bluuebunny/crossref_metadata_2025 huggingface dataset:
A subterminal growth zone at arm tip likely underlies life-long indeterminate growth in brittle stars
Authors: Mashanov Vladimir , Whaley Lauren , Davis Kenneth , Heinzeller Thomas , Machado Denis Jacob , Reid Robert W. , Kofsky Janice , Janies Daniel
Published: April 2022

Background

Echinoderms are a phylum of marine invertebrates with close phylogenetic relationships to chordates. Many members of the phylum Echinodermata are capable of extensive post-traumatic regeneration and life-long indeterminate growth. Different from regeneration, the life-long elongation of the main body axis in adult echinoderms has received little attention. The anatomical location and the nature of the dividing progenitor cells contributing to adults’ growth is unknown.

Results

We show that the proliferating cells that drive the life-long growth of adult brittle star arms are mostly localized to the subterminal (second from the tip) arm segment. Each of the major anatomical structures contains dividing progenitors. These structures include: the radial nerve, water-vascular canal, and arm coelomic wall. Some of those proliferating progenitor cells are capable of multiple rounds of cell division. Within the nervous system, the progenitor cells were identified as a subset of radial glial cells that do not express Brn1/2/4, a transcription factor with a conserved role in the neuronal fate specification. In addition to characterizing the growth zone and the nature of the precursor cells, we provide a description of the microanatomy of the four distal-most arm segments contrasting the distal with the proximal segments, which are more mature.

Conclusions

The growth of the adult brittle star arms occurs via proliferation of progenitor cells in the distal segments, which are most abundant in the second segment from the tip. At least some of the progenitors are capable of multiple rounds of cell division. Within the nervous system the dividing cells were identified as Brn1/2/4-negative radial glial cells.
Correlation between quality and geographical origins of Leonuri Herba revealed by the qualitative fingerprint profiling and quantitative determination of chemical components
Authors: Lam Kelly Yinching , Wang Yinghao , Lam Tszking , Ku Chuenfai , Yeung Wingping , Zhao Zhongzhen
Published: April 2022

Background

Leonuri Herba (Yimucao) is a very common Chinese herbs for treating menstrual and maternal diseases for thousands of years in China. However, the herb collected in different origins was easily found in the markets which induce the unstable quality for clinic use. In this study, a comprehensive strategy of using multiple chromatographic analysis and chemometric analysis was firstly investigated for chemical discrimination of Leonuri Herba from different geographical origins.

Methods

UHPLC-QTOF-MS/MS was applied to identify the peaks of Leonuri Herba and chemical fingerprints were established in 30 batches from different geographical origins. Meanwhile, dissimilarities of chemical compositions among different origins were further investigated by principal component analysis and cluster analysis. And a quantitative UHPLC-QTOF-MS/MS approach were established to investigate the potential marker for quality control of Leonuri Herba.

Results

A total of 49 chromatographic peaks of Leonuri Herba were identified by UHPLC-QTOF-MS/MS. Leonuri Herba were classified into four categories, and eight major compounds detected could be used as chemical markers for discrimination. Also, the eight components, including leonurine, 4',5-dihydroxy-7-methoxyflavone, rutin, hyperoside, apigenin, quercetin, kaempferol and salicylic acid, were simultaneously quantified using the extracting ion mode of UHPLC-QTOF-MS/MS.

Conclusion

The current strategy not only clearly expounded the correlation between quality and geographical origins of Leonuri Herba, but also provided a fast, accurate and comprehensive qualitative and quantitative method for assessing the quality of Leonuri Herba.
The national economic burden of rare disease in the United States in 2019
Authors: Yang Grace , Cintina Inna , Pariser Anne , Oehrlein Elisabeth , Sullivan Jamie , Kennedy Annie
Published: April 2022

Background

To provide a comprehensive assessment of the total economic burden of rare diseases (RD) in the United States (U.S.) in 2019. We followed a prevalence-based approach that combined the prevalence of 379 RDs with the per-person direct medical and indirect costs, to derive the national economic burden by patient age and type of RD. To estimate the prevalence and the direct medical cost of RD, we used claims data from three sources: Medicare 5% Standard Analytical File, Transformed Medicaid Statistical Information System, and Optum claims data for the privately insured. To estimate indirect and non-medical cost components, we worked with the rare disease community to design and implement a primary survey.

Results

There were an estimated 15.5 million U.S. children (N = 1,322,886) and adults (N = 14,222,299) with any of the 379 RDs in 2019 with a total economic burden of $997 billion, including a direct medical cost of $449 billion (45%), $437 billion (44%) in indirect costs, $73 billion in non-medical costs (7%), and $38 billion (4%) in healthcare costs not covered by insurance. The top drivers for excess medical costs associated with RD are hospital inpatient care and prescription medication; the top indirect cost categories are labor market productivity losses due to absenteeism, presenteeism, and early retirement.

