bluuebunny/crossref_metadata_2025 huggingface dataset:
Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis
Authors: D'Gama Alissa M. , England Eleina , Madden Jill A. , Shi Jiahai , Chao Katherine R. , Wojcik Monica H. , Torres Alcy R. , Tan Wen‐Hann , Berry Gerard T. , Prabhu Sanjay P. , Agrawal Pankaj B.
Published: October 2020

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy‐10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo‐reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate‐to‐pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non‐single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between “syndromic” cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.
Chimerism involving a RB1 pathogenic variant in monochorionic dizygotic twins with twin–twin transfusion syndrome
Authors: Armitage Anna M. , Kundra Monica A. , Ghiam Neda , Atwal Paldeep S. , Morel Dayna , Hruska Kathleen S. , Torene Rebecca , Harbour J. William , Forghani Irman
Published: October 2020

We report the first case of blood chimerism involving a pathogenic RB1 variant in naturally conceived monochorionic‐dizygotic twins (MC/DZ) with the twin–twin‐transfusion syndrome (TTTS), presumably caused by the exchange of stem‐cells. Twin A developed bilateral retinoblastoma at 7 months of age. Initial genetic testing identified a de novo RB1 pathogenic variant, with a 20% allelic ratio in both twins' blood. Subsequent genotyping of blood and skin confirmed dizygosity, with the affected twin harboring the RB1 pathogenic variant in skin and blood, and the unaffected twin carrying the variant only in blood.
Drug‐induced cardiomyopathy: Characterization of a rat model by [18F]FDG/PET and [99mTc]MIBI/SPECT
Authors: Houson Hailey , Hedrick Andria , Awasthi Vibhudutta
Published: October 2020

Background

Drug‐induced cardiomyopathy is a significant medical problem. Clinical diagnosis of myocardial injury is based on initial electrocardiogram, levels of circulating biomarkers, and perfusion imaging with single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality that provides better resolution and sensitivity than SPECT, improves diagnostic accuracy, and allows therapeutic monitoring. The objective of this study was to assess the detection of drug‐induced cardiomyopathy by PET using 2‐deoxy‐2‐[18F]fluoro‐D‐glucose (FDG) and compare it with the conventional SPECT technique with [99mTc]‐Sestamibi (MIBI).

Methods

Cardiomyopathy was induced in Sprague Dawley rats using high‐dose isoproterenol. Nuclear [18F]FDG/PET and [99mTc]MIBI/SPECT were performed before and after isoproterenol administration. [18F]FDG (0.1 mCi, 200‐400 µL) and [99mTc]MIBI (2 mCi, 200‐600 µL) were administered via the tail vein and imaging was performed 1 hour postinjection. Isoproterenol‐induced injury was confirmed by the plasma level of cardiac troponin and triphenyltetrazolium chloride (TTC) staining.

Results

Isoproterenol administration resulted in an increase in circulating cardiac troponin I and showed histologic damage in the myocardium. Visually, preisoproterenol and postisoproterenol images showed alterations in cardiac accumulation of [18F]FDG, but not of [99mTc]MIBI. Image analysis revealed that myocardial uptake of [18F]FDG reduced by 60% after isoproterenol treatment, whereas that of [99mTc]MIBI decreased by 45%.

Conclusion

We conclude that [18F]FDG is a more sensitive radiotracer than [99mTc]MIBI for imaging of drug‐induced cardiomyopathy. We theorize that isoproterenol‐induced cardiomyopathy impacts cellular metabolism more than perfusion, which results in more substantial changes in [18F]FDG uptake than in [99mTc]MIBI accumulation in cardiac tissue.
Growth and survival characteristics of spa mice
Authors: Brandenburg Joline E. , Fogarty Matthew J. , Sieck Gary C.
Published: October 2020

