bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Authors: Pretorius Etheresia , Vlok Mare , Venter Chantelle , Bezuidenhout Johannes A. , Laubscher Gert Jacobus , Steenkamp Janami , Kell Douglas B.
Published: August 2021

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis.

Methods

We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.

Results

We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.

Conclusions

Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.
Noncoding RNAs involved in the STAT3 pathway in glioma
Authors: Bian Zheng , Ji Wei , Xu Bin , Huo Zhengyuan , Huang Hui , Huang Jin , Jiao Jiantong , Shao Junfei , Zhang Xiaolu
Published: August 2021

Glioma is the most common malignant primary brain tumour in adults. Despite improvements in neurosurgery and radiotherapy, the prognosis of glioma patients remains poor. One of the main limitations is that there are no proper clinical therapeutic targets for glioma. Therefore, it is crucial to find one or more effective targets. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of genes. Abnormal expression of STAT3 is involved in the process of cell proliferation, migration, invasion, immunosuppression, angiogenesis, dryness maintenance, and resistance to radiotherapy and chemotherapy in glioma. Therefore, STAT3 has been considered an ideal therapeutic target in glioma. Noncoding RNAs (ncRNAs) are a group of genes with limited or no protein-coding capacity that can regulate gene expression at the epigenetic, transcriptional and posttranscriptional level. In this review, we summarized the ncRNAs that are correlated with the ectopic expression of STAT3 in glioma.
Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells
Authors: Niu Jiajing , Wang Jiamei , Zhang Qi , Zou Zhihua , Ding Yushuang
Published: August 2021

Background

Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood.

Methods

Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays.

Results

Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2arrest and apoptosis.

Conclusion

As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.
Supramolecular peptide nano-assemblies for cancer diagnosis and therapy: from molecular design to material synthesis and function-specific applications
Authors: Wang Yan , Zhang Xiaoyuan , Wan Keming , Zhou Nan , Wei Gang , Su Zhiqiang
Published: August 2021

Peptide molecule has high bioactivity, good biocompatibility, and excellent biodegradability. In addition, it has adjustable amino acid structure and sequence, which can be flexible designed and tailored to form supramolecular nano-assemblies with specific biomimicking, recognition, and targeting properties via molecular self-assembly. These unique properties of peptide nano-assemblies made it possible for utilizing them for biomedical and tissue engineering applications. In this review, we summarize recent progress on the motif design, self-assembly synthesis, and functional tailoring of peptide nano-assemblies for both cancer diagnosis and therapy. For this aim, firstly we demonstrate the methodologies on the synthesis of various functional pure and hybrid peptide nano-assemblies, by which the structural and functional tailoring of peptide nano-assemblies are introduced and discussed in detail. Secondly, we present the applications of peptide nano-assemblies for cancer diagnosis applications, including optical and magnetic imaging as well as biosensing of cancer cells. Thirdly, the design of peptide nano-assemblies for enzyme-mediated killing, chemo-therapy, photothermal therapy, and multi-therapy of cancer cells are introduced. Finally, the challenges and perspectives in this promising topic are discussed. This work will be useful for readers to understand the methodologies on peptide design and functional tailoring for highly effective, specific, and targeted diagnosis and therapy of cancers, and at the same time it will promote the development of cancer diagnosis and therapy by linking those knowledges in biological science, nanotechnology, biomedicine, tissue engineering, and analytical science.
The prevalence and socio-behavioural and clinical covariates of oral health related quality of life in Ugandan mothers with and without HIV-1
Authors: Birungi Nancy , Fadnes Lars Thore , Engebretsen Ingunn Marie Stadskleiv , Tumwine James Kashugyera , Åstrøm Anne Nordrehaug ,   ANRS 12174 and 12341 study groups
Published: August 2021

Background

There is limited evidence regarding oral health related quality of life of HIV positive populations in sub-Saharan Africa. Focusing HIV positive- and HIV negative Ugandan mothers, this study assessed the influence of HIV status on oral health related quality of life in terms of oral impacts on daily performances, whilst adjusting for clinical- and socio-behavioural factors. We also examined whether any association of clinical and socio-behavioural factors with oral impacts on daily performances vary according to mothers’ HIV status.