Conclusions

Our findings highlight the scale of the RD economic burden and call for immediate attention from the scientific communities, policy leaders, and other key stakeholders such as health care providers and employers, to think innovatively and collectively, to identify new ways to help improve the care, management, and treatment of these often-devastating diseases.
Increased COVID-19 mortality rate in rare disease patients: a retrospective cohort study in participants of the Genomics England 100,000 Genomes project
Authors: Zhang Huayu , Thygesen Johan H. , Shi Ting , Gkoutos Georgios V. , Hemingway Harry , Guthrie Bruce , Wu Honghan ,   Genomics England Research Consortium
Published: April 2022

Background

Several common conditions have been widely recognised as risk factors for COVID-19 related death, but risks borne by people with rare diseases are largely unknown. Therefore, we aim to estimate the difference of risk for people with rare diseases comparing to the unaffected.

Method

To estimate the correlation between rare diseases and COVID-19 related death, we performed a retrospective cohort study in Genomics England 100k Genomes participants, who tested positive for Sars-Cov-2 during the first wave (16-03-2020 until 31-July-2020) of COVID-19 pandemic in the UK (n = 283). COVID-19 related mortality rates were calculated in two groups: rare disease patients (n = 158) and unaffected relatives (n = 125). Fisher’s exact test and logistic regression was used for univariable and multivariable analysis, respectively.

Results

People with rare diseases had increased risk of COVID19-related deaths compared to the unaffected relatives (OR [95% CI] = 3.47 [1.21– 12.2]). Although, the effect was insignificant after adjusting for age and number of comorbidities (OR [95% CI] = 1.94 [0.65–5.80]). Neurology and neurodevelopmental diseases was significantly associated with COVID19-related death in both univariable (OR [95% CI] = 4.07 [1.61–10.38]) and multivariable analysis (OR [95% CI] = 4.22 [1.60–11.08]).

Conclusions

Our results showed that rare disease patients, especially ones affected by neurology and neurodevelopmental disorders, in the Genomics England cohort had increased risk of COVID-19 related death during the first wave of the pandemic in UK. The high risk is likely associated with rare diseases themselves, while we cannot rule out possible mediators due to the small sample size. We would like to raise the awareness that rare disease patients may face increased risk for COVID-19 related death. Proper considerations for rare disease patients should be taken when relevant policies (e.g., returning to workplace) are made.
Multidisciplinary care for patients with epidermolysis bullosa from birth to adolescence: experience of one Italian reference center
Authors: Retrosi Chiara , Diociaiuti Andrea , De Ranieri Cristiana , Corbeddu Marialuisa , Carnevale Claudia , Giancristoforo Simona , Marchili Maria Rosaria , Salvatori Guglielmo , Atti Marta Luisa Ciofi degli , El Hachem Maya , Raponi Massimiliano
Published: April 2022

Background

Epidermolysis bullosa (EB) is a disabling and chronic genodermatosis characterized by mucocutaneous fragility with blister formation after minimal trauma. Severity ranges between very mild forms to extremely severe or lethal subtypes. Depending on disease subtypes, blisters may be localized also in larynx, bladder, esophagus, and most frequent disease complications are malnutrition, chronic anemia, osteoporosis, limb contracture and early development of squamous cell carcinomas. EB is classified into four major groups: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB (KEB). No specific treatment is available; however, a multidisciplinary management is mandatory in order to treat the lesions, to prevent complication, and to give a psychological support to the patient and family members.

Objective

To report the experience on a therapeutic education plan of an Italian reference center for epidermolysis bullosa in the last 30 years.

Methods

In our study we included all patients with EB from 1990 to the present, dividing them into three age groups (< 5 years, > 5–12 years and > 12–18 years). The therapeutic plan involved all multidisciplinary team members, since born until adolescence. The multidisciplinary team has been progressively established; the dermatologists act as patient case manager, in collaboration with the pediatrician, endocrinologist, dietician, dentist, plastic surgeon, digestive surgeon, geneticist, psychologist and a dedicated nurse. Other dedicated specialists are involved upon patient needs.

Results

Two hundred fifteen patients have been recruited and followed in our hospital since 1990. One hundred forty patients (65%) are on follow-up, 27 patients (13%) died and only 11 (5%) were lost to follow-up. Our patients manifested the specific complications related to their EB subtype in keeping with the data reported in the literature. Eighteen (8%) patients affected with JEB severe died within the first year of life, 9 patients (5%) died for squamous cell carcinoma in adulthood and were affected with recessive DEB; only 1 patient died for squamous cell carcinoma at the age of 16.