Characterization of growth and survival of mice displaying early onset hypertonic symptoms is critical as these animals are important for research investigating mechanisms and treatments of pediatric conditions associated with hypertonia, such as cerebral palsy. Currently, most animal models of cerebral palsy reproduce risk factors for developing this condition, with most failing to develop the physical symptoms or failing to survive in the postnatal period. The B6.Cg‐Glrbspa/J (Gly receptor mutation) transgenic mouse (spa mouse), displays symptoms of early onset hypertonia, though little has been reported on growth and survival, with no reports of growth and survival since genotyping became available. We found that the majority of spa mice display symptoms by P14‐P16. Of mice surviving to weaning, only ~9% were spa mice. By weaning age, spa mice had significantly lower weights than their heterozygote and wild‐type littermates. Of mice that died after weaning and prior to use in experiments or being culled, 48% were spa mice. The poor growth and decreased survival of spa mice across multiple developmental and adult ages resembled the varied survival rates observed in humans with mild or severe cerebral palsy. The understanding of the expected survival of these mice is helpful for planning breeding and animal numbers for experiments. Due to the symptoms and timing of symptom onset, spa mice will be valuable in uncovering mechanisms and long‐term effects of early onset hypertonia in order to move toward interventions for these conditions.
Anisotropic Seeded Growth of Ag Nanoplates Confined in Shape‐Deformable Spaces
Authors: Chen Jinxing , Bai Yaocai , Feng Ji , Yang Fan , Xu Panpan , Wang Zichen , Zhang Qiao , Yin Yadong
Published: October 2020

Conventional templating synthesis confines the growth of seeds in rigid spaces to achieve faithful morphological replication. Herein, we explore the use of spherical shape‐deformable polymeric nanoshells to regulate the anisotropic growth of Ag nanoplates. The flexible shells deform adaptively to accommodate the initial overgrowth of the seeds but restrict the growth in the directions where the shells are fully stretched, eventually producing nanoplates with an unconventional circular profile. The diameter of the final Ag nanoplates can be precisely predicted by stretching and flattering the nanoshells into a plate‐like capsule while retaining their original internal surface area. Furthermore, unlike conventional templates, the polymer shells eventually turn themselves into a conformal coating that binds to the surface of the full‐grown Ag nanoplates and significantly enhances their stability against oxidative etching.
A Series of Mesoporous Rare‐Earth Metal–Organic Frameworks Constructed from Organic Secondary Building Units
Authors: Lv Xiu‐Liang , Feng Liang , Wang Kun‐Yu , Xie Lin‐Hua , He Tao , Wu Wei , Li Jian‐Rong , Zhou Hong‐Cai
Published: October 2020

Further development of metal–organic frameworks (MOFs) requires an establishment of hierarchical interaction within the framework. Herein, we report a series of mesoporous rare‐earth (RE) MOFs that are constructed from an unusual 12‐connected π‐stacked pyrene secondary building unit (SBU) and a typical 12‐connected RE6 cluster (RE=Eu, Y, Yb, Tb, Ce). The judicious design of a butterfly‐shape pyrene ligand with a tert‐butyl substituent enables the formation of the disordered 12‐connected organic SBUs on its strong intermolecular π–π interactions. The assembly of 12‐connected inorganic cuboctahedron SBUs and 12‐connected organic distorted hexagonal prism SBUs generates an unprecedented network that can be further simplified into a 4,4‐connected pts net linked from planar square and tetrahedra. This work provides fresh insights into the design and synthesis of frameworks constructed from coordinatively, covalently, and noncovalently linked building units.
Azadiphosphaindan‐1,3‐diyle: Eine Gruppe von resonanzstabilisierten Biradikalen
Authors: Bresien Jonas , Michalik Dirk , Schulz Axel , Villinger Alexander , Zander Edgar
Published: October 2020

