bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal nicotine exposure was associated with long‐term impact on the cardiovascular system and regulation—Review
Authors: Nordenstam Felicia
Published: May 2021

Aim

The aim of this structured review was to discuss knowledge of nicotine use during pregnancy and long‐term effects on children's cardiovascular function.

Methods

PubMed and MEDLINE were searched for original papers that covered various forms of nicotine exposure during pregnancy and this identified 314 papers published in English from inception of the databases to 1 March 2021. The research focus was prenatal exposure that had long‐term effects on the cardiovascular system. The search was expanded from the reference list of the selected papers, which identified another 17 papers.

Results

The 34 original papers that were included covered 172,696 subjects from foetuses to 19 years of age. Cardiovascular autonomic dysfunction was discussed in 12 of the papers and 16 studies reported on blood pressure. The remaining studies covered structural or functional changes in arterial wall or heart. There were convincing data on autonomic dysfunction and increased blood pressure. Some data were conflicting and problems with misclassification of exposure were evident.

Conclusion

Prenatal nicotine exposure was associated with long‐term developmental changes in the cardiovascular system and regulation. There were no safe periods, doses or nicotine products during pregnancy and women should abstain when planning a pregnancy.
Interferon‐α‐2b aerosol inhalation is associated with improved clinical outcomes in patients with coronavirus disease‐2019
Authors: Yu Jiong , Lu Xuan , Tong Ling , Shi Xiaowei , Ma Jing , Lv Feifei , Wu Jian , Pan Qiaoling , Yang Jinfeng , Cao Hongcui , Li Lanjuan
Published: May 2021

Aims

Type 1 interferon (IFN) is used to treat patients with coronavirus disease‐2019 (COVID‐19) but robust supporting evidence is lacking. We investigated the association between IFN‐α‐2b and the clinical outcomes of patients with COVID‐19.

Methods

A total of 1401 patients were enrolled, with 852 (60.8%) patients receiving 5 000 000 U of IFN‐α‐2b via aerosol inhalation twice daily. The primary outcome was a composite measure consisting of mechanical ventilation, intensive care unit (ICU) admission and death. A subgroup analysis was performed to investigate the impact of the IFN‐α‐2b initiation schedule on symptom onset.

Results

The risk probability for crude endpoints was lower in the IFN‐α‐2b group (3.8%) than in the non‐IFN‐α‐2b group (9.3%, P < .001). After adjusting the confounding factors, IFN‐α‐2b therapy achieved a reduction of 64% in occurrence of endpoint events (hazard ratio, 0.36; 95% confidence interval [CI], 0.21–0.62). In the subgroup analysis, compared with patients who received IFN‐α‐2b treatment 0–2 days after symptom onset, the hazard ratio for endpoints was 2.2 (95% CI, 0.43–11.13) in patients who received the therapy 3–5 days after symptom onset, 5.89 (95% CI, 0.99–35.05) in patients who received the therapy 6–8 days after symptom onset, and remained at a high level thereafter.

Conclusions

IFN‐α‐2b aerosol inhalation therapy may be associated with improved clinical outcomes in patients with COVID‐19, and delayed IFN‐α‐2b intervention was associated with increased probabilities of risk events. Further randomized clinical trials are needed to validate the preliminary findings of this study.
First‐in‐human trial assessing the pharmacokinetic‐pharmacodynamic profile of a novel recombinant human chorionic gonadotropin in healthy women and men of reproductive age
Authors: Broksø Kyhl Lars‐Erik , Hesse Christiane , Larsson Per , Bruzelius Katharina , Mannaerts Bernadette
Published: May 2021

The purpose of this first‐in‐human trial was to examine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel recombinant human chorionic gonadotropin (rhCG; FE 999302, choriogonadotropin beta) to support its clinical development for various therapeutic indications. The single and multiple dose PK of choriogonadotropin beta (CG beta) were evaluated in women and the single dose PK and PD of CG beta were compared to those of CG alfa in men. CG beta was safe and well‐tolerated in all 84 healthy subjects. In women, the area under the curve (AUC) and the peak serum concentration (Cmax) increased approximately dose proportionally following single and multiple doses of CG beta. The apparent clearance (CL/F) was ~ 0.5 L/h, the mean terminal half‐life (t½) ~ 45 h and the apparent distribution volume (Vz/F) ~ 30 L. After single administration in men, the mean AUC was 1.5‐fold greater for CG beta than for CG alfa. Mean Cmax and Vz/F were comparable for the 2 preparations. In accordance with the differences in AUC, the CL/F was lower for CG beta (CL/F 0.5 vs. 0.8 L/h), explained by a longer t½ (47 vs. 32 h). Serum testosterone levels induced by a single dose rhCG reflected the PK profiles with a slight delay, resulting in 59% higher AUC for CG beta. The PK parameters for CG beta were comparable in men and in women. In conclusion, the PK differs between the two rhCG preparations, causing higher exposure and a higher PD response for CG beta, which may require relatively lower therapeutic doses.
Effects of vancomycin‐induced gut microbiome alteration on the pharmacodynamics of metformin in healthy male subjects
Authors: Kim Eunwoo , Kim Andrew Hyoungjin , Lee Yujin , Ji Sang Chun , Cho Joo‐Youn , Yu Kyung‐Sang , Chung Jae‐Yong
Published: May 2021