Conclusions

An adequate management of EB patients require a multidisciplinary approach with an educational plan to guarantee an appropriate treatment and to support and accompany patients and their families since birth along life. The dynamic educational plan adopted in our hospital showed good clinical and psychological outcome in our population, allowing adherence to treatment, reducing the frequency of complications and improving life expectancy and quality of life.
Health belief model for empowering parental toothbrushing and sugar intake control in reducing early childhood caries among young children—study protocol for a cluster randomized controlled trial
Authors: Wang Ketian , Lee Gillian Hiu Man , Liu Pei , Gao Xiaoli , Wong Samuel Yeung Shan , Wong May Chun Mei
Published: April 2022

Background

It has been recognized that oral health education for parents is critical for preventing early childhood caries (ECC). Few parents practiced caries prevention procedures for their children in daily life, though. A novel intervention scheme using mobile messages will be developed in this study under the framework of the health belief model (HBM). The objective of the present randomized clinical trial (RCT) is to evaluate the effectiveness of the new scheme in promoting oral health of young children by reducing dental caries.

Methods

This RCT will involve 26–36 child care centers or kindergartens with nursery classes (clusters) located in Hong Kong. A total of 518–628 child-parent dyads (child age 18–30 months) will be recruited and randomly allocated at the cluster level into the test or control group with a 1:1 ratio. For parents in the test group, the intervention will consist of a set of HBM-based text messages sent regularly in 48 weeks. A standard text message will be sent to the parents in the control group in the first week. The primary outcome will be dental caries measured by dmft/dmfs of the children after 2 years (around 4 years of age). The secondary outcomes will be toothbtushing and sugar intake.

Discussion

HBM-based intervention via a low-cost text messaging vehicle may serve as a viable way to empower parents to establish proper oral health behaviors for their children and safeguard the oral health of children in Hong Kong.

Trial registration

ClinicalTrials.govNCT04665219. Registered on 11 December 2020.
Effect of novel training to normalize altered finger force direction post-stroke: study protocol for a double-blind randomized controlled trial
Authors: Seo Na Jin , Kamper Derek G. , Ramakrishnan Viswanathan , Harvey Jillian B. , Finetto Christian , Schranz Christian , Scronce Gabrielle , Coupland Kristen , Howard Keith , Blaschke Jenna , Baker Adam , Meinzer Caitlyn , Velozo Craig A. , Adams Robert J.
Published: April 2022

Background

Functional task performance requires proper control of both movement and force generation in three-dimensional space, especially for the hand. Control of force in three dimensions, however, is not explicitly treated in current physical rehabilitation. To address this gap in treatment, we have developed a tool to provide visual feedback on three-dimensional finger force. Our objective is to examine the effectiveness of training with this tool to restore hand function in stroke survivors.

Methods

Double-blind randomized controlled trial. All participants undergo 18 1-h training sessions to practice generating volitional finger force of various target directions and magnitudes. The experimental group receives feedback on both force direction and magnitude, while the control group receives feedback on force magnitude only. The primary outcome is hand function as measured by the Action Research Arm Test. Other outcomes include the Box and Block Test, Stroke Impact Scale, ability to direct finger force, muscle activation pattern, and qualitative interviews.

Discussion

The protocol for this clinical trial is described in detail. The results of this study will reveal whether explicit training of finger force direction in stroke survivors leads to improved motor control of the hand. This study will also improve the understanding of neuromuscular mechanisms underlying the recovery of hand function.

Trial registration

ClinicalTrials.govNCT03995069. Registered on June 21, 2019
Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial
Authors: Wehmeyer Malte H. , Horvatits Thomas , Buchholz Anika , Krause Linda , Walter Sarah , Zapf Antonia , Lohse Ansgar W. , Kluwe Johannes ,   the STOPPIT-trial group
Published: April 2022

Background

Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication.

Methods

The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021.

Discussion

The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis.

Trial registration

EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). ClinicalTrials.gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).
Evaluations of candidate markers of dihydroartemisinin-piperaquine resistance in Plasmodium falciparum isolates from the China–Myanmar, Thailand–Myanmar, and Thailand–Cambodia borders
Authors: Ye Run , Zhang Yilong , Zhang Dongmei
Published: April 2022

Background

The fast-declining clinical efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) in Cambodia is a warning of the underlying westward dissemination of piperaquine resistance in the Greater Mekong Subregion (GMS). Mutations in the Plasmodium falciparum Kelch 13-propeller (PfK13) and the P. falciparum chloroquine resistance transporter (PfCRT), as well as plasmepsin 2/3 gene amplification, have been discovered as molecular markers for predicting DHA-PPQ treatment failure. Determining whether these genetic variations of P. falciparum are linked to DHA-PPQ resistance is critical, especially along the China–Myanmar (CM) border, where PPQ has been utilized for decades.

Methods

A total of 173 P. falciparum samples of dried blood spots (DBS) were collected along the CM border between 2007 and 2010, the Thailand–Cambodia (TC) border between 2009 and 2013, and the Thailand–Myanmar (TM) border between 2012 and 2014. PCR and sequencing were used to identified PfCRT mutations, while qPCR was used to determine the copy number of plasmepsin 2/3. The prevalence of DHA-PPQ resistance in three locations was investigated using data paired with K13 mutations.