Die Umsetzung von 1,2‐Bis(dichlorphosphanyl)benzol mit sterisch anspruchsvollen primären Aminen führte zur Bildung von 1,3‐Dichlor‐2‐aza‐1,3‐diphosphaindanen des Typs C6H4(μ‐PCl)2N‐R. Reduktion derselbigen ergab die entsprechenden 2‐Aza‐1,3‐diphosphaindan‐1,3‐diyle (1), die als phosphorzentrierte Singulett‐Biradikal(oid)e beschrieben werden können. Ihre Stabilität hängt von der Größe des Substituenten R ab: Während Derivate mit R=Dmp (2,6‐Dimethylphenyl) oder Ter (2,6‐Dimesitylphenyl) oligomerisierten, war das Derivat mit dem sehr sperrigen R=tBuBhp (2,6‐Bis(benzhydryl)‐4‐tert‐butylphenyl) in seiner monomeren Form stabil gegenüber Oligomerisierung. Die Oligomerisierung resultiert aus der Aktivierung des kondensierten Benzolrings durch ein weiteres Äquivalent des monomeren Biradikals und kann als formale [2+2]‐(Poly)additions‐Reaktion angesehen werden. Rechnungen zeigen, dass der biradikalische Charakter in 1 mit den literaturbekannten P‐zentrierten Biradikalen vergleichbar ist. Ringstromberechnungen zeigen eine Aromatizität innerhalb des gesamten Ringsystems von 1.
Towards Naked Zinc(II) in the Condensed Phase: A Highly Lewis Acidic ZnII Dication Stabilized by Weakly Coordinating Carborate Anions
Authors: Adet Nicolas , Specklin David , Gourlaouen Christophe , Damiens Thibault , Jacques Béatrice , Wehmschulte Rudolf J. , Dagorne Samuel
Published: October 2020

The employment of the hexyl‐substituted anion [HexCB11Cl11]− allowed the synthesis of a ZnII species, Zn[HexCB11Cl11]2, 3, in which the Zn2+ cation is only weakly coordinated to two carborate counterions and that is soluble in low polarity organic solvents such as bromobenzene. DOSY NMR studies show the facile displacement of at least one of the counterions, and this near nakedness of the cation results in high catalytic activity in the hydrosilylation of 1‐hexene and 1‐methyl‐1cyclohexene. Fluoride ion affinity (FIA) calculations reveal a solution Lewis acidity of 3 (FIA=262.1 kJ mol−1) that is higher than that of the landmark Lewis acid B(C6F5)3 (FIA=220.5 kJ mol−1). This high Lewis acidity leads to a high activity in catalytic CO2 and Ph2CO reduction by Et3SiH and hydrogenation of 1,1‐diphenylethylene using 1,4‐cyclohexadiene as the hydrogen source. Compound 3 was characterized by multinuclear NMR spectroscopy, mass spectrometry, single crystal X‐ray diffraction, and DFT studies.
An Open Microfluidic Chip for Continuous Sampling of Solute from a Turbulent Particle Suspension
Authors: Shallan Aliaa I. , Tavares Yakini , Navvab Kashani Moein , Breadmore Michael C. , Priest Craig
Published: October 2020

High solids content complicates in situ analysis of chemical processing, biological suspensions, and environmental streams. In most cases, analytical methods require at least one pre‐treatment step of a small volume of sample before a particle‐free fluid can be analyzed. We have developed a continuous in situ sampler that can “sip” particle‐free solution from a turbulent high solids content stream (a slurry). An open microfluidic chip with an extended slit opening shields the internal laminar flow from the turbulence outside. Unlike other open chips, our chip does not require close proximity to a solid surface and operates in turbulent environments for hours without maintenance. Two applications are demonstrated: monitoring FeIII in a stirred slurry of mixed ore particles at high solids loading (4 %wt) and paracetamol tablet dissolution profiles for two different formulations.
Arine als Radikalakzeptoren: TEMPO‐induzierte Kaskaden über Addition, Zyklisierung und Kreuzkupplung
Authors: Scherübl Maximilian , Daniliuc Constantin G. , Studer Armido
Published: October 2020

Die Anwendung von Arinen als Radikalakzeptoren wird beschrieben. Das stabile TEMPO‐Radikal (2,2,6,6‐Tetramethylpiperidinyl‐1‐oxyl) addiert an verschiedene ortho‐substituierte Benz‐ine, und die daraus erzeugten Arylradikale gehen 5‐exo‐ und 6‐endo‐Zyklisierungen ein. Die zyklisierten Radikale werden schließlich mit TEMPO abgefangen. Die vorgestellte Methode bietet über einen konzeptionell neuen Ansatz einen schnellen Zugang zu Dihydrobenzofuranen, Oxindolen und Sultonen.
Azadiphosphaindane‐1,3‐diyls: A Class of Resonance‐Stabilized Biradicals
Authors: Bresien Jonas , Michalik Dirk , Schulz Axel , Villinger Alexander , Zander Edgar
Published: October 2020