Methods

This cross-sectional study used data from a trial (n = 164) and a comparison group (n = 181). The trial comprised of mothers with HIV-1 participating in the ANRS 121741-PROMISE-PEP-trial (NCT00640263) conducted between 2009 and 2013 and from the ANRS 12341-PROMISE-PEP-M&S follow-up study conducted in 2017. The comparison group comprised of HIV negative mothers recruited in 2017. Interviews and clinical oral examinations were performed. The oral health related quality of life was assessed using the oral impacts on daily performances frequency scale. Caries experience and gingival bleeding were assessed using the World Health Organization’s Decayed, Missed and Filled teeth indices and community periodontal index. Logistic and negative binomial regression analyses were performed.

Results

29% of HIV-1 positive and 32% among the comparison reported any oral impact on daily performance. In adjusted logistic regression analysis, HIV status was not significantly associated with oral impacts on daily performances. Mother’s self-reported oral health, caries experience, gingival bleeding and oral health related quality of life of their children were independently associated with oral impacts on daily performances. Corresponding prevalence ratios and 95% confidence intervals were: 0.3 (0.2–0.6), 1.8 (1.0–3.2), 1.1 (1.0–1.1), and 2.1 (1.1–4.3). No significant interaction between HIV status and covariates were observed.

Conclusions

Oral health related quality of life was substantially impaired in Ugandan mothers but did not discriminate between HIV positive and negative participants. Mothers with impaired oral health related quality of life were more likely to have dental caries and children with impaired oral health related quality of life. HIV positive and negative mothers in Uganda deserve special attention regarding their oral disease and quality of life status.
Systematic functional interrogation of human pseudogenes using CRISPRi
Authors: Sun Ming , Wang Yunfei , Zheng Caishang , Wei Yanjun , Hou Jiakai , Zhang Peng , He Wei , Lv Xiangdong , Ding Yao , Liang Han , Hon Chung-Chau , Chen Xi , Xu Han , Chen Yiwen
Published: August 2021

Background

The human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites.

Results

To overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types.

Conclusions

Our study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.
Genetic diversity and population structure of Rhipicephalus sanguineus sensu lato across different regions of Colombia
Authors: Páez-Triana Luisa , Muñoz Marina , Herrera Giovanny , Moreno-Pérez Darwin A. , Tafur-Gómez Gabriel A. , Montenegro Diego , Patarroyo Manuel A. , Paniz-Mondolfi Alberto , Ramírez Juan David
Published: August 2021

Background

There has been a long-standing debate over the taxonomic status of Rhipicephalus sanguineus sensu lato. Different studies worldwide have reported the occurrence of different well-defined lineages, in addition to Rhipicephalus sanguineus sensu stricto. To date, there are very few studies examining the diverse aspects of this tick in Colombia. We assessed the population structure and genetic diversity of R. sanguineus s.l. in eight departmental regions across Colombia.

Methods

A total of 170 ticks were collected from dogs in different departments of Colombia. All specimens were morphologically compatible with R. sanguineus s.l. and subjected to genetic analysis. DNA sequences were obtained for the 12S rDNA, cytochrome oxidase I (COI) and internal transcribed spacer 2 (ITS2) markers. A concatenated set of all mitochondrial markers was also constructed. Next, maximum likelihood phylogenetic trees were constructed using the sequences generated herein and sequences available in GenBank. Finally, we assessed different summary statistics and analysed population structure and divergence with Fst and Dxy and demographic changes with Tajima's D and Fu and Li’s statistical tests.

Results

Analysis of the 12S rDNA and COI revealed that all R. sanguineus s.l. specimens collected across different regions of Colombia clustered within the tropical lineage. Micro-geographical analyses showed that the tick population from Amazonas formed a distinct cluster separated from the other sequences, with moderate Fst and Dxy values. However, no signs of a robust population structure were found within the country. The results of Fu’s FS tests, together with the haplotype networks and diversity values, signal a possible population expansion of this tick species in Colombia.

Conclusions

Evidence provided herein supports the tropical lineage as the main circulating lineage in Colombia, exhibiting a general lack of genetic structure except for the Amazonas region.