Results

Three fragments of the pfcrt gene were amplified for all 173 samples, and seven SNPs were identified (M74I, N75E/D, K76T, H97L, I218F, A220S, I356L). No new PfCRT mutations conferring resistance to PPQ (T93S, H97Y, F145I, M343L, and G353V) were discovered, except for one mutant I218F identified in the TM border (2.27%, 1/44). Additionally, mutant H97L was found in the TC, TM, and CM borders at 3.57% (1/28), 6.82% (3/44), and 1% (1/101), respectively. A substantial K13 C580Y variant prevalence was found in the TC and TM border, accounting for 64.29% (18/28) and 43.18% (19/44), respectively, while only 1% (1/101) was found in the CM border. The K13 F446I variant was only identified and found to reach a high level (28.71%, 29/101) in the CM border. Furthermore, 10.71% (3/28) of TC isolates and 2.27% (1/44) of TM isolates carried more than one copy of plasmepsin 2/3 and K13 C580Y variant, while no plasmepsin 2/3 amplification was identified in the CM isolates.

Conclusions

Compared with the P. falciparum samples collected from the TC and TM borders, fewer parasites carried plasmepsin 2/3 amplification and novel PfCRT variants, while more parasites carried predominant K13 mutations at position F446I, in the CM border. Clear evidence of DHA-PPQ resistance associated with candidate markers was not found in this border region suggesting a further evaluation of these markers and continuous surveillance is warranted.

Graphical Abstract
Albuminuria but not low eGFR is closely associated with atherosclerosis in patients with type 2 diabetes: an observational study
Authors: Wang Jun-Wei , Ke Jiang-Feng , Zhang Zhi-Hui , Lu Jun-Xi , Li Lian-Xi
Published: April 2022

Background

There is still controversy regarding the associations of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Therefore, it is necessary to explore the correlation between them in T2DM patients.

Methods

We conducted a survey involving 2565 T2DM patients from a single center. The study cohort was classified into three groups based on the levels of albuminuria: normal UAE (UAE < 30 mg/24 h), moderate UAE (UAE between 30 and 299 mg/24 h) and high UAE (UAE ≥ 300 mg/24 h). Additionally, the patients were divided into three separate groups according to eGFR levels, including low eGFR (eGFR < 60 ml/min/1.73 m2), intermediate eGFR (eGFR 60–89 ml/min/1.73 m2) and normal eGFR (eGFR ≥ 90 ml/min/1.73 m2) groups. Atherosclerotic lesions were compared among the three UAE and eGFR groups. Regression analyses were used to assess the associations of atherosclerotic lesions with UAE and eGFR in T2DM.

Results

After controlling for age, sex and diabetes duration, the prevalence of atherosclerotic plaque and stenosis were significantly increased from the normal to high UAE groups (plaque: 72.2%, 78.6% and 87.3%, respectively, p = 0.016 for trend; stenosis: 14.0%, 25.5% and 37.3%, respectively, p < 0.001 for trend). Likewise, the values of carotid intima-media thickness (CIMT) and femoral intima-media thickness (FIMT) were also obviously increased from the normal to high UAE groups (CIMT: p < 0.001 for trend; FIMT: p = 0.001 for trend). Conversely, only the FIMT value was clearly increased from the low to normal eGFR groups (p = 0.001 for trend). Fully adjusted regression analyses revealed that UAE was closely associated with the presence of atherosclerotic plaque (OR 1.20, 95% CI 1.03–1.40, p = 0.020) and stenosis (OR 1.17, 95% CI 1.01–1.35, p = 0.036), and with the values of CIMT (β 0.05, 95% CI 0.01–0.10, p = 0.029) and FIMT (β 0.07, 95% CI 0.03–0.11, p = 0.001) in T2DM patients. However, there was no significant association between eGFR levels and atherosclerotic lesions in T2DM after adjustment for multiple confounding factors.

Conclusions

Overall, albuminuria rather than low eGFR is closely associated with atherosclerotic lesions in T2DM patients. Albuminuria is an independent risk factor for carotid and femoral atherosclerotic lesions in T2DM. Therefore, albuminuria may be a potential early marker to predict the development of atherosclerosis in patients with T2DM.
LINC00114 stimulates growth and glycolysis of esophageal cancer cells by recruiting EZH2 to enhance H3K27me3 of DLC1
Authors: Qin Jianzhang , Li Yishuai , Li Zhe , Qin Xuebo , Zhou Xuetao , Zhang Hao , Li Shujun
Published: April 2022

Objective

LINC00114 could promote the development of colorectal cancer, but its mechanism has been rarely discussed in esophageal cancer (EC). Herein, we explored the molecular mechanism of LINC00114 via mediating enhancer of zeste homolog 2/deleted in liver cancer 1 (EZH2/DLC1) axis in EC.