Metformin is a major treatment for type 2 diabetes. This study was conducted to investigate the impact of gut microbiome dysbiosis on the pharmacokinetics and antihyperglycemic effects of metformin. Healthy adult males aged 19–45 years with no defecation abnormalities were recruited for this 4‐period clinical study: baseline; post‐metformin (i.e., multiple oral doses of 1000 mg metformin on days 1–4); post‐vancomycin (i.e., multiple oral doses of 500 mg vancomycin on days 11–17 inducing gut microbiome changes); and post‐metformin + vancomycin (i.e., multiple oral doses of 1000 mg metformin on days 16–19). In each period, serum glucose and insulin concentrations following an oral glucose tolerance test, fecal samples for gut microbiome composition, and safety data were obtained. Following metformin dosing, plasma and urine samples for pharmacokinetics were collected. Nine subjects completed the study. The pharmacokinetics of metformin remained unchanged, and the antihyperglycemic effect was significantly decreased after vancomycin administration (p value = 0.039), demonstrating the weak relationship between the pharmacokinetics and pharmacodynamics of metformin. Relative abundances of some genus were changed after vancomycin administration, and tended to correlate with the antihyperglycemic effects of metformin (p value = 0.062 for Erysipelatoclostridium; p value = 0.039 for Enterobacter; and p value = 0.086 for Faecalibacterium). Adverse events occurred in all subjects and were resolved without sequelae. In conclusion, a decrease in the antihyperglycemic effect of metformin was observed after concomitant administration with vancomycin, without changes in metformin pharmacokinetics. The antihyperglycemic effect was tended to correlate with the relative abundance of several genus, suggesting that the effect of metformin is partly attributable to the gut microbiome (ClinicalTrials.gov, NCT03809260).
Particle size affects pharmacokinetics of milled oxycodone hydrochloride tablet products following nasal insufflation in nondependent, recreational opioid users
Authors: Raofi Saeid , Kinjo Minori , Sun Dajun , Li Zhichuan , Boyce Heather , Natarajan Karthika , Frost Mitchell , Zhao Liang , Luke Markham , Lionberger Robert , Kelsh Debra , Kim Myong‐Jin
Published: May 2021

This study assessed the impact of product particle sizes (fine: 106–500 µm; coarse: 500–1000 µm) on oxycodone pharmacokinetics (PK) following nasal insufflation of milled oxycodone extended‐release (ER) abuse‐deterrent (AD) tablets using immediate‐release (IR) non‐AD product as reference. Additionally, this study assessed the effects of different excipient to drug ratio (EDR) by comparing two products with fine particle size but different EDRs, again using IR non‐AD as the control. Thirty milligrams of oxycodone were administered in each treatment. Coarsely milled 30 mg ER tablets demonstrated significantly lower maximum plasma concentration (Cmax) and partial areas under the concentration‐time curve (AUCs) than those of the finely milled IR tablets. Finely milled ER tablets demonstrated similar Cmax and partial AUCs but higher total systemic exposures than those of finely milled IR tablets. Finely milled 80 mg ER tablets were bioequivalent to IR tablet on all parameters. The finely milled 30 mg ER tablet was not bioequivalent to the coarsely milled 30 mg ER tablet and had higher values for all parameters. The finely milled 30 mg ER tablets (EDR 6.9) showed no PK differences with finely milled 80 mg ER tablets (EDR 4.9). No serious adverse events were reported. The study demonstrated a significant effect of particle sizes (106–1000 µm) on PK of milled and insufflated oxycodone ER AD tablets. EDR difference did not have any significant effects on the PK of finely milled oxycodone ER AD tablets. Particle size distribution should be considered when nasal AD properties of opioid drug products are investigated during drug development.
Left ventricular outflow tract area after percutaneous transseptal transcatheter mitral valve implantation: A three‐dimensional transesophageal echocardiography study
Authors: Hayashi Atsushi , Ikenaga Hiroki , Nagaura Takafumi , Yoshida Jun , Uno Goki , Rader Florian , Makar Moody , Chakravarty Tarun , Siegel Robert J. , Kar Saibal , Makkar Raj R. , Shiota Takahiro
Published: May 2021

Background

Left ventricular (LV) outflow tract (LVOT) obstruction increases mortality in patients undergoing transcatheter mitral valve implantation (TMVI) in degenerated bioprostheses, annuloplasty rings, and native mitral valves. We aimed to evaluate the LVOT area after TMVI using 3‐dimensional (3D) transesophageal echocardiography (TEE) and to investigate the preprocedural cardiac geometry that affects the LVOT area after TMVI.

Methods

We retrospectively reviewed echocardiography data in 43 patients who had TMVI. A change in pressure gradient across LVOT from before to after TMVI (∆PG) and postprocedure 3D LVOT cross‐sectional area at the level of the most distal portion of the mitral valve stent that was closest to the LV apex were assessed as evidence of LVOT narrowing.

Results

Transcatheter mitral valve implantation with the use of balloon‐expandable valve system was performed for 24 bioprostheses, 7 annuloplasty rings, and 12 native valves. Compared to patients without increase in LVOT gradient (∆PG <10 mm Hg; n = 33), patients with increase in LVOT gradient (∆PG ≥10 mm Hg; n = 10) had smaller LV end‐systolic volume (LVESV), greater LV ejection fraction (LVEF), and smaller aorto‐mitral (AM) angle. The LVOT area at the valve stent distal edge showed strong association with ∆PG (r = −.68, P < .0001). Only a small AM angle was associated with a small LVOT area at the valve stent distal edge on multivariable analysis, independent of LVESV and LVEF.