Conversion of 1,2‐bis(dichlorophosphino)benzene with sterically demanding primary amines led to the formation of 1,3‐dichloro‐2‐aza‐1,3‐diphosphaindanes of the type C6H4(μ‐PCl)2N‐R. Reduction yielded the corresponding 2‐aza‐1,3‐diphosphaindane‐1,3‐diyls (1), which can be described as phosphorus‐centered singlet biradical(oid)s. Their stability depends on the size of the substituent R: While derivatives with R=Dmp (2,6‐dimethylphenyl) or Ter (2,6‐dimesitylphenyl) underwent oligomerization, the derivative with very bulky R=tBuBhp (2,6‐bis(benzhydryl)‐4‐tert‐butylphenyl) was stable with respect to oligomerization in its monomeric form. Oligomerization involved activation of the fused benzene ring by a second equivalent of the monomeric biradical and can be regarded as formal [2+2] (poly)addition reaction. Calculations indicate that the biradical character in 1 is comparable with literature‐known P‐centered biradicals. Ring‐current calculations show aromaticity within the entire ring system of 1.
Arynes as Radical Acceptors: TEMPO‐Mediated Cascades Comprising Addition, Cyclization, and Trapping
Authors: Scherübl Maximilian , Daniliuc Constantin G. , Studer Armido
Published: October 2020

The application of arynes as radical acceptors is described. The stable radical TEMPO (2,2,6,6‐tetramethyl piperidine 1‐oxyl) is shown to add to various ortho‐substituted benzynes generating the corresponding aryl radicals which engage in 5‐exo or 6‐endo cyclizations. The cyclized radicals are eventually trapped by TEMPO. The introduced method provides ready access to various dihydrobenzofurans, oxindoles, and sultones by a conceptually novel approach.
Evaluation of scaffolding, inflammatory response, and wound healing support of a reverse thermal gel for myelomeningocele patching
Authors: Bardill James R. , Williams Sarah M. , Laughter Melissa R. , Park Daewon , Marwan Ahmed I.
Published: October 2020

A reverse thermal gel (RTG) is a promising patching material for in utero, minimally invasive coverage of myelomeningocele (MMC) defects. The injectable properties of the RTG brings the potential for significantly reduced surgical risks to the mother and fetus when compared to current open prenatal repair procedures. MMC patching materials require structural and wound healing support for tissue growth over the MMC defect area to allow a watertight seal to form and prevent further neural tissue exposure to the amniotic environment. Here, the previously described RTG is evaluated for the first time as a scaffold for skin cells, for long‐term inflammation effects in neonatal mice, and for wound healing capability. Results show that the RTG can support the growth and survival of keratinocytes, dermal fibroblasts, and neuronal cells in vitro. Injections into neonatal mice demonstrate a regressing inflammatory response and support of normal wound healing. Together, these results demonstrate that the RTG has the necessary scaffolding and wound healing support necessary for MMC patching applications.
Hydrodynamic pressure sensors with tunable sensitivity based on thermoresponsive hydrogels
Authors: Jiang Yonggang , Wang Ningkang , Zhuo Shuyun , He Qipei , Ma Zhiqiang , Liu Mingjie , Zhang Deyuan
Published: October 2020