Methods

LINC00114, EZH2 and DLC1 expression in EC tissues and cells were tested. LINC00114, EZH2 and DLC1 expression were altered in EC cells through transfection with different constructs, and cell proliferation, migration, invasion, apoptosis and glycolysis were subsequently observed. The interaction between LINC00114 and EZH2 and that between EZH2 and DLC1 were explored. Tumor formation was also conducted to confirm the in vitro results.

Results

The expression levels of LINC00114 and EZH2 were elevated while those of DLC1 were reduced in EC. Inhibiting LINC00114 or reducing EZH2 blocked cell proliferation, migration, invasion and glycolysis and induce cell apoptosis in EC. LINC00114 promoted H3K27 trimethylation of DLC1 by recruiting EZH2. Knockdown of DLC1 stimulated cell growth and glycolysis in EC and even mitigated the role of LINC00114 inhibition in EC. In vivo experiment further confirmed the anti-tumor effect of LINC00114 inhibition in EC.

Conclusion

The data indicate that LINC00114 promotes the development of EC by recruiting EZH2 to enhance H3K27me3 of DLC1.
Acute myeloid leukemia causing acute thrombosis of the coronary arteries: a case report
Authors: Ferrel Meganne N. , Ryan John J. , Han Frederick T.
Published: April 2022

Background

This case report demonstrates acute myeloid leukemia causing acute thrombosis of coronary arteries with anterolateral ST elevation myocardial infarction and ventricular tachycardia in an otherwise healthy woman. Few case reports have been documented on patients with concomitant conditions of acute myeloid leukemia and acute myocardial infarction, and it is important to note that prognosis for patients with both is worse than that of either condition. While both conditions together are rare, other non-atherosclerotic causes of acute coronary syndromes are likewise important considerations in the context of myocardial ischemia.

Case presentation

A 59-year-old Caucasian woman with no notable past medical history presented to her primary care provider with 2 weeks of severe fatigue, anorexia, and malaise, associated with chills, night sweats, and myalgias. Peripheral blood smear identified 92% blasts consistent with acute myeloid leukemia and computed tomography identified a right segmental pulmonary embolism and thrombotic infarcts in the spleen, bilateral kidneys, right lung, and liver. Laboratory testing also demonstrated disseminated intravascular coagulopathy. She was admitted to the intensive care unit for treatment and subsequently developed ventricular tachycardia, anterolateral ST segment elevation, acute dysarthria, and nonreactive pupils. Pulseless electrical activity developed with unsuccessful resuscitative measures. The patient died secondary to presumed cerebrovascular and coronary thromboses causing stroke and anterolateral infarct complicated by ventricular tachycardia and pulseless electrical activity.

Conclusion

This case is notable as a case of acute myeloid leukemia causing acute thrombosis of coronary arteries with anterolateral ST elevation myocardial infarction, ventricular tachycardia, and pulseless electrical activity. Prognosis of concomitant acute myeloid leukemia and acute myocardial infarction is poor. Management is challenging due to thrombocytopenia, platelet dysfunction, and systemic coagulopathy, and administration of thrombolytic agents can be fatal. This is an extreme presentation of a case of acute myocardial infarction with disseminated intravascular coagulopathy causing acute coronary thrombosis and sudden death with dramatic electrocardiogram and telemetry findings recorded with rapid progression from normal sinus rhythm to acute myocardial infarction to terminal rhythm.
Challenges to the broad application of allogeneic natural killer cell immunotherapy of cancer
Authors: Kennedy Philippa R. , Felices Martin , Miller Jeffrey S.
Published: April 2022

Natural killer (NK) cells are innate immune cells that recognize malignant cells through a wide array of germline-encoded receptors. Triggering of activating receptors results in cytotoxicity and broad immune system activation. The former is achieved through release of cytotoxic granules and presentation of death receptor ligands, while the latter is mediated by inflammatory cytokines, such as interferon-γ and tumor necrosis factor α. Early success with ex vivo activation of NK cells and adoptive transfer suggest they are a safe therapeutic with promising responses in advanced hematologic malignancies. In particular, adoptive NK cell therapies can serve as a ‘bridge’ to potentially curative allogeneic stem cell transplantation. In addition, strategies are being developed that expand large numbers of cells from limited starting material and mature NK cells from precursors. Together, these make ‘off-the-shelf’ NK cells possible to treat a wide range of cancers. Research efforts have focused on creating a range of tools that increase targeting of therapeutic NK cells toward cancer—from therapeutic antibodies that drive antibody-dependent cellular cytotoxicity, to chimeric antigen receptors. As these novel therapies start to show promise in clinical trials, the field is rapidly moving toward addressing other challenges that limit NK cell therapeutics and the goal to treat solid tumors. This review describes the state of therapeutic NK cell targeting of tumors; discusses the challenges that need to be addressed before NK cells can be applied as a wide-ranging treatment for cancer; and points to some of the innovations that are being developed to surmount these challenges. Suppressive cells in the tumor microenvironment pose a direct threat to therapeutic NK cells, through presentation of inhibitory ligands and secretion of suppressive cytokines and metabolites. The nutrient- and oxygen-starved conditions under which NK cells must function necessitate an understanding of therapeutic NK cell metabolism that is still emerging. Prior to these challenges, NK cells must find their way into and persist in the tumor itself. Finally, the desirability of a ‘single-shot’ NK cell treatment and the problems and benefits of a short-lived rejection-prone NK cellular product are discussed.
Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes
Authors: Yang Shengnan , Liu Peipei , Gao Tingting , Song Dingyun , Zhao Xinyu , Li Yupeng , Wu Jun , Wang Liu , Wang Zai , Hao Jie , Wang Chen , Dai Huaping
Published: April 2022