Conclusion

Small LV size, preserved LVEF, and small AM angle were associated with LVOT narrowing. 3D‐derived AM angle might be independently associated with LVOT narrowing in patients undergoing transcatheter mitral valve‐in‐valve, valve‐in‐ring, and valve‐in‐native valve implantation, independent of LVESV and LVEF.
A novel assay for screening WIP1 phosphatase substrates in nuclear extracts
Authors: Storchova Radka , Burdova Kamila , Palek Matous , Medema René H. , Macurek Libor
Published: May 2021

Upon exposure to genotoxic stress, cells activate DNA damage response (DDR) that coordinates DNA repair with a temporal arrest in the cell cycle progression. DDR is triggered by activation of ataxia telangiectasia mutated/ataxia telangiectasia and Rad3‐related protein kinases that phosphorylate multiple targets including tumor suppressor protein tumor suppressor p53 (p53). In addition, DNA damage can activate parallel stress response pathways [such as mitogen‐activated protein kinase p38 alpha (p38)/MAPK‐activated protein kinase 2 (MK2) kinases] contributing to establishing the cell cycle arrest. Wild‐type p53‐induced phosphatase 1 (WIP1) controls timely inactivation of DDR and is needed for recovery from the G2 checkpoint by counteracting the function of p53. Here, we developed a simple in vitro assay for testing WIP1 substrates in nuclear extracts. Whereas we did not detect any activity of WIP1 toward p38/MK2, we confirmed p53 as a substrate of WIP1. Inhibition or inactivation of WIP1 in U2OS cells increased phosphorylation of p53 at S15 and potentiated its acetylation at K382. Further, we identified Deleted in breast cancer gene 1 (DBC1) as a new substrate of WIP1 but surprisingly, depletion of DBC1 did not interfere with the ability of WIP1 to regulate p53 acetylation. Instead, we have found that WIP1 activity suppresses p53‐K382 acetylation by inhibiting the interaction between p53 and the acetyltransferase p300. Newly established phosphatase assay allows an easy comparison of WIP1 ability to dephosphorylate various proteins and thus contributes to identification of its physiological substrates.
Oxalic extraction of high methoxyl pectin and its application as a stabiliser
Authors: Huang Ying‐Xing , Qi Jun‐Ru , Liao Jin‐song , Jiang Wen‐Xin , Cao Yong , Xiao Jie , Yang Xiao‐Quan
Published: May 2021

The objective of this work was to extract high methoxyl (HM) pectin with oxalic acid, characterise its physicochemical properties and evaluate its dispersion stability in acidified milk drink (AMD). HPSEC–MALLS analysis revealed that the obtained HM pectin was high in molecular weight (522.4 kDa). The ζ‐potential of the obtained HM pectin in aqueous solution at pH 4.0 was −31.5 mV. The AFM images proved that the obtained HM pectin contained several long linear molecules. The apparent diameter of AMD stabilised by the obtained HM pectin was 636 nm at the concentration of 3.0‰. The stability analysis of AMD and the microscopic observation with confocal laser scanning microscopy (CLSM) proved that the obtained HM pectin was a prominent stabiliser in AMD.
Glass forming region and bonding mechanism of low‐melting V2O5–TeO2–Bi2O3 glass applied in vacuum glazing sealing
Authors: Li Hong , Yu Haotian , Chen Peng , Yue Yi , Cao Xin , Shi Lifen , Li Changqing , Xiong Dehua
Published: May 2021

As a new kind of energy‐saving glass, vacuum glazing has excellent thermal and sound insulation properties and is widely used in building, household appliances and solar photovoltaic. The edge sealing material, along with sealing method, is key to the fabrication of vacuum glazing. Low transition temperature (Tg) and good fluidity at sealing temperature (Ts) make low‐melting glass of V2O5–TeO2–Bi2O3 (VTB) system perfect to be the edge sealing material for vacuum glazing. The glass forming region of VTB ternary system was mapped for the first time in this work. Low‐melting VTB glass of 40V2O5–50TeO2–5Bi2O3–3ZnO–2Na2O (wt%) was optimized to be the sealing material. Glass powder of this composition could be used to seal the edges of vacuum glazing at an extremely low temperature of 360°C. With the assistance of anodic‐bonding method, the bonding strength of vacuum glazing was dramatically enhanced. Vacuum glazing fabricated under the optimized process parameters of 420°C, 600 V, and 60 min possesses a highest bonding strength of 4.31 MPa. Furthermore, anodic‐bonding mechanism of low‐melting VTB glass applied in vacuum glazing sealing has been thoroughly researched.
LjaFGD: Lonicera japonica functional genomics database
Authors: Xiao Qiaoqiao , Li Zhongqiu , Qu Mengmeng , Xu Wenying , Su Zhen , Yang Jiaotong
Published: May 2021

Lonicera japonica Thunb., a traditional Chinese herb, has been used for treating human diseases for thousands of years. Recently, the genome of L. japonica has been decoded, providing valuable information for research into gene function. However, no comprehensive database for gene functional analysis and mining is available for L. japonica. We therefore constructed LjaFGD (www.gzybioinformatics.cn/LjaFGD and bioinformatics.cau.edu.cn/LjaFGD), a database for analyzing and comparing gene function in L. japonica. We constructed a gene co‐expression network based on 77 RNA‐seq samples, and then annotated genes of L. japonica by alignment against protein sequences from public databases. We also introduced several tools for gene functional analysis, including Blast, motif analysis, gene set enrichment analysis, heatmap analysis, and JBrowse. Our co‐expression network revealed that MYB and WRKY transcription factor family genes were co‐expressed with genes encoding key enzymes in the biosynthesis of chlorogenic acid and luteolin in L. japonica. We used flavonol synthase 1 (LjFLS1) as an example to show the reliability and applicability of our database. LjaFGD and its various associated tools will provide researchers with an accessible platform for retrieving functional information on L. japonica genes to further biological discovery.
Paediatric facial paralysis: An overview and insights into management
Authors: Malik Mohammad , Cubitt Jonathan J
Published: May 2021