Graphical Abstract
Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain
Authors: Liang Lindsay , Fazel Darbandi Siavash , Pochareddy Sirisha , Gulden Forrest O. , Gilson Michael C. , Sheppard Brooke K. , Sahagun Atehsa , An Joon-Yong , Werling Donna M. , Rubenstein John L. R. , Sestan Nenad , Bender Kevin J. , Sanders Stephan J.
Published: August 2021

Background

Genetic variants in the voltage-gated sodium channelsSCN1A,SCN2A,SCN3A, andSCN8Aare leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported inSCN8Aonly (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain.

Methods

RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples.

Results

In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. ForSCN2A,SCN3A, andSCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. InSCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories.

Conclusions

Exon usage inSCN1A,SCN2A,SCN3A, andSCN8Achanges dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
Pharmacy services for the 2019 Fédération Internationale de Natation (FINA) World Masters Championships in Gwangju, South Korea
Authors: Yang In Kyu , Shin Eun Ok , Kim Dong Gyun , Jung Hyun Cheol , Kim Kwang Joon , Ki Sung Hwan
Published: August 2021

Background

The role of sports pharmacists is being emphasized in international athletic events. This study aimed to describe the pharmacy services for the 2019 Fédération Internationale de Natation (FINA) World Masters Championships in Gwangju, South Korea.

Method

Research focused on athletes and coaching staff who received medications after visiting medical centers and pharmacies located in the athletes’ village from July 5 to July 29, 2019. We collected daily results of pharmacy operation and prescription interventions. The data were analyzed using Microsoft Excel, and were expressed as frequency (%).

Results

Throughout the tournament, 633 patients received medication at the athletes’ village pharmacy (gender: 338 men [53.4%], 295 women [46.6%]; nationality: 299 Korean [47.2%], 334 overseas players [52.8%]; patient type: 150 athletes [23.7%], 427 non-athletes [67.5%]). Therapy for musculoskeletal disorders was the most common (n = 29, 19.3%), and oral NSAIDs (n = 56, 22.0%) were the most frequently dispensed medication in athletes. Pharmacists intervened for 47 out of 491 prescriptions (9.6%), with dosage change (n = 21, 44.7%) being the most common intervention type.

Conclusion

Sports pharmacists at FINA World Masters Championships played a pivotal role in ensuring the safe usage of medications by all participants, especially athletes. This study results will be a useful reference for pharmacy services at future international or domestic sports competitions.
Complete genome sequence of Trueperella pyogenes strain Arash114, isolated from the uterus of a water buffalo (Bubalus bubalis) in Iran
Authors: Ashrafi Tamai Iradj , Mohammadzadeh Abdolmajid , Ghalyanchi Langeroudi Arash , Mahmoodi Pezhman , Ziafati Kafi Zahra , Pakbin Babak , Zahraei Salehi Taghi
Published: August 2021

Objective

Trueperella pyogeneshas been considered a major causative agent of metritis, abortion, and death in a broad range of domestic and wild animals, including cattle, swine, sheep, goats, camels, buffalo, deer, antelopes, reptiles, and birds.

Data description

Here, we report the complete chromosome sequence ofTrueperella pyogenesstrain Arash114, isolated from the uterus of a water buffalo (Bubalus bubalis) died due to the infection caused by this pathogen. The genome assembly comprised 2,338,282 bp, with a 59.5% GC content. Annotation of the genome showed 46 tRNA genes, 6 rRNA, 1 CRISPR and 2059 coding sequences. Also, several genes coding for antimicrobial resistance such astetWand virulence factor includingplo,nanH,nanP,cbpand 4 fimbrial proteins were found. This study will advance our knowledge regarding the metabolism, virulence factors, antibiotic resistance and evolution of Arash114 strain and serve as an appropriate template for future researches.
Chronic and moderate consumption of reduced-alcohol wine confers cardiac benefits in a rat model of pulmonary arterial hypertension
Authors: Diaba-Nuhoho Patrick , Cour Martin , Hadebe Nkanyiso , Marais David , Lecour Sandrine , Blackhurst Dee
Published: August 2021

Objectives

In pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction develops via mechanisms involving oxidative stress. Moderate and chronic red wine (RW) consumption reduces oxidative stress and confers cardioprotection but its effect on PAH is unknown. We evaluated whether moderate and chronic consumption of reduced-alcohol RW (RARW) confers cardioprotection in a monocrotaline (MCT)-induced PAH rat model.

