bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust group sequential designs for trials with survival endpoints and delayed response
Authors: Ghosh Pranab , Ristl Robin , König Franz , Posch Martin , Jennison Christopher , Götte Heiko , Schüler Armin , Mehta Cyrus
Published: December 2021

Randomized clinical trials in oncology typically utilize time‐to‐event endpoints such as progression‐free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log‐rank test. The power of the log‐rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log‐rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel‐T for metastatic hormone‐refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall‐cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log‐rank test may not be optimal for testing immuno‐oncology drugs in randomized clinical trials. Moreover, the new immuno‐oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max‐combo test, which utilizes the maximum of two weighted log‐rank statistics, as a robust alternative to the log‐rank test. The new test is implemented for two‐stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max‐combo test: the Fleming and Harrington (1981) weights and the Magirr and Burman (2019) modest  weights.
Loss of a newly discovered microRNA in Chinese hamster ovary cells leads to upregulation of N‐glycolylneuraminic acid sialylation on monoclonal antibodies
Authors: Fischer Simon , Mathias Sven , Stadermann Anna , Yang Shumin , Schmieder Valerie , Zeh Nikolas , Schmidt Nicoletta , Richter Patrick , Wright Sara , Zimmermann Eike , Ley Yan , van der Meer Julia , Hartsch Thomas , Bernloehr Christian , Otte Kerstin , Bradl Harald , Gamer Martin , Schulz Patrick
Published: December 2021

Chinese hamster ovary (CHO) cells are known not to express appreciable levels of the sialic acid residue N‐glycolylneuraminic acid (NGNA) on monoclonal antibodies. However, we actually have identified a recombinant CHO cell line expressing an IgG with unusually high levels of NGNA sialylation (>30%). Comprehensive multi‐OMICs based experimental analyses unraveled the root cause of this atypical sialylation: (1) expression of the cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase (CMAH) gene was spontaneously switched on, (2) CMAH mRNA showed an anti‐correlated expression to the newly discovered Cricetulus griseus (cgr) specific microRNA cgr‐miR‐111 and exhibits two putative miR‐111 binding sites, (3) miR‐111 expression depends on the transcription of its host gene SDK1, and (4) a single point mutation within the promoter region of the sidekick cell adhesion molecule 1 (SDK1) gene generated a binding site for the transcriptional repressor histone H4 transcription factor HINF‐P. The resulting transcriptional repression of SDK1 led to a downregulation of its co‐expressed miR‐111 and hence to a spontaneous upregulation of CMAH expression finally increasing NGNA protein sialylation.
LncRNA GAS5 positively regulates IL‐10 expression in patients with generalized myasthenia gravis
Authors: Peng Shuangshuang , Huang Yangping
Published: December 2021

Introduction

LncRNA growth arrest‐specific transcript 5 (GAS5) has been proven to be involved in autoimmune diseases. Rheumatoid arthritis is a type of autoimmune disease that may affect myasthenia gravis (MG) patients. However, its direct role in MG is unknown.

Methods

Our study included 62 generalized MG patients. GAS5 expression was analyzed with real‐time quantitative RT‐PCR (qRT‐PCR). The interaction between GAS5 and interleukin 10 (IL‐10) was explored in overexpressed cells using real time quantitative polymerase chain reactions (RT‐qPCRs) and western blot. The correlation of GAS5 and IL‐10 was analyzed using Pearson's correlation analysis. The diagnostic value of GAS5 for MG was analyzed using receiver operating characteristic (ROC) curve analysis.

Results

GAS5 and IL‐10 mRNA levels in peripheral blood mononuclear cells (PBMCs) were significantly lower in MG patients than healthy controls. Downregulated GAS5 effectively distinguished MG patients from healthy controls. GAS5 expression was positively correlated with IL‐10 expression in both MG patients and healthy controls. GAS5 overexpression significantly upregulated IL‐10 expression in PBMCs derived from both MG patients and healthy controls.

Conclusion

LncRNA GAS5 may improve generalized MG by positively regulating IL‐10 expression.
Screening Children with a History of Maltreatment for PTSD in Frontline Social Care Organisations: An Explorative Study
Authors: Duffy Michael , Walsh Colm , Mulholland Ciaran , Davidson Gavin , Best Paul , Bunting Lisa , Herron Stephen , Quinn Paul , Gillanders Catherine , Sheehan Caroline , Devaney John
Published: December 2021