The aim of this article is to provide an overview on paediatric facial paralysis, looking into aetiology, epidemiology, assessment and investigation and subsequent treatment options available. Facial paralysis describes the inability to activate the muscles of fascial expression. Overall, it affects 2.7 per 100 000 children under 10 years old and 10.1 per 100 000 children over 10 years old each year. There are many causes of facial paralysis and the outcomes and necessary treatments vary depending on the cause. The mainstays of medical management are corticosteroids and facial therapy; however, when the facial palsy persists, facial deformity surgery is an option to improve the facial symmetry, protect vision and recreate dynamic movement.
Freezing stress damage and growth viability in Vaccinium macrocarpon Ait. bud structures
Authors: Villouta Camilo , Workmaster Beth Ann , Atucha Amaya
Published: May 2021

After a freezing event, it can be challenging to extrapolate levels of freezing damage to plant growth viability based on the presence or absence of symptoms in specific bud tissues. This study investigated the relationship between freezing damage in terminal buds during ecodormancy and their viability during the subsequent growing season. We identified the bud structure that best explained this relationship, and developed a model to explain the changes in bud cold hardiness. Vertical shoots (uprights) of Vaccinium macrocarpon Ait. were sampled in central Wisconsin during Spring of 2018 and 2019. Sets of uprights with terminal buds were subjected to controlled freezing tests, followed by either visual freeze damage evaluation or assessment of shoot viability by growth assays. We determined the Browning Lethal‐Temperature50 (BLT50), as temperature for 50% damage (tissue browning) at each bud structure, and Growth Lethal‐Temperature50 (GLT50) temperature where 50% reduction in growth viability occurred. Two models were constructed to explain: (1) bud structure damage and growth viability, and (2) GLT50's seasonal changes, representing the cold hardiness variations, and environmental factors. The correlation between the BLT50 and GLT50 values was closest for the bud scales and bud axis, indicating the better correspondence between levels of freezing damage with the impact on the growth potential. In addition, the latter was also the most suitable candidate for modeling due to easier damage evaluation. The freezing stress damage of the bud axis explained comparatively best the resulting growth viability. Seasonal changes in GLT50 were best explained by temperature indices based on daily minimum and on maximum temperatures over 10‐day periods. However, among the model components, daily maximum temperatures had the greatest influence on V. macrocarpon cold hardiness changes during ecodormancy.
Characterization of the novel HLA‐C*05:01:58 allele by sequencing‐based typing
Authors: Blandin Lucie , Guidicelli Gwendaline , Blouin Laura , Lemal Richard , Rouzaire Paul
Published: May 2021

HLA‐C*05:01:58 differs from HLA‐C*05:01:01:02 by a single nucleotide change in codon 112 in exon 3.
Role of highly sensitive nucleic acid amplification testing for plasma cytomegalovirus DNA load in diagnosis of cytomegalovirus gastrointestinal disease among kidney transplant recipients
Authors: Taksinwarajarn Touchapong , Sobhonslidsuk Abhasnee , Kantachuvesiri Surasak , Thongprayoon Charat , Cheungpasitporn Wisit , Bruminhent Jackrapong ,   the Ramathibodi Transplant Infectious Diseases (RTID) group
Published: May 2021

Background

High plasma cytomegalovirus (CMV) DNA load is generally associated with CMV tissue‐invasive disease in solid organ transplant recipients. However, some tissue‐invasive diseases, especially CMV gastrointestinal (GI) disease, have undetectable to very low plasma CMV DNA loads. Highly sensitive nucleic acid amplification testing (NAAT) has been increasingly used to quantify low‐level CMV DNA loads. Our primary objective was to investigate the epidemiology of CMV GI disease and evaluate the validity of plasma CMV NAAT for the diagnosis of CMV GI disease in kidney transplant (KT) recipients.

Methods

We conducted a retrospective study of all KT recipients who developed CMV GI disease from January 2016 to December 2018. Plasma CMV DNA load was measured using real‐time PCR. The cut‐off value of plasma CMV DNA load for diagnosing and risk factors of CMV GI disease were analyzed.

Results

A total 17 (3.4%) cases of CMV GI disease occurred in 494 KT recipients. Fifteen (88%) patients had CMV D + /R + serostatus. Fourteen (82%) patients developed CMV GI disease within 6 months after KT. Plasma CMV DNA loads were detectable in all (100%) patients with a median load 11,102 (IQR 2,935‐107,160) IU/ml. A plasma CMV DNA load of 4,063 IU/ml was established as al cut‐off for diagnosing CMV GI disease (AUC 0.74, sensitivity 76.5%, specificity 70%, PPV 68, NPV 78). In multivariate analysis, prolonged cold ischemic time (HR 1.14, 95% CI 1.05‐1.23, P = .002) and CMV D + /R ‐ serostatus (HR 9.31, 95% CI 2.12‐40.74, P = .003) were associated with CMV GI disease.

Conclusions

Using highly sensitive NAAT could potentially assist in the diagnosis of CMV GI disease in a CMV D + /R + serostatus setting. KT recipients with CMV seromismatch and prolonged cold ischemic time are at higher risk of CMV GI disease.
A prospective study on COVID‐19 convalescent plasma donor (CCP) recruitment strategies in a resource constrained blood centre
Authors: Biswas Durba , Maiti Chikam , Talukder Biplabendu , Azharuddin Md , Saha Sayantan , Pandey Sumita , Das Arijit , Adhikari Setu Das , Ray Yogiraj , Sarkar Biswanath S. , Paul Sekhar R. , Saha Bibhuti , Paul Sandip , Chatterjee Shilpak , Ganguly Dipyaman , Bhattacharya Prasun
Published: May 2021

Background and Objectives

The COVID‐19 pandemic has spread across 87 million people with more than 1·8 million deaths in the world. As there is no definite treatment modality, the use of convalescent plasma has become increasingly popular worldwide. This study aimed to identify an appropriate strategy of donor recruitment and to evaluate the appropriateness of pre‐set plasma donation guidelines.