Results

Rats were randomly grouped: control; MCT; RARW; MCT + RARW. Wine was diluted to mimic moderate intake for humans, and consumed from 7 days before, until 28 days after MCT-injection. Echocardiography measured pulmonary artery acceleration time (PAAT) and RV thickness. Conjugated dienes (CD), and thiobarbituric acid reactive substances (TBARS) concentrations were assessed. MCT induced RV thickness and decreased PAAT compared to controls [1.22 ± 0.09 mm vs 0.46 ± 0.02 mm and 14 ± 1 vs 23 ± 2 m/s, respectively (p < 0.001)]. Chronic RARW consumption limited MCT-induced RV hypertrophy and increased PAAT. CD and TBARS increased in MCT-treated animals compared to controls (672 ± 43 nmol/L vs 453 ± 35 nmol/L; p < 0.01 and 13 ± 2 µmol/L vs 4 ± 0.3 µmol/L; p < 0.01). RARW reduced MCT-induced CD (472 ± 27 nmol/L vs 672 ± 43 nmol/L; p < 0.01).

Conclusion

Chronic and moderate intake of RARW ameliorates MCT-induced PAH in rats, which may be partly attributable to reduction of lipid peroxidation.
Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis
Authors: Kong Yue , Shao Yang , Ren Chunxia , Yang Gong
Published: August 2021

Endometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and can be divided into three categories: endometrial epithelial stem/progenitor cells, CD140b+CD146+ or SUSD2+ endometrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the menstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent proliferation, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medicine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occurrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming overreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the limited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the lesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endometriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like properties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we outlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, regenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproductive and cancerous diseases.
Serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of mesenchymal stem cells on experimental renal fibrosis
Authors: Ishiuchi Naoki , Nakashima Ayumu , Doi Shigehiro , Kanai Ryo , Maeda Satoshi , Takahashi Shinya , Nagao Masataka , Masaki Takao
Published: August 2021

Background

Mesenchymal stem cells (MSCs) repair injured tissue in a paracrine manner. To enhance their therapeutic properties, preconditioning with various factors has been researched. We have previously showed that MSCs cultured in serum-free medium (SF-MSCs) promote their immunosuppressive ability, thereby enhancing their anti-fibrotic effect. Here, we examined whether serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of MSCs on renal fibrosis in rats with ischemia–reperfusion injury (IRI).

Methods

SF-MSCs were incubated under 1% O2conditions (hypo-SF-MSCs) or 21% O2conditions (normo-SF-MSCs) for 24 h before collection. After IRI procedure, hypo-SF-MSCs or normo-SF-MSCs were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were killed and their kidneys were collected to evaluate inflammation and fibrosis. In in vitro experiments, we investigated whether hypo-SF-MSCs enhanced secretion of anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from hypo-SF-MSCs or normo-SF-MSCs.

Results

Normo-SF-MSCs showed attenuation of senescence, which increased their proliferative capacity. Although no significant difference in cellular senescence was found between normo-SF-MSCs and hypo-SF-MSCs, hypo-SF-MSCs further increased their proliferative capacity compared with normo-SF-MSCs. Additionally, administration of hypo-SF-MSCs more strongly ameliorated renal fibrosis than that of normo-SF-MSCs. Moreover, although hypo-SF-MSCs strongly attenuated infiltration of inflammatory cells compared with the control rats, which were treated with PBS, this attenuation was almost equal between normo-SF-MSCs and hypo-SF-MSCs. In vitro experiments revealed that hypo-SF-MSCs more significantly inhibited transforming growth factor (TGF)-β/Smad signaling compared with normo-SF-MSCs. Moreover, hypoxic preconditioning increased hepatocyte growth factor (HGF) secretion even under serum-free conditions, whereas knockdown of HGF in hypo-SF-MSCs attenuated inhibition of TGF-β/Smad signaling.