Traumatic experiences during childhood are common and often lead to chronic mental health conditions such as posttraumatic stress disorder (PTSD). The primary aim of this study was to determine whether a well‐validated screening tool for PTSD administered in frontline services effectively identifies diagnosable PTSD in young people with a history of maltreatment. In total, 141 young people in community care settings were screened using three screening instruments (Child Revised Impact of Events Scale‐8; Generalised Anxiety Disorder‐2; Patient Health Questionnaire‐2). Participants described a range of adverse life events: 110 of the 141 participants reported at least one adverse life experience (mean number for the total sample was 2.8), with 44.2 per cent (n = 46) experiencing at least one form of interpersonal trauma; and 102 participants (72.3 per cent) screened positively for probable PTSD and subsequent mental health assessments confirmed this condition in 64.7 per cent of these participants. Further, 36.9 per cent (n = 52) and 46.8 per cent (n = 66) met the threshold for probable depression and anxiety, respectively. Three items were associated with positive PTSD screens: a history of being on the child protection register, previous mental health contact and interpersonal index trauma. Interpersonal traumas were also associated with higher risks of offending. It seems feasible to use screening measures effectively within frontline social care services if staff are provided with appropriate training and support to identify young people with PTSD who may benefit from evidence‐based mental health therapies.

Key Practitioner Messages

There is strong evidence of the link between childhood adversities and poor mental health, including PTSD.

This study found that a short instrument can be embedded within social care services to screen children and young people for PTSD.

It is important that frontline staff have the necessary training and tools to understand the effects of trauma and screen children's mental health in order to facilitate access to effective therapies at an early stage.
Controlling Protein Enrichment in Lipid Sponge Phase Droplets using SNAP‐Tag Bioconjugation
Authors: Moinpour Mahta , Fracassi Alessandro , Brea Roberto J. , Salvador‐Castell Marta , Pandey Sudip , Edwards Madison M. , Seifert Soenke , Joseph Simpson , Sinha Sunil K. , Devaraj Neal K.
Published: December 2021

All cells use organized lipid compartments to facilitate specific biological functions. Membrane‐bound organelles create defined spatial environments that favor unique chemical reactions while isolating incompatible biological processes. Despite the fundamental role of cellular organelles, there is a scarcity of methods for preparing functional artificial lipid‐based compartments. Here, we demonstrate a robust bioconjugation system for sequestering proteins into zwitterionic lipid sponge phase droplets. Incorporation of benzylguanine (BG)‐modified phospholipids that form stable covalent linkages with an O6‐methylguanine DNA methyltransferase (SNAP‐tag) fusion protein enables programmable control of protein capture. We show that this methodology can be used to anchor hydrophilic proteins at the lipid‐aqueous interface, concentrating them within an accessible but protected chemical environment. SNAP‐tag technology enables the integration of proteins that regulate complex biological functions in lipid sponge phase droplets, and should facilitate the development of advanced lipid‐based artificial organelles.
Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice
Authors: Wang Ruiting , Kairen Chen , Li Lu , Zhang Lingling , Gong Haifeng , Huang Xinzhong
Published: December 2021

Mitochondrial homeostasis plays essential role for the proper functioning of the kidney. NADH‐ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an enzyme in the complex I of electron transport chain (ETC) in mitochondria. In the present study, we examined the effects of NDUFV1 on renal function in unilateral ureteral obstruction (UUO) model mice. Our data showed that increased expression of NDUFV1 improves kidney function as evidenced by the decreases in blood urea nitrogen and serum creatinine in UUO mice. Moreover, NDUFV1 also maintains renal structures and alleviates renal fibrosis induced by UUO surgery. Mechanistically, NDUFV1 mitigates the increased oxidative stress in the kidney in UUO model mice. Meanwhile, increased expression of NDUFV1 in the kidney improves the integrity of the complex I and potentiates the complex I activity. Overall, these results indicate that the ETC complex I plays a beneficial role against renal dysfunction induced by acute kidney injury such as UUO. Therefore, NDUFV1 might be a druggable target for developing agents for dealing with disabled mitochondria‐associated renal diseases.
TRIM7 suppresses cell invasion and migration through inhibiting HIF‐1α accumulation in clear cell renal cell carcinoma
Authors: Yuan Chao , Liu Junli , Liu Ling , Jia Hongying , Gao Qi , Wang Xiaoyan , Zhao Jingjie
Published: December 2021

Clear cell renal cell carcinoma (ccRCC) is one frequent form of urologic malignancy characterized by deregulated hypoxia‐inducible factor signaling, genetic and epigenetic alterations. Metastasis is the leading cause of mortality from ccRCC, and understanding the underlying mechanism of this event will provide better strategies for its management. Here, we identify tripartite motif containing 7 (TRIM7) as a tumor suppressor in ccRCC cells, which negatively regulates hypoxia‐inducible factor 1α (HIF‐1α) signaling through targeting the proto‑oncogene Src. We observed the downregulated expression of TRIM7 in clinical ccRCC tissues and its correlation with the poor prognosis. In Caki‐1 cells, depletion of TRIM7 increased cell migration and invasion under normoxic and hypoxic conditions. TRIM7 markedly reduced the abundance of Src protein via the ubiquitin‐proteasome pathway. Further study showed that TRIM7 affected HIF‐1α accumulation through targeting either the Src‐triggered PI3K/AKT/mTOR signaling pathway or reactive oxygen species production. Overall, our findings highlight a novel mechanism for negative regulation of HIF‐1 signaling pathway by TRIM7 and define a promising therapeutic strategy for ccRCC by modulating TRIM7.
Impact of blood pressure on coronary perfusion and valvular hemodynamics after aortic valve replacement
Authors: Vogl Brennan J. , Darestani Yousef M. , Lilly Scott M. , Thourani Vinod H. , Alkhouli Mohamad A. , Lindman Brian R. , Hatoum Hoda
Published: December 2021

Objective

Our objective was to evaluate the impact of various blood pressures (BPs) on coronary perfusion and valvular hemodynamics following aortic valve replacement (AVR).