Material and Methods

In this prospective study conducted from May to September 2020, the donors were recruited under the following two circumstances: Group I, patients in the post–COVID‐19 follow‐up in the clinic, and Group II, patients recovered from COVID‐19 recruited through mass and electronic media. A pre‐set donor selection criteria and laboratory investigation was designed according to national and international guidelines. Approximately 500 ml of COVID‐19 convalescent plasma (CCP) was collected from recovered individuals in each group by two different cell separators. The overall donor’s attendance rate, deferral rate, adverse events and donor compliance was analysed and compared between the two groups.

Results

There was a significant difference in attendance in relation to registration between the groups (P < 0·0001). Donor deferral was significantly higher in group II compared with group I. The single most frequent cause of donor deferral was low antibody index (P = 0·0001). The total donor adverse event rate in CCP donation was significantly lower compared with routine plateletpheresis procedures. The donor’s compliance to blood centre’s protocol was satisfactory in both the groups.

Conclusion

Recruitment of patients in the post–COVID‐19 follow‐up in the clinic was more effective than the general recruitment through mass and electronic media for convalescence plasma donation in a resource‐constrained blood centre.
Semi-occluded vocal tract exercises in healthy young adults: Articulatory, acoustic, and aerodynamic measurements during phonation at threshold
Authors: Lulich Steven M. , Patel Rita R.
Published: May 2021

Semi-occluded vocal tract exercises (SOVTEs) are increasingly popular as therapeutic exercises for patients with voice disorders. This popularity is reflected in the growing research literature, investigating the scientific principles underlying SOVTEs and their practical efficacy. This study examines several acoustic, articulatory, and aerodynamic variables before, during, and after short-duration (15 s) SOVTEs with a narrow tube in air. Participants were 20 healthy young adults, and all variables were measured at threshold phonation levels. Acoustic variables were measured with a microphone and a neck accelerometer, and include fundamental frequency, glottal open quotient, and vocal efficiency. Articulatory variables were measured with ultrasound, and include measures of the tongue tip, tongue dorsum, and posterior tongue height, and horizontal tongue length. Aerodynamic variables were measured with an intraoral pressure transducer and include subglottal, intraoral, and transglottal pressures. Lowering of the posterior tongue height and tongue dorsum height were observed with gender-specific small changes in the fundamental frequency, but there were no significant effects on the transglottal pressure or vocal efficiency. These findings suggest that the voices of healthy young adults already approach optimal performance, and the continued search for scientific evidence supporting SOVTEs should focus on populations with voice disorders.
Do coronavirus genes slip into human chromosomes?
Authors: Cohen Jon
Published: May 2021

Further evidence supports challenged claim, but significance remains unclear.
A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements
Authors: Fish Lisa , Khoroshkin Matvei , Navickas Albertas , Garcia Kristle , Culbertson Bruce , Hänisch Benjamin , Zhang Steven , Nguyen Hoang C. B. , Soto Larisa M. , Dermit Maria , Mardakheh Faraz K. , Molina Henrik , Alarcón Claudio , Najafabadi Hamed S. , Goodarzi Hani
Published: May 2021

Characterizing a cancer spliceosome

Cells undergo many genomic changes as they progress toward metastatic cancer. One aspect of this change is to RNA expression and splicing isoforms, but how these differences affect tumor progression is not well characterized. Fish
et al.
developed a computational framework called pyTEISER that identifies structural cis-regulatory elements that control diverse types of RNA regulation. Applying pyTEISER to models of breast cancer metastasis, they discovered an RNA short-stem-loop element that forms a “structural splicing enhancer” that acts in cis to regulate alternative splicing of RNA transcripts. One of these interactions encompasses the RNA-binding protein SNRPA1 and results in alternative exon inclusion that affects metastatic capacity in xenograft models. Thus, RNA element binding may play a role in splicing regulation and is potentially an important component of the cis-splicing code.

Science
, this issue p.
eabc7531
Very weak bonds to artificial atoms formed by quantum corrals
Authors: Stilp Fabian , Bereczuk Andreas , Berwanger Julian , Mundigl Nadine , Richter Klaus , Giessibl Franz J.
Published: May 2021

Bonding to a quantum corral

Chemical bonds generally form between electronic states of atoms; in principle, other electronic states could also form bonds. Stilp
et al.
found that the electronic states created within quantum corrals, large rings of iron atoms on a copper surface, can form chemical bonds with metal atoms on an atomic force microscope tip. The corral states form from many electrons but have a large spatial extent compared with an atomic orbital. The covalent bond to a 48-atom corral state had an energy of just 5 millielectron volts.