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration.

Methods

To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations.

Results

IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β.

Conclusion

IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.
Galaxy workflows for fragment-based virtual screening: a case study on the SARS-CoV-2 main protease
Authors: Bray Simon , Dudgeon Tim , Skyner Rachael , Backofen Rolf , Grüning Björn , von Delft Frank
Published: April 2022

We present several workflows for protein-ligand docking and free energy calculation for use in the workflow management system Galaxy. The workflows are composed of several widely used open-source tools, including rDock and GROMACS, and can be executed on public infrastructure using either Galaxy’s graphical interface or the command line. We demonstrate the utility of the workflows by running a high-throughput virtual screening of around 50000 compounds against the SARS-CoV-2 main protease, a system which has been the subject of intense study in the last year.
Characterized source model of the 2013 Lushan earthquake (Mw 6.6) by the empirical Green’s function method
Authors: Wu Hao , Irikura Kojiro , Miyakoshi Ken , Somei Kazuhiro
Published: April 2022

Ground motions near the source area of the mainshock of the 2013 Lushan earthquake (Mw 6.6) in Sichuan Province in China were reproduced using the characterized source model and the empirical Green’s function method (EGFM). The best-fit characterized source model consisted of one strong motion generation area (SMGA) and a background area. The synthesized ground motions of the characterized source model were in fairly good agreement with the observed ground motions in the frequency range from 0.5 to 30.0 Hz at ten strong motion stations. For the 2013 Lushan earthquake (Mw 6.6), both the relationships between the SMGA and the seismic moment, and those between the flat amplitude of the acceleration source spectrum in the short period and the seismic moment almost followed the empirical scaling relationships of inner fault parameters developed for crustal earthquakes. The reasons for the largest peak ground acceleration (PGA) (> 1 g) in the strong-motion observation history of China recorded at the 51BXD strong motion station were investigated from the source and site effects. We found that the directivity effect did not contribute to the largest record by comparing the effect of different positions of the rupture starting point on the synthesized ground motions. The nonlinear effect of shallow layers was negligible, as indicated by the similarity of the earthquake H/V spectral ratios between the mainshock and EGF events. A large shear-wave velocity contrast might not exist in the shallow layers as the station was situated on the slope of a small rock hill. Finally, we agreed with previous studies that the hanging-wall effect and topographic effect might be the reasons for generating the largest record at Station 51BXD.

Graphical Abstract
An assessment of solvent residue contaminants related to cannabis-based products in the South African market
Authors: Viviers Hendrik Jacobus , Petzer Anél , Gordon Richard
Published: April 2022

Organic solvents are used for manufacturing herbal medicines and can be detected as residues of such processing in the final products. It is important for the safety of consumers to control these solvent residues. South African cannabis-based product samples were analysed for solvent residue contaminants as classified by the United States Pharmacopeia (USP), chapter 467. The origin of these samples ranged anywhere from crude extract, product development samples, and market ready final products. Samples were submitted to a contract laboratory over a period of 2 years from 2019 to 2021. To date, no data of this kind exist in South Africa specifically relating to cannabis-based medicinal, recreational, or complementary products. A total of 279 samples were analysed in duplicate by full evaporation headspace gas-chromatography mass-spectrometry and the results are reported in an anonymised format. The results showed an alarming 37% sample solvent residue failure rate with respect to adherence to USP 467 specification. It is important to ensure regulation is enforced to control product quality. The South African public need to be educated about the risks associated with cannabis-based products.
Metasurface with dynamic chiral meta-atoms for spin multiplexing hologram and low observable reflection
Authors: Wang He , Qin Zhe , Huang Lingling , Li Yongfeng , Zhao Ruizhe , Zhou Hongqiang , He Haoyang , Zhang Jieqiu , Qu Shaobo
Published: April 2022