Background

Lower systolic and diastolic (SBP/DBP) pressures from the recommended optimal target range of SBP < 120–130 mmHg and DBP < 80 mmHg after AVR have been independently associated with increased cardiovascular and all‐cause mortality.

Methods

The hemodynamic assessment of a 26 mm SAPIEN 3 transcatheter aortic valve (TAV), 29 mm Evolut R TAV, and 25 mm Magna Ease surgical aortic valve (SAV) was performed in a pulsed left heart simulator with varying SBP, DBP, and heart rate (HR) conditions (60 and 120 bpm) at 5 L/min cardiac output (CO). Average coronary flow (CF), effective orifice areas (EOAs), and valvulo‐arterial impedance (Zva) were calculated.

Results

At HR of 60 bpm, at SBP < 120 mmHg and DBP < 60 mmHg, CF decreased below the physiological lower limit with several different valves. Zva and EOA were found to increase and decrease respectively with increasing SBP and DBP. The same results were found with an HR of 120 bpm. The trends of CF variation with BP were similar in all valves however the drop below the lower physiological CF limit was valve dependent.

Conclusion

In a controlled in vitro system, with different aortic valve prostheses in place, CF decreased below the physiologic minimum when SBP and DBP were in the range targeted by blood pressure guidelines. Combined with recent observations from patients treated with AVR, these findings underscore the need for additional studies to identify the optimal BP in patients treated with AVR for AS.
Ambient Temperature Polymerization of Methyl Methacrylate Mediated by Ate Complexes
Authors: Fouilloux Hugo , Thomas Christophe M.
Published: December 2021

Finding catalysts that are both robust and highly active at room temperature can often be considered as a daunting challenge. Yet, these features are desirable for polymer synthesis as they allow to produce materials of interest easily and sustainably. Herein, commercial reagents are used to form in situ “ate” complexes which were found to be highly active in the room temperature anionic polymerization of methyl methacrylate. Also of particular interest is their ability to polymerize rac‐lactide, and even form block copolymers of poly(methyl methacrylate) and poly(lactic acid).
Electronic Circular Dichroism Imaging (ECDi) Casts a New Light on the Origin of Solid‐State Chiroptical Properties
Authors: Górecki Marcin , Lipparini Filippo , Albano Gianluigi , Jávorfi Tamás , Hussain Rohanah , Siligardi Giuliano , Pescitelli Gennaro , Di Bari Lorenzo
Published: December 2021

Solid‐state ECD (ss‐ECD) spectra of a model microcrystalline solid, finasteride, dispersed into a KCl pellet were recorded by using the synchrotron radiation source at the Diamond B23 beamline. Scanning a surface of 36 mm2 with a step of 0.5 mm, we measured a set of ECD imaging (ECDi) spectra very different from each other and from the ss‐ECD recorded with a bench‐top instrument (1 cm2 area). This is due to the anisotropic part of the ECD (ACD), which averages to zero in solution or on a large number of randomly oriented crystallites, but can otherwise be extremely large. Two‐way singular value decomposition (SVD) analysis, through experimental and simulated TDDFT spectra, disclosed that the measured and theoretical principal components are in line with each other. This finding demonstrates that the observed isotropic ss‐ECD spectrum is governed by the anisotropy of locally oriented crystals. It also introduces a new quality for ss‐ECD measurements and opens a new future for probing and mapping chiral materials in the solid state such as active pharmaceutical ingredients (APIs).
Stereoselective Synthesis of Tertiary Allylic Amines by Titanium‐Catalyzed Hydroaminoalkylation of Alkynes with Tertiary Amines
Authors: Kaper Tobias , Geik Dennis , Fornfeist Felix , Schmidtmann Marc , Doye Sven
Published: December 2021

Intermolecular hydroaminoalkylation reactions of symmetrical and unsymmetrical alkynes with tertiary amines take place in the presence of catalytic amounts of TiBn4, Ph3C[B(C6F5)4], and a sterically demanding aminopyridinato ligand precursor. The resulting products, synthetically and pharmaceutically useful tertiary β,γ‐disubstituted allylic amines, are formed in convincing yields and with excellent stereoselectivity. Particularly promising for future applications is the fact that even the industrial side product trimethylamine can be used as a substrate.
Analysis insights for three FRET pairs of chemically unlinked two‐molecule FRET cytometry
Authors: Ni Zhongran , Gale Alexander , Johnson Michael S. , Sedger Lisa M.
Published: December 2021