Science
, abe2600, this issue p.
1196
A cell type–specific cortico-subcortical brain circuit for investigatory and novelty-seeking behavior
Authors: Ahmadlou Mehran , Houba Janou H. W. , van Vierbergen Jacqueline F. M. , Giannouli Maria , Gimenez Geoffrey-Alexander , van Weeghel Christiaan , Darbanfouladi Maryam , Shirazi Maryam Yasamin , Dziubek Julia , Kacem Mejdy , de Winter Fred , Heimel J. Alexander
Published: May 2021

A brain circuit that drives and gates curiosity

Curiosity is what drives organisms to investigate each other and their environment. It is considered by many to be as intrinsic as hunger and thirst, but the neurobiological mechanisms behind curiosity have remained elusive. In mice, Ahmadlou
et al.
found that a specific population of genetically identified γ-aminobutyric acid (GABA)—ergic neurons in a brain region called the zona incerta receive excitatory input in the form of novelty and/or arousal information from the prelimbic cortex, and these neurons send inhibitory projections to the periaqueductal gray region (see the Perspective by Farahbakhsh and Siciliano). This circuitry is necessary for the exploration of new objects and conspecifics.

Science
, this issue p.
eabe9681
; see also p.
684
A paradigm shift to combat indoor respiratory infection
Authors: Morawska Lidia , Allen Joseph , Bahnfleth William , Bluyssen Philomena M. , Boerstra Atze , Buonanno Giorgio , Cao Junji , Dancer Stephanie J. , Floto Andres , Franchimon Francesco , Greenhalgh Trisha , Haworth Charles , Hogeling Jaap , Isaxon Christina , Jimenez Jose L. , Kurnitski Jarek , Li Yuguo , Loomans Marcel , Marks Guy , Marr Linsey C. , Mazzarella Livio , Melikov Arsen Krikor , Miller Shelly , Milton Donald K. , Nazaroff William , Nielsen Peter V. , Noakes Catherine , Peccia Jordan , Prather Kim , Querol Xavier , Sekhar Chandra , Seppänen Olli , Tanabe Shin-ichi , Tang Julian W. , Tellier Raymond , Tham Kwok Wai , Wargocki Pawel , Wierzbicka Aneta , Yao Maosheng
Published: May 2021

Building ventilation systems must get much better
The hunt for habitable planets gets a new tool
The Hunt for Planet B
Nathaniel Kahn, director
Crazy Boat Pictures, 2021. 93 min.
Authors: Rugheimer Sarah
Published: May 2021

A new documentary captures the lead-up to the long-awaited launch of the James Webb telescope
River basins on the edge of change
Authors: Tauro Flavia
Published: May 2021

Water scarcity after the Millennium Drought reveals the finite resilience of water systems
Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection
Authors: Ma Lina , Sahu Sanjaya K. , Cano Marlene , Kuppuswamy Vasanthan , Bajwa Jamal , McPhatter Ja’Nia , Pine Alexander , Meizlish Matthew L. , Goshua George , Chang C. Hong , Zhang Hanming , Price Christina , Bahel Parveen , Rinder Henry , Lei Tingting , Day Aaron , Reynolds Daniel , Wu Xiaobo , Schriefer Rebecca , Rauseo Adriana M. , Goss Charles W. , O’Halloran Jane A. , Presti Rachel M. , Kim Alfred H. , Gelman Andrew E. , Dela Cruz Charles S. , Lee Alfred I. , Mudd Philip A. , Chun Hyung J. , Atkinson John P. , Kulkarni Hrishikesh S.
Published: May 2021

Increased complement activation is observed in COVID-19 compared with non-COVID respiratory illness and is a key marker of organ failure.
Parsimonious Mechanistic Modeling of Bacterial Runoff into Irrigation Ponds To Inform Food Safety Management of Agricultural Water Quality
Authors: Vazquez Kathleen M. , Muñoz-Carpena Rafael , Danyluk Michelle D. , Havelaar Arie H.
Published: May 2021

Preventive management of agricultural waters requires understanding of the drivers of bacterial contamination events. We propose mechanistic modeling as a way forward to understand and predict such events and have developed and tested a parsimonious model for rain-driven surface runoff contributing to generic
Escherichia coli
contamination of irrigation ponds in Central Florida.
Sinorhizobium medicae
WSM419 Genes That Improve Symbiosis between
Sinorhizobium meliloti
Rm1021 and
Medicago truncatula
Jemalong A17 and in Other Symbiosis Systems
Authors: Ghosh Prithwi , Adolphsen Katie N. , Yurgel Svetlana N. , Kahn Michael L.
Published: May 2021

The legume symbiosis with rhizobia is highly specific. Rhizobia that can nodulate and fix nitrogen on one legume species are often unable to associate with a different species.
Mechanism through Which Retrocyclin Targets Flavivirus Multiplication
Authors: Jia Xiaoying , Guo Jiao , Yuan Weirong , Sun Lingling , Liu Yang , Zhou Minmin , Xiao Gengfu , Lu Wuyuan , Garzino-Demo Alfredo , Wang Wei
Published: May 2021

Retrocyclin is an artificially humanized circular θ-defensin peptide, containing 18 residues, previously reported to possess broad antimicrobial activity. In this study, we found that retrocyclin-101 inhibited flavivirus (ZIKV and JEV) infections. Retrocyclin-101 inhibited NS2B-NS3 serine protease activity, suggesting that the catalytic triad of the protease is the target. Moreover, retrocyclin-101 bound to the DE loop of the E protein of flavivirus, which prevented its entry.
The gender and geography of publishing: a review of sex/gender reporting and author representation in leading general medical and global health journals
Authors: Merriman Rebekah , Galizia Ilaria , Tanaka Sonja , Sheffel Ashley , Buse Kent , Hawkes Sarah
Published: May 2021

Introduction

Diverse gender and geographical representation matters in research. We aimed to review medical and global health journals’ sex/gender reporting, and the gender and geography of authorship.

Methods

542 research and non-research articles from 14 selected journals were reviewed using a retrospective survey design. Paper screening and systematic data extraction was conducted with descriptive statistics and regression analyses calculated from the coded data. Outcome measures were journal characteristics, the extent to which published articles met sex/gender reporting guidelines, plus author gender and location of their affiliated institution.