Lateral line system of fish performs hydrodynamic flow‐field perception with ultrasensitivity via mechanosensory neuromasts, which vary in geometrical dimension and sensitivity for a wide detection range. To achieve tunable sensitivity and wide detection range in engineered sensors, here we present a hydrodynamic pressure sensor inspired by the canal lateral line system of fish, which comprises of a microfluidic canal, and piezoelectric microcantilevers integrated with thermoresponsive hydrogel cupulae and microheaters. The poly(N‐isopropylacrylamide)‐based hydrogel cupula can not only increase the sensitivity by a hydrogel‐based drag enhancement mechanism, but also regulate the sensitivity by changing the cupula volume via localized heating. We characterized the pressure sensitivity and frequency response of the sensor, and the results demonstrated that the sensor possessed a wide detection range but a lower sensitivity during heater‐on, while it performed higher sensitivity with narrow detection range during heater‐off. The tunable hydrodynamic pressure sensors show many potential applications in flow analysis and hydrodynamic imaging.
How the biaxially stretching mode influence dielectric and energy storage properties of polypropylene films
Authors: Xiong Jie , Wang Xin , Zhang Xiao , Xie Yunchuan , Lu Junyong , Zhang Zhicheng
Published: October 2020

The most important polymer film used in commercial capacitors is biaxially oriented polypropylene (BOPP), which could be produced by sequentially or simultaneously biaxial orientation after the melt‐extrusion. In order to disclose the influence of the stretching technique on the properties of films, the BOPP films with varied thickness were fabricated by sequential and simultaneous orientation, respectively. Compared to the sequentially biaxially stretched films, the crystal grains in the simultaneously biaxially stretched films are more isotropically dispersed. As temperature increases, all the BOPP films exhibit similar dielectric constant, and the simultaneous films have much lower dielectric loss thanks to the finer blended crystalline and amorphous phases. When the film thickness is smaller than 5 μm, the breakdown field strength, energy density and discharging time of the simultaneous films can be increased by at least 10% comparing to the sequential ones, which is very important for reducing the volume of the film capacitors. All the results suggest the simultaneously biaxial orientation mode shows significant advantages in producing thin BOPP films with better mechanical and electrical properties.
Superelastic and hydrophobic‐oleophilic modified melamine foam by ultralow amount of graphene for oil/water separation
Authors: Zhang Linjiong , Feng Lianfang , Gu Xueping , Zhang Cailiang
Published: October 2020

Oil spills and organic chemical leakage have caused serious environmental problems, calling for highly effective adsorbents at low cost. Superelastic and hydrophobic‐oleophilic modified melamine foams with ultralow amounts of well‐dispersed graphene were prepared via dip‐coating. The composite foams showed high selectivity for adsorbing various organic chemicals from water and could be regenerated easily. Moreover, excellent adsorption capacity ranging from 80 to 170 times its own weight was found depending on the density of organic chemicals. These coated foams show great potential for continuous oil/water separation and oil fume removal.
Differences Between Attached and Detached Cadaveric Prosections on Students' Identification Ability During Practical Examinations
Authors: Mattingly Spencer , Hardesty Elizabeth , Chovanec Kevin , Cobos Marlon E. , Garcia Jacqueline , Grizzle Meghan , Huerta Amanda , Ohtake Jesse , Romero‐Alvarez Daniel , Gonzalez Victor H.
Published: October 2020

Cadaveric prosections are effective learning tools in anatomy education. They range from a fully dissected, sometimes plastinated, complete cadaver (in situ prosections), to a single, carefully dissected structure detached from a cadaver (ex situ prosections). While most research has focused on the advantages and disadvantages of dissection versus prosection, limited information is available on the instructional efficacy of different prosection types. This contribution explored potential differences between in situ and ex situ prosections regarding the ability of undergraduate students to identify anatomical structures. To determine if students were able to recognize the same anatomical structure on both in situ and ex situ prosections, or on either one individually, six structures were tagged on both prosection types as part of three course summative examinations. The majority of students (61%–68%) fell into one of the two categories: those that recognized or failed to recognize the same structure on both in situ and ex situ prosections. The percentage of students who recognized a selected structure on only one type of prosection was small (1.6%–31.6%), but skewed in favor of ex situ prosections (P ≤ 0.01). These results suggest that overall students' identification ability was due to knowledge differences, not the spatial or contextual challenges posed by each type of prosection. They also suggest that the relative difficulty of either prosection type depends on the nature of the anatomical structure. Thus, one type of prosection might be more appropriate for teaching some structures, and therefore the use of both types is recommended.
Rapid detection of chiral drug ephedrine using erythrosin B for the resonance Rayleigh scattering probe
Authors: Zhang Yuhui , Tan Xuanping , Wu Huan , Yang Jidong
Published: October 2020