Förster resonance energy transfer (FRET) is the direct energy exchange between two‐component fluorescent molecules. FRET methods utilize chemically linked molecules or unlinked fluorescent molecules such as fluoresscent protein–protein interactions. FRET is therefore a powerful indicator of molecular proximity, but standardized determination of FRET efficiency is challenged when investigating natural (chemically unlinked) interactions. In this paper, we have examined the interactions of tumor necrosis factor receptor‐1 (TNFR1) molecules expressed as recombinant C‐terminal fusion proteins of cyan, yellow, or red fluorescent protein (‐CFP, ‐YFP, or ‐RFP) to evaluate two‐molecule chemically unlinked FRET by flow cytometry. We demonstrate three independent FRET pairs of TNFR1 CFP→YFP (FRET‐1), YFP→RFP (FRET‐2) and CFP→RFP (FRET‐3), by comparing TNFR1+TNFR1 with non‐interacting TNFR1+CD27 proteins, on both LSR‐II and Fortessa X‐20 cytometers. We describe genuine FRET activities reflecting TNFR1 homotypic interactions. The FRET events can be visualized during sample acquisition via the use of “spiked” FRET donor cells, together with TNFR1+TNFR1 co‐transfected cells, as FRET channel mean fluorescence intensity (MFI) overlays. FRET events can also be indicated by comparing concatenated files of cells expressing either FRET positive events (TNFR1+TNFR1) or FRET negative events (TNFR1+CD27) to generate single‐cell scatter plots showing loss of FRET donor brightness. Robust determination of FRET efficiency is then confirmed at the single‐cell level by applying matrix calculations based on the measurements of FRET, using donor, acceptor, and FRET fluorescent intensities (I), detector channel emission coefficient (S), fluorescent protein extinction coefficients (ε) and the α factor. In this TNFR1‐based system the mean CFP→YFP FRET‐1 efficiency is 0.43 (LSR‐II) and 0.41 (Fortessa X‐20), the mean YFP→RFP FRET‐2 efficiency is 0.30 (LSR‐II) and 0.29 (Fortessa X‐20), and the mean CFP→RFP FRET‐3 efficiency is 0.56 (LSR‐II) and 0.54 (Fortessa X‐20). This study also embraces multi‐dimensional clustering using t‐SNE, Fit‐SNE, UMAP, Tri‐Map and PaCMAP to further demonstrate FRET. These approaches establish a robust system for standardized detection of chemically unlinked TNFR1 homotypic interactions with three individual FRET pairs.
Research Documents for Populations with Limited English Proficiency: Translation Approaches Matter
Authors: Colina Sonia , Rodríguez‐Guerra Miriam , Marrone Nicole , Ingram Maia , Navarro Karla J. , Arizmendi Genesis , Coco Laura
Published: December 2021

To avoid excluding individuals with limited English proficiency from participating in research, the consent form and other documents should be presented to them in their primary language and in a format that is understandable. However, evidence suggests that, when documents are translated for prospective and actual research participants with limited English proficiency, these individuals often fail to engage with the documents and the research in the same terms as their English‐speaking counterparts do. We argue that this is because methodological challenges remain after a decision to translate has been made. This study investigated how translation approaches affected reader response and intelligibility. Participants were asked to review two translated versions of a survey (which reflected a functionalist and a literal approach to translation) followed by semistructured interviews. Quantitative and qualitative analysis revealed a preference for a functionalist translation and a higher number of problems raised in regard to the literal translation. The recommendations we offer here include considering the most appropriate translation approach for a specific genre and purpose.
Half‐Sandwich Ruthenium Complexes Bearing Hemilabile κ2‐(C,S)−Thioether‐Functionalized NHC Ligands: Application to Amide Synthesis from Alcohol and Amine
Authors: Egly Julien , Chen Weighang , Maisse‐François Aline , Bellemin‐Laponnaz Stéphane , Achard Thierry
Published: December 2021

Amide synthesis is one of the most crucial transformations in chemistry and biology. Among various catalytic systems, N‐heterocyclic carbene (NHC)‐based ruthenium (Ru) catalyst systems have been proven to be active for direct synthesis of amides by sustainable acceptorless dehydrogenative Coupling of primary alcohols with amines. Most often, these catalytic systems usually use monodentate NHC and thus require an additional ligand to obtain high reactivity and selectivity. In this work, a series of cationic Ru(II)(η6‐p‐cymene) complexes with thioether‐functionalized N‐heterocyclic carbene ligands (imidazole and benzimidazole‐based) have been prepared and fully characterized. These complexes have then been used in the amidation reaction and the most promising one (i. e. 3 c) has been applied on a large range of substrates. High conversions albeit with moderate yields have generally been obtained.
Recent Advances in Chemical Modifications of Nitriles
Authors: Xia Yujie , Jiang Huanfeng , Wu Wanqing
Published: December 2021