Conclusions

These results indicate that administration of ex vivo-expanded, hypoxia-preconditioned SF-MSCs may be a useful cell therapy to prevent renal fibrosis.
Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
Authors: Takahashi Hiroshi , Nakashima Taku , Masuda Takeshi , Namba Masashi , Sakamoto Shinjiro , Yamaguchi Kakuhiro , Horimasu Yasushi , Miyamoto Shintaro , Iwamoto Hiroshi , Fujitaka Kazunori , Hamada Hironobu , Hattori Noboru
Published: August 2021

Background

Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair. However, little is known about lung-resident ALDHbr. This study was performed to clarify the characteristics of lung-resident ALDHbr cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis.

Methods

The characteristics of lung-resident/nonhematopoietic (CD45−) ALDHbr cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45−/ALDHbr for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45−/ALDHbr cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice.

Results

Lung CD45−/ALDHbr showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45−/ALDHbr cell population, and especially its CD45−/ALDHbr/PDGFRα+ subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45−/ALDHbr cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45−/ALDHbr/PDGFRα+ population was more remarkable in aged mice than in young mice.

Conclusions

Our results strongly suggest that the lung expression of ALDH and lung-resident CD45−/ALDHbr cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45−/ALDHbr cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment.
Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes
Authors: Blom Thomas , Meinsma Rutger , di Summa Franca , van den Akker Emile , van Kuilenburg André B. P. , Hansen Marten , Tytgat Godelieve A. M.
Published: August 2021

Background

The therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake.

Methods

Peripheral blood CD34+ cells were differentiated to human megakaryocytic cells using a standardized culture protocol. Prior to [3H]serotonin and [125I]MIBG uptake experiments, the differentiation status of megakaryocyte cultures was assessed by flow cytometry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess SERT and NET (norepinephrine transporter) mRNA expression. On day 10 of differentiation, [3H]serotonin and [125I]MIBG uptake assays were conducted. Part of the samples were co-incubated with the SSRI citalopram to assess SERT-specific uptake. HEK293 cells transfected with SERT, NET, and empty vector served as controls.

Results

In vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG. After 10 days of differentiation, megakaryocytic cell culture batches from three different hematopoietic stem and progenitor cell donors showed on average 9.2 ± 2.4 nmol of MIBG uptake per milligram protein per hour after incubation with 10–7 M MIBG (range: 6.6 ± 1.0 to 11.2 ± 1.0 nmol/mg/h). Co-incubation with the SSRI citalopram led to a significant reduction (30.1%—41.5%) in MIBG uptake, implying SERT-specific uptake of MIBG. A strong correlation between the number of mature megakaryocytes and SERT-specific MIBG uptake was observed.

Conclusion

Our study demonstrates that human megakaryocytes cultured in vitro are capable of MIBG uptake. Moreover, the SSRI citalopram selectively inhibits MIBG uptake via the serotonin transporter. The concomitant administration of citalopram to neuroblastoma patients during [131I]MIBG therapy might be a promising strategy to prevent the onset of thrombocytopenia.
Sulforaphane inhibits self-renewal of lung cancer stem cells through the modulation of sonic Hedgehog signaling pathway and polyhomeotic homolog 3
Authors: Wang Fanping , Sun Yanwei , Huang Xiaoyu , Qiao Caijuan , Zhang Wenrui , Liu Peijun , Wang Mingyong
Published: August 2021

Sulforaphane (SFN), an active compound in cruciferous vegetables, has been characterized by its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. CD133+ cells were isolated with MACs from lung cancer A549 and H460 cells. In this study, we found that SFN inhibited the proliferation of lung cancer cells and self-renewal of lung cancer stem cells simultaneously. Meanwhile, the mRNA and protein expressions of Shh, Smo, Gli1 and PHC3 were highly activated in CD133+ lung cancer cells. Compared with siRNA-control group, Knock-down of Shh inhibited proliferation of CD133+ lung cancer cells, and decreased the protein expression of PHC3 in CD133+ lung cancer cells. Knock-down of PHC3 also affected the proliferation and decreased the Shh expression level in CD133+ lung cancer cells. In addition, SFN inhibited the activities of Shh, Smo, Gli1 and PHC3 in CD133+ lung cancer cells. Furthermore, the inhibitory effect of SFN on the proliferation of siRNA-Shh and siRNA-PHC3 cells was weaker than that on the proliferation of siRNA-control cells. Sonic Hedgehog signaling pathway might undergo a cross-talk with PHC3 in self-renewal of lung cancer stem cells. SFN might be an effective new drug which could inhibit self-renewal of lung cancer stem cells through the modulation of Sonic Hedgehog signaling pathways and PHC3. This study could provide a novel way to improve therapeutic efficacy for lung cancer stem cells.
Idiotype/anti-idiotype antibodies: as a glorious savior in COVID-19 pandemics
Authors: Naveed Ahsan , Naz Deeba , Rahman Sajjad ur
Published: August 2021