Ephedrine (EH) and pseudoephedrine (PEH), which are chiral enantiomers commonly used clinically, have different pharmacological actions and treatment effects due to their chiral nature. In the presence of Pd2+, the reaction system of Ery B (erythrosin B)‐Pd2+ has a strong resonance Rayleigh scattering (RRS) intensity. Adding EH into this system reduced the RRS intensity, but PEH could not produce this phenomenon. The chiral recognition of these enantiomers could be achieved according to this spectral difference. At the same time, reduction in RRS strength of the reaction system is proportional to the concentration of EH. Under optimized conditions, the linear range is 40–960 ng/ml, and the detection limit is 3.9 ng/ml. A new method for the rapid detection of EH enantiomers can be established. Based on this assay, a new method for the determination of the chiral enantiomers of EH and PEH can be developed.
Phytochemicals impact on osteogenic differentiation of mesenchymal stem cells
Authors: Sharifi Simin , Moghaddam Farzin Arablouye , Abedi Atefeh , Maleki Dizaj Solmaz , Ahmadian Shahin , Abdolahinia Elaheh Dalir , Khatibi Seyed Mahdi Hosseiniyan , Samiei Mohammad
Published: October 2020

Medicinal plants have always been utilized for the prevention and treatment of the spread of different diseases all around the world. To name some traditional medicine that has been used over centuries, we can refer to phytochemicals such as naringin, icariin, genistein, and resveratrol gained from plants. Osteogenic differentiation and mineralization of stem cells can be the result of specific bioactive compounds from plants. One of the most appealing choices for therapy can be mesenchymal stem cells (MSCs) because it has a great capability of self‐renewal and differentiation into three descendants, namely, endoderm, mesoderm, and ectoderm. Stem cell gives us the glad tidings of great advances in tissue regeneration and transplantation field for treatment of diseases. Using plant bioactive phytochemicals also holds tremendous promises in treating diseases such as osteoporosis. The purpose of the present review article thus is to investigate what are the roles and consequences of phytochemicals on osteogenic differentiation of MSCs.
The transition of Rhodobacter sphaeroides into a microbial cell factory
Authors: Orsi Enrico , Beekwilder Jules , Eggink Gerrit , Kengen Servé W. M. , Weusthuis Ruud A.
Published: October 2020

Microbial cell factories are the workhorses of industrial biotechnology and improving their performances can significantly optimize industrial bioprocesses. Microbial strain engineering is often employed for increasing the competitiveness of bio‐based product synthesis over more classical petroleum‐based synthesis. Recently, efforts for strain optimization have been standardized within the iterative concept of “design‐build‐test‐learn” (DBTL). This approach has been successfully employed for the improvement of traditional cell factories like Escherichia coli and Saccharomyces cerevisiae. Within the past decade, several new‐to‐industry microorganisms have been investigated as novel cell factories, including the versatile α‐proteobacterium Rhodobacter sphaeroides. Despite its history as a laboratory strain for fundamental studies, there is a growing interest in this bacterium for its ability to synthesize relevant compounds for the bioeconomy, such as isoprenoids, poly‐β‐hydroxybutyrate, and hydrogen. In this study, we reflect on the reasons for establishing R. sphaeroides as a cell factory from the perspective of the DBTL concept. Moreover, we discuss current and future opportunities for extending the use of this microorganism for the bio‐based economy. We believe that applying the DBTL pipeline for R. sphaeroides will further strengthen its relevance as a microbial cell factory. Moreover, the proposed use of strain engineering via the DBTL approach may be extended to other microorganisms that have not been critically investigated yet for industrial applications.
Long intergenic noncoding RNA smad7 (Linc‐smad7) promotes the epithelial‐mesenchymal transition of HCC by targeting the miR‑125b/SIRT6 axis
Authors: Han Lili , Jia Lijun , Zan Ying
Published: October 2020