Nitrile represents a synthetically important class of compounds, relevant to the preparation of fine organic chemicals, natural products, and biologically active molecules. The electronegative nitrogen atom and electropositive carbon atom of cyano group endow nitriles with rich and diverse chemical properties. Traditional chemical transformations of nitriles usually involve the use of strong acids, bases, and other harsh conditions. To overcome these limitations, various catalytic methods have been explored both in homogeneous and heterogeneous systems. In this review, we summarize some of the recent progress on the development of efficient synthetic methods involving nitriles. Especially, the classic transformations of nitriles including hydration, hydrolysis and reduction reactions are discussed in detail, which provide rapid access to a series of important small molecules, such as amides, ketones, amines, and imines. The reaction development, as well as the design of the catalytic system will be discussed with special emphasis placed on the mechanistic aspects.
The First Total Synthesis of Racemic Chebulic Acid
Authors: Kieslich David , Christoffers Jens
Published: December 2021

The first total synthesis of racemic chebulic acid is reported, which is the aglycon of several antioxidant ingredients of the fruit of the Terminalia chebula tree. The route started with the straightforward preparation of an indanone‐based β‐oxoester from a benzaldehyde derivative (84 % over the first five steps). The side chain of the target compound was then introduced by conjugated addition of a cuprate reagent derived from dimethyl succinate, which was followed by the first key step of the synthesis: a cerium‐catalyzed α‐hydroxylation of an β‐oxoester. The second key step was the cyanide‐catalyzed ring transformation of the cyclic α‐hydroxy‐β‐oxoester to a δ‐lactone. Finally, chebulic acid was obtained after six‐fold demethylation of three methyl ester moieties and three phenolic ether functions. The overall synthetic route consists of nine consecutive steps and was accomplished in 15 % overall yield.
Recent insights in corrosion science from atomic spectroelectrochemistry
Authors: Choudhary Sanjay , Ogle Kevin , Gharbi Oumaïma , Thomas Sebastian , Birbilis Nick
Published: December 2021

A fundamental understanding of corrosion mechanisms is the key to developing suitable corrosion protection approaches, and for the prediction of service life of metallic structures. However, conventional corrosion testing methods such as mass loss and electrochemical testing do not guarantee estimation of "true" corrosion rate and often mask the underlying mechanisms, due to either low sensitivity or a lack of element‐resolved information. Relatively recent work in corrosion science has led to the development of a new class of corrosion testing approaches, namely atomic spectroelectrochemistry; whereby direct insight of dissolution and corrosion mechanisms can be obtained during electrochemical testing. Atomic spectroelectrochemistry provides real‐time and element resolved dissolution rate of material via coupling electrochemical flow cell with inductively coupled plasma – atomic spectroscopy. This concise review discusses the basic working principle of atomic spectroelectrochemistry and its recent applications in corrosion science to understand the true underlying corrosion mechanisms of a range of metallic materials.
Lichen impact on sandstone hardness is species‐specific
Authors: Tonon Chiara , Bernasconi Davide , Martire Luca , Pastero Linda , Viles Heather , Favero‐Longo Sergio E.
Published: December 2021

The balance between lichen biodeterioration and bioprotection processes on stone surfaces depends on many variables and is crucial to understanding the role of lichens in biogeomorphology and their threat to stone heritage conservation. However, stones colonized by lichens have still been mostly examined in terms of affected volumes and physico‐chemical modes of interactions, overlooking the overall effects on properties related to surface durability. In this study, the impact of lichen colonization patterns on Cortemilia sandstone was examined beneath thalli of three lichen species. Rock hardness, a proxy for rock durability, was measured at different depths from the surface using an Equotip hardness tester and compared to that of freshly cut surfaces and exposed surfaces uncolonized by lichens. Mineralogical analyses were performed by X‐ray powder diffraction on rock beneath lichen colonization, in comparison with unweathered rock. Equotip analyses quantified a differential, species‐specific decrease in stone hardness. This variability was related to differences in hyphal penetration patterns and, possibly, calcite (re‐)precipitation. In particular, in the case of the species most impacting rock hardness, X‐ray diffraction patterns of calcite showed a remarkable stability of crystallographic plane (01–12), known to be enhanced in the presence of organic chelants. These results confirm that decisions on lichen removal from stone surfaces should consider species‐specific behaviour. Moreover, the innovative approach of measuring stone hardness variation in association with the analysis of biomineralization processes contributes to unveil the extension of the sphere of lichen interaction within the stone substrate beyond the limit of the hyphal penetration.
The effect of dynamic high‐pressure microfluidization on the physicochemical and digestive properties of proteins in insoluble fraction of edible bird's nest
Authors: Wang Dehua , Zheng Xinyi , Fan Qunyan , Wang Peixin , Zeng Hongliang , Zhang Yi , Zheng Baodong , Lin Shaoling
Published: December 2021