The idiotype network is experimentally modified to provide protective immunity against various microbial pathogens. Both internal and non-internal image-idiotype antibodies can trigger specific immune responses to antigens. The current outbreak of Severe Acute Respiratory Syndrome 2 (SARS-2) has provided a great opportunity to take advantage of idiotype / anti-idiotype antibodies as a protective regimen when no approved vaccine is available on earth. The current review identifies successful applications of idiotype/ anti-idiotype antibodies in various viral diseases and highlights their importance in COVID-19 pandemics. In the absence of vaccines and targeted therapies, polyclonal idiotype/ anti-idiotype antibodies against the viral structure may be a potential approach to the prevention and treatment of COVID-19 patients.
Transfer Student Experiences and Identity Navigation in STEM: Overlapping Figured Worlds of Success
Authors: Zuckerman Austin L. , Lo Stanley M.
Published: August 2021

Successful transitions from community colleges to the university setting are essential for increasing the number of transfer students who complete science, technology, engineering, and mathematics (STEM) degree programs. In this study, Holland’s framework of figured worlds was used to examine how transfer students pursuing STEM negotiated their identities in their transition to the university.
How to unloop a self-adherent sheet
Authors: Wilting Twan J. S. , Essink Martin H. , Gelderblom Hanneke , Snoeijer Jacco H.
Published: August 2021

The mechanics of adherent sheets is central to applications ranging from patching a band aid, coating technology, to the breakthrough discovery of peeling graphene flakes using sticky tape. These processes are often hindered by the formation of blisters and loops, which are notoriously difficult to remove. Here we describe and explain a remarkable phenomenon that arises when one attempts to remove a loop in a self-adherent sheet that is formed by, e.g., folding two adhesive sides of a tape together. One would expect the loop to simply unloop when pulling on its free ends. Surprisingly, however, the loop does not immediately open up but shrinks in size, held together by a tenuous contact region that propagates along the tape. This adhesive contact region only ruptures once the loop is reduced to a critical size. We experimentally show that the loop-shrinkage results from an interaction between the peeling front and the loop, across the contact zone. This new type of interaction falls outside the realm of the classical elastica theory and is responsible for a highly nonlinear increase in the peeling force. Our results reveal and quantify the increased force required to remove loops in self-adherent media, which is of importance for blister removal and exfoliation of graphene sheets.
Tbx4 function during hindlimb development reveals a novel mechanism to explain the origins of proximal limb defects
Authors: Duboc Veronique , Sulaiman Fatima , Feneck Eleanor , Kucharska Anna , Bell Donald , Holder-Espinasse Muriel , Logan Malcolm P.O.
Published: August 2021

We dissect genetically a gene regulatory network, including the transcription factors Tbx4, Pitx1 and Isl1 that act cooperatively to establish the hindlimb bud and identify key differences in the pathways that initiate formation of the hindlimb and forelimb. Using live image analysis of limb mesenchyme cells undergoing chondrogenesis in micromass culture, we distinguish a series of changes in cellular behaviours and cohesiveness that are required for chondrogenic precursors to undergo differentiation. Furthermore, we provide evidence that the proximal hindlimb defects in the Tbx4 mutant result from a failure in the early differentiation step of chondroprogenitors into chondrocytes, providing a novel explanation for the origins of proximally-biased limb defects.
Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice
Authors: Bohnert Bernhard N. , Gonzalez-Menendez Irene , Dörffel Thomas , Schneider Jonas C. , Xiao Mengyun , Janessa Andrea , Kalo M. Zaher , Fehrenbacher Birgit , Schaller Martin , Casadei Nicolas , Amann Kerstin , Daniel Christoph , Birkenfeld Andreas L. , Grahammer Florian , Izem Lahoucine , Plow Edward F. , Quintanilla-Martinez Leticia , Artunc Ferruh
Published: August 2021

Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the Prkdc gene in C57BL/6 (PrkdcC6418/C6418) and 129S1/SvImJ (PrkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with PrkdcT6418/T6418 developed proteinuria. Genetic deficiency of Plg (Plg−/−) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of Plg in Plg+/+ mice after doxorubicin injection involving histone H2B as Plg receptor. In doxorubicin-resistant C57BL/6 mice, Plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two-hit process requiring the C6418T SNP in the Prkdc gene and subsequent glomerular binding of Plg.

This article has an associated First Person interview with the first author of the paper.
Environmental Uncertainty as a Moderator of Entrepreneurship Orientation and Innovation Capability during the Pandemic: A Case of Written Batik SMEs in Yogyakarta
Authors: Utomo Humam Santosa , Susanta Susanta
Published: August 2021

Background:Written batik is one of Indonesia's cultural heritages that must be preserved. During the Covid-19 pandemic, written batik producers in Indonesia experienced increasing challenges due to the uncertainty of the business environment. Innovation is a solution to the problems faced by SMEs during a pandemic to survive. This study aims to examine the effect of entrepreneurship orientation on innovation capability. This study also examines the role of moderating environmental uncertainty in strengthening the effect of entrepreneurship orientation on innovation capability.

Methods:The research was conducted at the centre of small and medium-sized batik companies Giriloyo, Bantul, Yogyakarta, Indonesia. Respondents of this study were 130 small and medium companies selected by random sampling. The questionnaire is used as a primary data collection tool. WarpPLS has been used to analyze the effect between variables in this study.

Results:Entrepreneurial orientation is an important aspect in improving the innovation capabilities of SMEs. Environmental uncertainty during the COVID-19 pandemic has strengthened the effect of entrepreneurial orientation on innovation capabilities.

Conclusions:The findings of this study indicate that entrepreneurial orientation has a significant effect on innovation capabilities. Environmental uncertainty significantly strengthens the effect of entrepreneurship orientation on innovation capability.
Hypoxic preconditioning promotes survival of human adipocyte mesenchymal stem cell via expression of prosurvival and proangiogenic biomarkers
Authors: Suryawan I Gde Rurus , Pikir Budi Susetyo , Rantam Fedik Abdul , Ratri Anudya Kartika , Nugraha Ricardo Adrian
Published: August 2021

Background: Contributing factors for improved survival of human adipocytes mesenchymal stem cells (h-AMSCs) cultured through hypoxia preconditioning, in example apoptosis inhibition involving BCL2 and HSP27 expression, trigger signal expression (VEGF), SCF expression, OCT-4 expression, and CD44+ expression. The objective if this study was to explain the mechanism and role of hypoxic preconditioning and the optimal duration of hypoxic preconditioning exposure to improve survival of h-AMSCs.

Methods: An experimental laboratory explorative study (in vitro) with hypoxic preconditioning in h-AMSCs cultures. This research was conducted through four stages. First, isolation of h-AMSCs culture from adipose tissue of patients. Second, the characterization of h-AMSCs from adipose tissue by phenotype (flowcytometry) through CD44+, CD90+ and CD45-expression before being pre-conditioned for hypoxic treatment. Third, the hypoxic preconditioning in h-AMSCs culture (in vitro) was performed with an oxygen concentration of 1% for 24, 48 and 72 hours. Fourth, observation of survival from h-AMSCs culture was tested on the role of CD44+, VEGF, SCF, OCT-4, BCL2, HSP27 with Flowcytometry and apoptotic inhibition by Tunnel Assay method.

