databases as they take into account the semantics of information, guarantee reusability, and make information machine-readable that can offer more flexibility to intelligent services and applications. CH community is one of the first domains to make use semantic web technologies to deal with this issue. CIDOC CRM is the most used and famous ontology in CH domain, which is an ISO standard since 2006. Heritage sites are composed of many points of interest that attract visitors to find out about them. However, information about a particular POI is complex and interconnected with other people, events, and objects. In this paper, we aim to develop a POI-based data model for heritage sites in Iran using concepts from CIDOC CRM integrated with GeoSPARQL, the standard ontology in geospatial field, to incorporate spatial semantics with heritage information. This way the user can freely explore their preferred information about the places they desire. This can make it possible to use the data model for location-based services and applications in heritage sites.