Dynamic high‐pressure microfluidization (DHPM) has been demonstrated as an effective method to increase the solubility of proteins in water‐insoluble fraction of edible bird's nests (EBNIP). Here, we further explored the effects of DHPM treatment on the physicochemical and digestive properties of EBNIP. The results showed that DHPM treatment led to the increases in fat absorption capacities, foaming properties, and emulsifying properties of EBNIP with decreased water‐holding capacity being observed. This might result from the mechanical force during DHPM treatment can unfold the protein molecular chain, destroy the hydrogen bonds and inter‐linkage between protein molecules. In addition, the EBNIP samples with DHPM treatment exhibited increased in vitro digestibility, the degree of hydrolysis and free sialic acid release in in vitro gastrointestinal digestion assay. In conclusion, DHPM could be applied as a novel and effective processing method to modify protein macromolecules in production of edible bird's nest (EBN)‐related food.
Organic matter inputs and depositional palaeoenvironment recorded by biomarkers of marine‐terrestrial transitional shale in the Southern North China Basin
Authors: Liu Peng , Zhang Ting , Xu Qiuchen , Wang Xiaofeng , Liu Changjie , Guo Ruiliang , Lin Haifei , Yan Min , Qin Lei , Li Yong
Published: December 2021

In recent years, significant breakthroughs have been achieved in shale gas exploration and exploitation of marine and continental shales in petroliferous basins of China. As an important petroliferous basin in China, marine–terrestrial transitional shale was widely distributed among the Southern North China Basin (SNCB). However, biomarkers distribution characteristics of marine–terrestrial transitional shale in the SNCB, which can reveal the organic matter inputs and paleoenvironmental characteristics, is not widely concerned. In general, organic matter in a transitional environment can be affected by the amounts of organic matters input from fresh water and aquatic organisms from the sea. To systematically investigate the organic geochemical characteristics of biomarkers in marine–terrestrial transitional shale from SNCB, core samples from the Upper Shihezi, Shanxi and Taiyuan formations were obtained from a single borehole in the SNCB. Gas chromatography–mass spectrometry (GC–MS) analysis was conducted on the saturated hydrocarbons. n‐Alkanes, acyclic isoprenoid alkanes, terpanes, and steranes were detected to study the change in organic matter inputs and sedimentary paleoenvironment of the marine–terrestrial transitional shale. The results reveal that organic matter inputs obviously changed during the sedimentary period in the study area of the SNCB. In addition, the terrestrial higher plants contributed more organic matter to shale from the Upper Shihezi Formation compared to the Taiyuan Formation and the Shanxi Formation. The shift of organic matter inputs is consistent with marine regression in the Early Permian period, which may significantly influence the organic matter input characteristics. Meanwhile, the marine–terrestrial transitional shale, including samples from the Taiyuan, Shanxi and Upper Shihezi formations, was deposited in a relatively oxic condition during the depositional process.
Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia
Authors: Koskuvi Marja , Lehtonen Šárka , Trontti Kalevi , Keuters Meike , Wu Ying‐Chieh , Koivisto Hennariikka , Ludwig Anastasia , Plotnikova Lidiia , Virtanen Pekka L. J. , Räsänen Noora , Kaipainen Satu , Hyötyläinen Ida , Dhungana Hiramani , Giniatullina Raisa , Ojansuu Ilkka , Vaurio Olli , Cannon Tyrone D. , Lönnqvist Jouko , Therman Sebastian , Suvisaari Jaana , Kaprio Jaakko , Lähteenvuo Markku , Tohka Jussi , Giniatullin Rashid , Rivera Claudio , Hovatta Iiris , Tanila Heikki , Tiihonen Jari , Koistinaho Jari
Published: December 2021

Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)‐derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron‐astrocyte co‐cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co‐twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.
Retrospective memory integration accompanies reconfiguration of neural cell assemblies
Authors: Wang Ye , Deng Yaling , Cao Lihong , Zhang Jiahong , Yang Lei
Published: December 2021

Memory is a dynamic process that is based on and can be altered by experiences. Integrating memories of multiple experiences (memory integration) is the basis of flexible and complex decision‐making. However, the mechanism of memory integration in neural networks of the brain remains poorly understood. In this study, we built a recurrent spiking network model and investigated the neural mechanism of memory integration before a decision is made (retrospective memory integration) at the neural circuit level. Our simulations suggest that retrospective memory integration accompanies reconfiguration of neural cell assemblies. Additionally, partially blocking neural network plasticity leads to failure of memory integration. These findings can potentially guide the experimental investigation of the neural mechanism of retrospective memory integration and serve as the basis for developing new artificial intelligence algorithms.
Advances in endocrine toxicity of nanomaterials and mechanism in hormone secretion disorders
Authors: Yao Yongshuai , Tang Meng
Published: December 2021