Results: The result of regression test showed that time difference had an effect on VEGF expression (p<0.001;β=-0.482) and hypoxia condition also influenced VEGF expression (p<0.001;β=0.774). The result of path analysis showed that SCF had effect on OCT-4 expression (p<0.001; β=0.985). The regression test results showed that time effects on HSP27 expression (p<0.001; β=0.398) and hypoxia precondition also affects HSP27 expression (p<0.001; β=0.847). Pathway analysis showed that BCL2 expression inhibited apoptosis (p=0.030; β=-0.442) and HSP27 expression also inhibited apoptosis (p<0,001;β=-0.487).

Conclusion: Hypoxic preconditioning of h-AMSC culture has proven to increase the expression of VEGF, SCF, OCT-4, and BCL2 and HSP27. This study demonstrated and explained the existence of a new mechanism of increased h-AMSC survival in cultures with hypoxic preconditioning (O2 1%) via VEGF, SCF, OCT-4, BCL2, and HSP 27.
Continuing Cardiopulmonary Symptoms, Disability, and Financial Toxicity 1 Month After Hospitalization for Third‐Wave COVID‐19: Early Results From a US Nationwide Cohort
Authors: Iwashyna Theodore J , Kamphuis Lee A , Gundel Stephanie J , Hope Aluko A , Jolley Sarah , Admon Andrew J , Caldwell Ellen , Monahan Max L , Hauschildt Katrina , Thompson B Taylor , Hough Catherine L ,   NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network
Published: August 2021

BACKGROUND

Patients discharged after COVID‐19 report ongoing needs.

OBJECTIVES

To measure incident symptoms after COVID‐19 hospitalization.

DESIGN, SETTING, AND PARTICIPANTS

Preplanned early look at 1‐month follow‐up surveys from patients hospitalized August 2020 to January 2021 in NHLBI PETAL Network's Biology and Longitudinal Epidemiology: COVID‐19 Observational (BLUE CORAL) study. English‐ or Spanish‐speaking hospitalized adults without substantial pre‐COVID‐19 disability with a positive molecular test for SARS‐CoV‐2.

RESULTS

Overall, 253 patients were hospitalized for a median of 5 days (interquartile range [IQR], 3‐8), and had a median age of 60 years (IQR, 45‐68). By race/ethnicity, 136 (53.8%) were non‐Hispanic White, 23 (9.1%) were non‐Hispanic Black, and 83 (32.8%) were Hispanic. Most (139 [54.9%]) reported a new or worsened cardiopulmonary symptom, and 16% (n = 39) reported new or increased oxygen use; 213 (84.2%) patients reported not feeling fully back to their pre‐COVID‐19 level of functioning. New limitations in activities of daily living were present in 130 (52.8%) patients. Financial toxicities, including job loss or change (49 [19.8%]), having a loved one take time off (93 [37.8%]), and using up one's savings (58 [23.2%]), were common. Longer lengths of hospital stay were associated with greater odds of 1‐month cardiopulmonary symptoms (adjusted odds ratio [aOR], 1.82 per additional week in the hospital; 95% CI, 1.11‐2.98) and new disability (aOR, 2.06; 95% CI, 1.21‐3.53). There were not uniform demographic patterns of association.

LIMITATIONS

We prioritized patients’ reports of their own incident problems over objective testing.

CONCLUSION

Patients who survived COVID‐19 in the United States during late 2020/early 2021 still faced new burdens 1 month after hospital discharge.
O MOVIMENTO NEGRO CAMINHA, O FEMINISMO NEGRO CAMINHA E O MOVIMENTO DE MULHERES NEGRAS CAMINHA
Authors: Lessa Luciana Falcão
Published: August 2021

O Movimento de Mulheres Negras em Salvador emerge com características interseccionais. Isso quer dizer que essas mulheres se organizam em torno dos principais eixos de opressão: gênero, raça, classe e região, destarte não organizaram um movimento único, mas sim grupos de mulheres em torno de demandas relacionadas a comunidades/bairros. Entretanto, não atuam de forma isolada, esses Grupos e Coletivos dialogam e, ao mesmo tempo, garantem a discussão sobre a condição da mulher negra em todo o território baiano. O movimento de mulheres negras reconhece a importância do Movimento Negro Unificado (MNU) e do Feminismo Negro, mas afirma a sua especificidade ao se configurar como um movimento de base, pautando a opressão sexista e o empoderamento das mulheres negras, associando teoria e luta coletiva.