Long intergenic noncoding RNA smad7 (Linc‐smad7) has been recently identified as a new long non‐coding RNA (lncRNA). However, the role of Linc‐smad7 in the tumourigenesis of human cancers remains unknown. This study uncovered that Linc‐smad7 was increased in HCC samples and HCC cell lines using RT‐qPCR assays. Furthermore, the overexpression of Linc‐smad7 indicated poor clinicopathological features and outcomes for HCC patients. In addition, Linc‐smad7 promoted HCC cells proliferation, migration, invasion and EMT, as determined by MTT, colony formation, Transwell assays and western blot analysis. Functionally, it was demonstrated that Linc‐smad7 could bind with microRNA‑125b (miR‑125b), and the restoration of miR‑125b rescued the promoting effects of Linc‐smad7 on HCC cells. Finally, it was observed that sirtuin 6 (SIRT6) was positively regulated by Linc‐smad7 in HCC as the direct target of miR‑125b, and decreased SIRT6 reversed the effects of Linc‐smad7 on promoting HCC. In conclusion, the current study first identified Linc‐smad7 is increased in HCC, facilitating HCC cells proliferation, migration, invasion and EMT via regulating the miR‑125b/SIRT6 axis.
The EUTOS long‐term survival score predicts disease‐specific mortality and molecular responses among patients with chronic myeloid leukemia in a practice‐based cohort
Authors: Sato Eriko , Iriyama Noriyoshi , Tokuhira Michihide , Takaku Tomoiku , Ishikawa Maho , Nakazato Tomonori , Sugimoto Kei‐Ji , Fujita Hiroyuki , Kimura Yuta , Fujioka Isao , Asou Norio , Komatsu Norio , Kizaki Masahiro , Hatta Yoshihiro , Kawaguchi Tatsuya
Published: October 2020

The European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score predicts disease‐specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML‐related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML‐CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML‐CSG), which included patients diagnosed with CML‐CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first‐line therapy. Among 342 eligible patients, the ELTS scores indicated low‐, intermediate‐, and high‐risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease‐specific mortality and worse event‐free survival, progression‐free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low‐, intermediate‐, and high‐risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML‐CP.
Challenges and Decision Making for the Classification of Two Complex Periodontal Cases
Authors: Siqueira Rafael , Andrade Nathalia , Yu Shan‐Huey , Kornman Kenneth S. , Wang Hom‐Lay
Published: October 2020

Focused Clinical Question

What are the fundamental debates and questions related to the newly developed two‐vector system for classification of periodontal diseases that have emerged as to how to accurately assign, stage, and grade periodontitis cases? The aim of the present manuscript is to demonstrate the essential thought processes that are needed in utilizing the new periodontitis classification system to diagnose two gray zone cases.

Clinical case 1 includes an 83‐year‐old male diagnosed with periodontitis and classified as Stage III Generalized Grade B periodontitis, while clinical case 2, a 73‐year‐old male was classified as presenting Stage IV Generalized Grade B periodontitis. Although clinical and radiographic evaluations revealed similarities between the cases, the thought process that includes clinical judgment is described to guide a more accurate diagnosis following the guidelines of the new classification system.

Conclusion

The two cases demonstrated here offer an opportunity for clinicians to recognize the essential role of sound clinical judgment in certain cases when applying the new periodontal disease classification system and also clarify questions emerging from implementing this classification system.
Long‐term results of a prospective, single‐arm evaluation of everolimus‐eluting bioresorbable vascular scaffolds in infrapopliteal arteries
Authors: Varcoe Ramon L. , Menting Theo P. , Thomas Shannon D. , Lennox Andrew F.
Published: October 2020

Objectives

The aim of this study was to perform a long‐term evaluation of an everolimus eluting, bioresorbable vascular scaffold (BVS) in the treatment of de novo atherosclerotic disease within crural arteries.

Methods

A prospective, single‐arm study was performed enrolling patients with chronic lower limb ischemia between 2013 and 2018.