The size of nanoparticles is about 1–100 nm. People are exposed to nanoparticles in environmental pollutants from ancient times to the present. With the maturity of nanotechnology in the past two decades, the production of manufactured nanomaterials is rapidly increasing and they are used in a wide range of aerospace, medicine, food, and industrial applications. However, both natural and manufactured nanomaterials have been proved to pose a threat to diverse organs and systems. The endocrine system is critical to maintaining homeostasis. Endocrine disorders are associated with many diseases, including cancer, reduced fertility, and metabolic diseases. Therefore, we review the literatures dealing with the endocrine toxicity of nanomaterial. This review provides an exhaustive description of toxic effects of several common nanomaterials in the endocrine system; more involved are reproductive endocrinology. Then physicochemical factors that determine the endocrine toxicity of nanomaterials are discussed. Furthermore, oxidative stress, changes in steroid production and metabolic enzymes, organelle disruption, and alterations in signal pathways are introduced as potential mechanisms that may cause changes in hormone levels. Finally, we suggest that a risk assessment of endocrine toxicity based on standard procedures and consideration of endocrine disrupting effects of nanomaterials in the field and its environmental and population effects could be future research directions for endocrine toxicity of nanomaterials.
Controlling the bone regeneration properties of bioactive glass: Effect of particle shape and size
Authors: Borden Mark , Westerlund Lance Erik , Lovric Vedran , Walsh William
Published: December 2021

The ability of particulate bioactive glass to function as an effective bone graft material is directly related to its in vivo dissolution, ion release, and interparticle spacing (area associated with bone in‐growth). A spherical shape represents an optimal geometry to control bioactive glass bone formation properties. Spherical particles were fabricated from 45S5 bioactive glass with unimodal (90–180, 180–355, and 355–500 μm) and bimodal size ranges (180–355/355–500 and 90–180/355–500 μm). Particles were formed into bone graft putties and compared to a commercially available product composed of irregular 45S5 bioactive glass particles (32–710 μm). Scanning electron microscopy characterization of spherical particles showed a relatively uniform sphere shape and smooth surfaces. Irregular particles were characterized by random shapes with flat surfaces and sharp edges. X‐ray fluorescence and X‐ray diffraction indicated that the spheroidization process maintained the properties of 45S5 bioactive glass. Cross‐sectional micro‐computed tomography imaging of the putty samples demonstrated that smaller spheres and irregular particles resulted denser packing patterns compared to the larger spheres. Isolated particles were immersed in simulated body fluid for 14 days to measure silicon ion release and bioactivity. Inductively coupled plasma spectroscopy showed faster ion release from smaller particles due to increased surface area. Bioactivity characterization of 14‐day simulated body fluid exposed particle surfaces showed the presence of a hydroxycarbanoapatite mineral layer (characteristic of 45S5 bioactive glass) on all bioactive glass particles. Results demonstrated that spherical particles maintained the properties of the starting 45S5 bioactive glass, and that particle shape and size directly affected short‐term glass dissolution, ion release, and interparticle spacing.
The emerging role of selenium metabolic pathways in cancer: New therapeutic targets for cancer
Authors: Kalimuthu Kalishwaralal , Keerthana Chenicheri K. , Mohan Manikandan , Arivalagan Jaison , Christyraj Johnson Retnaraj Samuel Selvan , Firer Michael A. , Choudry Mohammad Haroon Asif , Anto Ruby John , Lee Yong J.
Published: December 2021

Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, which is critical in the synthesis of selenoproteins, such as glutathione peroxidases and thioredoxin reductases. Selenoproteins, which play a key role in several biological processes, including ferroptosis, drug resistance, endoplasmic reticulum stress, and epigenetic processes, are guided by Se uptake. In this review, we critically analyze the molecular mechanisms of Se metabolism and its potential as a therapeutic target for cancer. Sec insertion sequence binding protein 2 (SECISBP2), which is a positive regulator for the expression of selenoproteins, would be a novel prognostic predictor and an alternate target for cancer. We highlight strategies that attempt to develop a novel Se metabolism‐based approach to uncover a new metabolic drug target for cancer therapy. Moreover, we expect extensive clinical use of SECISBP2 as a specific biomarker in cancer therapy in the near future. Of note, scientists face additional challenges in conducting successful research, including investigations on anticancer peptides to target SECISBP2 intracellular protein.
The expression and clinical significance of CD59 and FLAER in Chinese adult AML patients
Authors: Li Lijuan , Yu Shunjie , Liu Shanshan , Meng Fanqiao , Ren Xiaotong , Liu Zhaoyun , Fu Rong
Published: December 2021

Background

The role of CD59 and fluorescently labeled aerolysin (FLAER) in acute myeloid leukemia (AML) remains unclear and requires further investigation. To explore the relationship between CD59, FLAER, and AML, we investigated CD59 and FLAER expression in AML and analyzed their relationship with clinical characteristics of AML patients.