Results

Five of the fourteen journals explicitly encourage sex/gender analysis in their author instructions, but this did not lead to increased sex/gender reporting beyond the gender of study participants (OR=3.69; p=0.000 (CI 1.79 to 7.60)). Just over half of research articles presented some level of sex/gender analysis, while 40% mentioned sex/gender in their discussion. Articles with women first and last authors were 2.4 times more likely to discuss sex/gender than articles with men in those positions (p=0.035 (CI 1.062 to 5.348)). First and last authors from high-income countries (HICs) were 19 times as prevalent as authors from low-income countries; and women from low-income and middle-income countries were at a disadvantage in terms of the impact factor of the journals they published in.

Conclusion

Global health and medical research fails to consistently apply a sex/gender lens and remains largely the preserve of authors in HIC. Collaborative partnerships and funding support are needed to promote gender-sensitive research and dismantle historical power dynamics in authorship.
Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation
Authors: Zhou Shujuan , Meng Fanyan , Du Shiyao , Qian Hanqing , Ding Naiqing , Sha Huizi , Zhu Mei , Yu Xiaoxiao , Wang Lifeng , Liu Baorui , Wei Jia
Published: May 2021

Background

Poor infiltration and limited activation of transferred T cells are fundamental factors impeding the development of adoptive cell immunotherapy in solid tumors. A tumor-penetrating peptide iRGD has been widely used to deliver drugs deep into tumor tissues. CD3-targeting bispecific antibodies represent a promising immunotherapy which recruits and activates T cells.

Methods

T-cell penetration was demonstrated in tumor spheroids using confocal microscope, and in xenografted tumors by histology and in vivo real-time fluorescence imaging. Activation and cytotoxicity of T cells were assessed by flow cytometry and confocal microscope. Bioluminescence imaging was used to evaluate in vivo antitumor effects, and transmission electron microscopy was used for mechanistic studies.

Results

We generated a novel bifunctional agent iRGD-anti-CD3 which could immobilize iRGD on the surface of T cells through CD3 engaging. We found that iRGD-anti-CD3 modification not only facilitated T-cell infiltration in 3D tumor spheroids and xenografted tumor nodules but also induced T-cell activation and cytotoxicity against target cancer cells. T cells modified with iRGD-anti-CD3 significantly inhibited tumor growth and prolonged survival in several xenograft mouse models, which was further enhanced by the combination of programmed cell death protein 1 (PD-1) blockade. Mechanistic studies revealed that iRGD-anti-CD3 initiated a transport pathway called vesiculovacuolar organelles in the endothelial cytoplasm to promote T-cell extravasation.

Conclusion

Altogether, we show that iRGD-anti-CD3 modification is an innovative and bifunctional strategy to overcome major bottlenecks in adoptive cell therapy. Moreover, we demonstrate that combination with PD-1 blockade can further improve antitumor efficacy of iRGD-anti-CD3-modified T cells.
Visual hallucinations
Authors: Weil Rimona S , Lees A J
Published: May 2021

Visual hallucinations have intrigued neurologists and physicians for generations due to patients’ vivid and fascinating descriptions. They are most commonly associated with Parkinson’s disease and dementia with Lewy bodies, but also occur in people with visual loss, where they are known as Charles Bonnet syndrome. More rarely, they can develop in other neurological conditions, such as thalamic or midbrain lesions, when they are known as peduncular hallucinosis. This review considers the mechanisms underlying visual hallucinations across diagnoses, including visual loss, network dysfunction across the brain and changes in neurotransmitters. We propose a framework to explain why visual hallucinations occur most commonly in Parkinson’s disease and dementia with Lewy bodies, and discuss treatment approaches to visual hallucinations in these conditions.
The Hamiltonian of f(R) gravity
Authors: Abdelmohssin Faisal A.Y. , El Mekki Osman M.H.
Published: May 2021

We derive conjugate momenta variable tensors and the Hamiltonian equation of the source-free f(R) gravity from first principles using the Legendre transformation of these conjugate momenta variable tensors, conjugate coordinates variables — fundamental metric tensor and its first ordinary partial derivatives with respect to space–time coordinates and second ordinary partial derivatives with respect to space–time coordinates — and the Lagrangian of the f(R) gravity. Interpreting the derived Hamiltonian as the energy of the f(R) gravity we have shown that it vanishes for linear Lagrangians in Ricci scalar curvature without source (e.g., Einstein–Hilbert Lagrangian without matter fields), which is the same result obtained using the stress–energy tensor equation derived from variation of the matter field Lagrangian density. The resulting Hamiltonian equation forbids any negative power law model in the dependence of the f(R) gravity on Ricci scalar curvature: f(R) = αR–r, where r and α are positive real numbers; it also forbids any polynomial equation that contains terms with negative powers of the Ricci scalar curvature including a constant term, in which cases the Hamiltonian function in the Ricci scalar and therefore the energy of the f(R) gravity would attain a negative value and would not be bounded from below. The restrictions imposed by the non-negative Hamiltonian have far-reaching consequences as a result of applying f(R) gravity to the study of black holes and the Friedmann–Lemaître–Robertson–Walker model in cosmology.
Chemical and molecular scale speciation of copper, zinc, and boron in agricultural soils of the Canadian prairies
Authors: Rahman Noabur , Hangs Ryan , Peak Derek , Schoenau Jeff
Published: May 2021