Spin light manipulation based on chiral metasurfaces is a striking hotspot that has intrigued huge attention. Circular dichroism, a unique phenomenon of chiral atoms/molecules, has been regarded as another auxiliary dimension for guiding electromagnetic waves, which has been explored in the field of artificial material sciences yet a challenging issue. Here, a generic strategy based on dynamic chiral meta-atom for revealing strong circular dichroism as well as applicable electromagnetic functionality is proposed in microwave regime. We demonstrate a dynamic metasurface that enables the fully independent holograms reconstruction for one circular polarization or the other at the active operating state. On the other hand, the electromagnetic scattering is realized for lowering observable backward reflection at the passive state. Numerical simulation and experimental verification are conducted to manifest the feasibility. It is expected that the proposed strategy can be applied to broaden the horizon for dynamic chiral meta-devices and may find applications in information encryption, anti-counterfeiting, and other dynamic systems.
Central sensitization and adult attention deficit hyperactivity disorder in medical students with chronic back pain: a cross-sectional study
Authors: Ibrahim Maha E. , Hefny Mohamed A.
Published: April 2022

Background

Chronic back pain is a common health complaint among university students. A subset of chronic back pain patients suffer from increased pain sensitivity, a process termed central sensitization. Chronic pain is also associated with cognitive dysfunction, involving attention, memory, and learning. Those are key features of adult attention deficit hyperactivity disorder. This study aimed to assess the associations between adult attention deficit hyperactivity disorder and central sensitization in students with chronic back pain.

Results

Two hundred twenty-seven students completed the survey, and 90 (39.6%) had back pain for more than 3 months. Students with back pain had significantly higher central sensitization (P<0.01) and higher attention deficit scores (P=0.05). Significant positive correlations were found between scores of the two questionnaires (r= 0.55, P<0.01). Regression analysis adjusted for age and gender showed that higher attention deficit scores were associated with back pain (odd’s ratio:1.025, P=0.05). The odd’s ratio was attenuated after adding central sensitization to the model (odd’s ratio: 0.99, P=0.70).

Conclusions

The findings of this study suggest that attention deficit hyperactivity disorder is associated with elevated central sensitization in patients with chronic back pain. Our results support the hypothesis that central sensitization mediates the effect of attention deficit on back pain.
“It made me feel like a bigger part of the STEM community”: Incorporation of Learning Assistants Enhances Students’ Sense of Belonging in a Large Introductory Biology Course
Authors: Clements Thomas P. , Friedman Katherine L. , Johnson Heather J. , Meier Cole J. , Watkins Jessica , Brockman Amanda J. , Brame Cynthia J.
Published: April 2022

Incorporation of undergraduate learning assistants (LAas) increased students’ sense of belonging in an introductory biology course, promoting engagement, allowing more use of active learning, and reducing feelings of isolation. These findings demonstrate that LAs can contribute to multiple elements of inclusive STEM teaching.
CYP21A2 Gene Expression in a Humanized 21-Hydroxylase Mouse Model Does Not Affect Adrenocortical Morphology and Function
Authors: Schubert Tina , Reisch Nicole , Naumann Ronald , Reichardt Ilka , Landgraf Dana , Quitter Friederike , Thirumalasetty Shamini Ramkumar , Heninger Anne-Kristin , Sarov Mihail , Peitzsch Mirko , Huebner Angela , Koehler Katrin
Published: April 2022

Steroid 21-hydroxylase is an enzyme of the steroid pathway that is involved in the biosynthesis of cortisol and aldosterone by hydroxylation of 17α-hydroxyprogesterone and progesterone at the C21 position. Mutations in CYP21A2, the gene encoding 21-hydroxylase, cause the most frequent form of the autosomal recessive disorder congenital adrenal hyperplasia (CAH). In this study, we generated a humanized 21-hydroxylase mouse model as the first step to the generation of mutant mice with different CAH-causing mutations. We replaced the mouse Cyp21a1 gene with the human CYP21A2 gene using homologous recombination in combination with CRISPR/Cas9 technique. The aim of this study was to characterize the new humanized mouse model. All results described are related to the homozygous animals in comparison with wild-type mice. We show analogous expression patterns of human 21-hydroxylase by the murine promoter and regulatory elements in comparison to murine 21-hydroxylase in wild-type animals. As expected, no Cyp21a1 transcript was detected in homozygous CYP21A2 adrenal glands. Alterations in adrenal gene expression were observed for Cyp11a1, Star, and Cyb11b1. These differences, however, were not pathological. Outward appearance, viability, growth, and fertility were not affected in the humanized CYP21A2 mice. Plasma steroid levels of corticosterone and aldosterone showed no pathological reduction. In addition, adrenal gland morphology and zonation were similar in both the humanized and the wild-type mice. In conclusion, humanized homozygous CYP21A2 mice developed normally and showed no differences in histological analyses, no reduction in adrenal and gonadal gene expression, or in plasma steroids in comparison with wild-type littermates.
A política e a economia do governo Bolsonaro: uma análise sobre a captura do orçamento
Authors: Silva Marcos Fernandes Gonçalves da , Teixeira Marco Antonio Carvalho
Published: April 2022