Methods

We employed flow cytometry (FCM) to analyze CD59 and FLAER expression in 161 AML patients at Tianjin Medical University General Hospital and evaluated its association with sex, white blood cell (WBC) count, platelet (PLT) count, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D‐Dimer(D‐D), and lactate dehydrogenase (LDH), followed by analyzing its connection with disease progression and complete remission (CR).

Results

CD59 and FLAER deficiencies were identified in AML patients. Compared with CR group, non‐CR group patients revealed more CD59 and FLAER deficiency. Compared with non‐acute promyelocytic leukemia (M3) group, M3 group patients had more CD59 and FLAER deficiency. CD59−level in primordial cells of M3 patients was positively correlated with primordial cell ratio (r = 0.660,p = 0.003). Additionally, we discovered that the decline in CD59 and FLAER levels might be linked to higher D‐D and LDH in AML patients. The difference was statistically significant (p < 0.05).

Conclusions

We demonstrated that the decline in CD59 and FLAER levels was associated with leukemia cell proliferation and abnormal coagulation function in AML, suggesting that they could serve as a predictor of AML coagulation dysfunction, particularly in M3.
A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure
Authors: Scarpignato Carmelo , Leifke Eckhard , Smith Neila , Mulford Darcy J. , Lahu Gezim , Facius Axel , Howden Colin W.
Published: December 2021

Vonoprazan, a potassium‐competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed‐effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non‐Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non‐Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non‐Asian populations.
Chiral resolution of DL‐glutamic acid by a chiral additive
Authors: Zhou Xin‐hui , Liu Qing , Wang Hai‐shui
Published: December 2021

BACKGROUND

Enantiomerically pure compounds occupy an important position in industrial production of pharmaceuticals, food, chemical engineering, etc. The separation of d and l molecules is an important and challenging task. The ‘tailor‐made’ additive method is a simple and efficient crystallization separation technology. However, according to reports, there is a poor crystal yield when obtaining a relatively ideal enantiopurity and vice versa. Furthermore, the crystallization time always needs to be controlled strictly.

RESULTS

In this paper, we studied the effect of the amount and kinds of additives, crystal seeds and crystallization time on the purity and yields of crystals. Two strategies involving a chiral additive for the selective crystallization of only d‐glutamic acid from a solution of racemic dl‐glutamic acid (dl‐Glu) are presented. One strategy is based on the addition of sufficient additive (l‐arginine or l‐phenylalanine with a mole fraction of 40%) and β‐d‐Glu crystal seeds, the crystal yield reaching 23–25%. The other relies on carrying out the crystallization twice in the presence of the additive (5 mol%) and the crystal seeds, the yield reaching 30–34%.

CONCLUSIONS

Two separation methods with a relatively high crystal yield and optical purity were established. The proposed strategies could meet the requirements of both crystal purity and yield on chiral separation, and the separation of d‐ and l‐Glu is nearly perfect. Furthermore, the methods are very easy to operate, and require no hand picking. Most importantly, our methods are barely influenced by the crystallization time. © 2021 Society of Chemical Industry (SCI).
Adult‐onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage‐gated potassium channel downregulation in male mice
Authors: Suda Machiko , Takatsuru Yusuke , Amano Izuki , Haraguchi Shogo , Koibuchi Noriyuki
Published: December 2021

Thyroid hormones play an important role in the central and peripheral nervous system functions. Approximately 50% of adult‐onset hypothyroid patients have sensory symptoms including pain, possibly caused by peripheral neuropathy. However, the mechanism causing the pain has not been clarified. We generated an adult‐onset hypothyroid model animal by administering 50 ppm propylthiouracil (PTU) for 5 weeks to male mice. Female mice were not tested in this study. Mechanical hypersensitivity, determined by the von Frey hair test, was observed during the PTU exposure and recovered after the exposure termination. The sciatic nerve compound action potential was also analyzed. Under single‐pulse stimulation, no significant change in the threshold and conduction velocity was observed in the PTU‐administered group. On the other hand, under train‐pulse stimulation, the latency delay in the Aδ‐fiber component was less in the PTU‐administered group in Week 4 of PTU exposure, indicating relative hyperexcitability. Fluticasone, which is the anti‐inflammatory agent with an ability to activate the voltage‐gated potassium channel subfamily A (Kv1), restored the decrease in the latency change ratio by PTU exposure under the train‐pulse stimulation supporting our hypothesis that Kv1 may be involved in the conductivity change. Kv1.1 protein level decreased significantly in the sciatic nerve of the PTU‐administered group. These results indicate that adult‐onset hypothyroidism causes mechanical hypersensitivity owing to hyperexcitability of the peripheral nerve and that reduction of Kv1.1 level may be involved in such alteration.
Client perspectives on broaching intersectionality in counseling
Authors: King Kelly M.
Published: December 2021

Broaching identity and power in counseling can deepen appreciation for the client's lived experience. In a cross‐sectional study, clients indicated which identities their counselor broached with them throughout counseling and their overall satisfaction with services. Exploratory analyses and implications for broaching intersectionality from a humanistic perspective are outlined.