The general incidence of copper (Cu), zinc (Zn), and boron (B) deficiencies in soils of the Canadian prairies may be related to identifiable, highly variable, inherent soil attributes. The objective of this study was to investigate the variability of selected properties and their relationship with the bioavailability, forms, and distribution of Cu, Zn, and B in a range of prairie soils. The nature of these micronutrient distributions were evaluated by measuring extractable concentrations, supply rates, and by separation into various chemical pools through sequential extraction and spectroscopic speciation analyses. Soil pH was found to be the least variable property [coefficient of variation (CV) < 13%], whereas carbonate content was the most variable (CV > 130%). The Cu and B availability showed strong negative correlation with the sand content in all soils. Path coefficient results indicated that organic carbon had the highest positive direct effect on availability and supply of Cu and B in Grey soils. Extractable Zn was positively correlated with organic carbon content of Brown and Dark Brown soils. Overall, high sand content and low organic matter were identified as important soil properties contributing to the deficiency of Cu, Zn, and B. The major proportion of Cu, Zn, and B was found in the recalcitrant residual fraction (59%–88%), with the smallest proportions in labile soluble, exchangeable forms (2%–8%). The X-ray absorption near edge structure revealed that Cu and Zn associated with carbonate minerals were dominant forms of these micronutrients present in all soils. Chemisorption is likely a major process regulating the bioavailability of Cu and Zn in prairie soils.
“Reconciliation” in undergraduate education in Canada: the application of Indigenous knowledge in conservation
Authors: Littlechild Danika Billie , Finegan Chance , McGregor Deborah
Published: May 2021

Both the Truth and Reconciliation Commission (TRC) and the National Inquiry into Missing and Murdered Indigenous Women and Girls (MMIWG) explicitly emphasized the role of educators in “reconciliation.” Alongside this, conservation practitioners are increasingly interacting with Indigenous Peoples in various ways, such as in the creation and support of Indigenous protected areas and (or) guardian programs. This paper considers how faculty teaching aspiring conservation practitioners can respond appropriately to the TRC and MMIWG Inquiry while preparing students to engage with Indigenous Peoples in a way that affirms, rather than questions Indigenous knowledge and aspirations. Our argument is threefold: first, teaching Indigenous content requires an approach grounded in transformational change, not one focused on an “add Indigenous and stir” pedagogy. Second, we assert that students need to know how to ethically engage with Indigenous Peoples more than they need knowledge of discreet facts. Finally, efforts to “Indigenize” the academy requires an emphasis on anti-racism, humility, reciprocity, and a willingness to confront ongoing colonialism and white supremacy. This paper thus focuses on the broad change that must occur within universities to adequately prepare students to build and maintain reconciliatory relationships with Indigenous Peoples.
Optimal collection of radiation emitted by a trapped atomic ensemble
Authors: Kurkó Árpád , Domokos Peter , Vukics András , Bækkegaard Thomas , Zinner Nikolaj Thomas , Fortágh József , Petrosyan David
Published: May 2021

Trapped atomic ensembles are convenient systems for quantum information storage in the long-lived sublevels of the electronic ground state and its conversion to propagating optical photons via stimulated Raman processes. Here we investigate a phase-matched emission of photons from a coherently prepared atomic ensemble. We consider an ensemble of cold atoms in an elongated harmonic trap with normal density distribution, and determine the parameters of paraxial optics to match the mode geometry of the emitted radiation and optimally collect it into an optical waveguide.
Time Measurement and Control Blocks for Bare-Metal C++ Applications
Authors: Bruns Friederike , Yarza Irune , Ittershagen Philipp , Grüttner Kim
Published: May 2021

Precisely timed execution of resource constrained bare-metal applications is difficult, because the embedded software developer usually has to implement and check the timeliness of the executed application through manual interaction with timers or counters. In the scope of this work, we propose a combined timing specification and concept for time annotation and control blocks in C++. Our proposed blocks can be used to measure and profile software block execution time. Furthermore, it can be used to control and enforce the software time behavior at runtime. After the application of these time blocks, a trace-based verification against the block-based timing specification can be performed to obtain evidence on the correct implementation and usage of the time blocks on the target platform. We have implemented our time block concept in a C++ library and tested it on an ARM Cortex A9 bare-metal platform. The combined usage of timing specification and our time block library has been successfully evaluated on a critical flight-control software for a multi-rotor system.
Event-B Hybridation
Authors: Dupont Guillaume , Ait-Ameur Yamine , Singh Neeraj Kumar , Pantel Marc
Published: May 2021

Hybrid systems are complex systems where a software controller interacts with a physical environment, usually named a plant, through sensors and actuators. The specification and design of such systems usually rely on the description of both continuous and discrete behaviours. From complex embedded systems to autonomous vehicles, these systems became quite common, including in safety critical domains. However, their formal verification and validation as a whole is still a challenge.

To address this challenge, this article contributes to the definition of a reusable and tool supported formal framework handling the design and verification of hybrid system models that integrate both discrete (the controller part) and continuous (the plant part) behaviours. This framework includes the development of a process for defining a class of basic theories and developing domain theories and then the use of these theories to develop a generic model and system-specific models. To realise this framework, we present a formal proof tool chain, based on the Event-B correct-by-construction method and its integrated development environment Rodin, to develop a set of theories, a generic model, proof processes, and the required properties for designing hybrid systems in Event-B.

Our approach relies on hybrid automata as basic models for such systems. Discrete and continuous variables model system states and behaviours are given using discrete state changes and continuous evolution following a differential equation. The proposed approach is based on refinement and proof using the Event-B method and the Rodin toolset. Two case studies borrowed from the literature are used to illustrate our approach. An assessment of the proposed approach is provided for evaluating its extensibility, effectiveness, scalability, and usability.