O objetivo deste artigo é analisar o final do governo Bolsonaro do ponto de vista da capacidade de arbitrar o conflito distributivo e de governar. Para tanto, analisa-se o processo orçamentário 2021/2022. A análise é de economia política e de política. Parte-se do suposto de que o orçamento é a expressão dos conflitos distributivos inerentes à sociedade e de que tais conflitos devem ser arbitrados. Do contrário, haverá perda  de agenda e  descontrole da política fiscal. O artigo descreve como elementos institucionais e estruturais estão por detrás da construção de orçamentos críveis, sustentáveis e efetivos e de seus contrários. Em primeiro lugar, faz-se uma análise de economia política e, por fim, de ciência política. A conclusão é que o processo orçamentário de 2021/2022 é um sintoma da crise de governabilidade, pois há evidências de que não houve arbitragem do conflito distributivo.
Effects of bariatric surgery on renal function and associated factors with bivariate analysis: a cohort study
Authors: Amaro Borborema Bezerra Juliana , Pachu Raia dos Santos Eduardo , Teixeira Brandt Carlos
Published: April 2022

Background: Obesity is a global pandemic, caused by genetic, biological and social factors, increasing the risk of many chronic diseases, including kidney disease. Bariatric surgery can control associated comorbidities and also improve renal function. Thus, the aim of this study was to evaluate the effect of bariatric surgery on renal function and associated factors, through bivariate analysis.

Methods: A cohort, prospective, analytical study was carried out in the Department of surgery and obesity, in Campina Grande - Paraíba, Brazil. Thirty-five obese patients were evaluated in the preoperative period of bariatric surgery and after one year of bariatric surgery. Sociodemographic and anthropometric data were collected, body mass index was calculated, and renal function was estimated through the glomerular filtration rate.

Results: Predominantly female (71.4%) and white (77.1%) patients were observed. Regarding the type of bariatric surgery, most patients (65.7%) underwent the sleeve technique. There was no significant difference between the mean levels of cystatin C pre and post bariatric surgery. There was a significant improvement in the mean glomerular filtration rates in the postoperative period (p=0.09). In further analysis of the association between the variables: type of bariatric surgery, diabetes or hypertension outcomes, no association was observed with the outcome improvement in glomerular filtration rate, without statistical significance, respectively (p = 0.312; p =0.217; p = 0.476). Similarly, there was no statistically significant difference between the variable loss of body mass index, under the effect of bariatric surgery, in relation to the outcome of the glomerular filtration rate (p = 0.904).

Conclusion: After analyzing the association between outcome of glomerular filtration rate and the studied variables, no association was observed between these variables, under the effect of bariatric surgery, with improvement in glomerular filtration rate. Thus, bariatric surgery is associated with improvement of renal function independently.
The efficacy of adjunctive alpha-blockers on ureteroscopy procedure for ureteral stones: a systematic review and meta-analysis
Authors: Serani Sesari Saras , Atmoko Widi , Birowo Ponco , Rasyid Nur
Published: April 2022

Background: Urolithiasis cases are a common condition, and the number is still growing today. The prevalence of urinary tract stones globally currently ranges from 2-20% with a recurrence rate of around 50%. The present study aims to investigate the efficacy of adjunctive alpha-blockers in improving the success rate of ureteroscopy (URS) procedure for urolithiasis.

Methods: We reviewed articles obtained from MEDLINE, CENTRAL, CINAHL, and Elsevier from 14 August to 9 September 2020, comparing alpha-blockers as adjunctive therapy, versus either a placebo or no drug at all, in post-URS urolithiasis patients. There were no restrictions on the type of URS and alpha-blockers given to patients. The quality of studies included was assessed using Cochrane’s Risk of Bias Assessment for Randomized-Controlled Trials.

Results: Forest plot analysis emphasizes the statistically significant difference among the group, where the adjunctive alpha-blocker group had pooled relative risk (RR) of being stone-free, readmitted due to initial URS failure, having an overall complication, having haematuria, getting their ureteral mucous injured, and suffering a colic episode was 1.71 (95% CI, 1.11–1.24), 0.50 (95% CI, 0.25–1.01), 0.41 (95% CI, 0.27–0.61), 0.42 (95% CI, 0.22–0.79), 0.31 (95% CI, 0.13–0.73), and 0.21 (95% CI, 0.06–0.69), respectively.

Conclusions: Alpha blockers minimize the frequency and duration of ureteral contractions, allowing smooth stone expulsion. With this knowledge, it is expected to help clinicians decide the importance of adjunctive alpha-blocker administration.