Results

Fifty‐five limbs in 48 patients (56% male; mean age 82.1 ± 8.0 years, range 65–97) were treated for critical limb ischemia (72.7%) or severe claudication (27.3%). Seventy‐one scaffolds were used to treat 61 lesions with a mean length of 20.1 ± 10.8 mm. During a mean follow‐up period of 35.2 ± 20.4 months, 22 (45.8%) patients had died. No late or very‐late scaffold thrombosis was observed. Overall, clinical improvement was observed in 90.9% and a limb‐salvage rate of 100% was observed. Binary restenosis was detected in 11/71(15.5%) scaffolds. Primary patency and freedom from clinically driven target lesion revascularization rates at 12, 24, 36, 48, and 60 months were 90.8% (95% confidence interval 80.7–95.8), 90.8% (80.7–95.8), 79.7% (65.8–88.4), 76.3% (61.1–86.2), 72.3% (55.5–83.4) and 97.2% (89.2–99.3), 97.2% (89.2–99.3), 90.7% (78.7–96.1), 90.7% (78.7–96.1), and 90.7% (78.7–96.1), respectively.

Conclusions

This long‐term study shows excellent rates of patency and freedom from target lesion revascularization using the absorb BVS below‐the‐knee. This proof of concept study lays the foundation for the next generation of BVS to be evaluated in infrapopliteal arteries.
Efficient Imine Formation by Oxidative Coupling at Low Temperature Catalyzed by High‐Surface‐Area Mesoporous CeO2 with Exceptional Redox Property
Authors: Wu Shipeng , Wang Yinghao , Cao Qiue , Zhao Qihua , Fang Wenhao
Published: October 2020

High‐surface‐area mesoporous CeO2 (hsmCeO2) was prepared by a facile organic‐template‐induced homogeneous precipitation process and showed excellent catalytic activity in imine synthesis in the absence of base from primary alcohols and amines in air atmosphere at low temperature. For comparison, ordinary CeO2 and hsmCeO2 after different thermal treatments were also investigated. XRD, N2 physisorption, UV‐Raman, H2 temperature‐programmed reduction, O2 temperature‐programmed desorption, EPR spectroscopy, and X‐ray photoelectron spectroscopy were used to unravel the structural and redox properties. The hsmCeO2 calcined at 400 °C shows the highest specific surface area (158 m2 g−1), the highest fraction of surface coordinatively unsaturated Ce3+ ions (18.2 %), and the highest concentration of reactive oxygen vacancies (2.4×1015 spins g−1). In the model reaction of oxidative coupling of benzyl alcohol and aniline, such an exceptional redox property of the hsmCeO2 catalyst can boost benzylideneaniline formation (2.75 and 5.55 mmol 
 h−1 based on >99 % yield at 60 and 80 °C, respectively) in air with no base additives. It can also work effectively at a temperature of 30 °C and in gram‐scale synthesis. These are among the best results for all benchmark ceria catalysts in the literature. Moreover, the hsmCeO2 catalyst shows a wide scope towards primary alcohols and amines with good to excellent yield of imines. The influence of reaction parameters, the reusability of the catalyst, and the reaction mechanism were investigated.
An efficient algorithm for Elastic I‐optimal design of generalized linear models
Authors: Li Yiou , Deng Xinwei
Published: October 2020

The generalized linear models (GLMs) are widely used in statistical analysis and the related design issues are undoubtedly challenging. The state‐of‐the‐art works mostly apply to design criteria on the estimates of regression coefficients. The prediction accuracy is usually critical in modern decision‐making and artificial intelligence applications. It is of importance to study optimal designs from the prediction aspects for GLMs. In this work, we consider Elastic I‐optimality as a prediction‐oriented design criterion for GLMs, and develop an efficient algorithm for such EI‐optimal designs. By investigating theoretical properties for the optimal weights of any set of design points and extending the general equivalence theorem to the EI‐optimality for GLMs, the proposed efficient algorithm adequately combines the Fedorov–Wynn algorithm and the multiplicative algorithm. It achieves great computational efficiency with guaranteed convergence. Numerical examples are conducted to evaluate the feasibility and computational efficiency of the proposed algorithm.
Efficient nonparametric estimation for skewed distributions
Authors: Favre‐Martinoz Cyril , Haziza David , Beaumont Jean‐François
Published: October 2020

Many variables encountered in practice have skewed distributions. While the sample mean is unbiased for the true mean regardless of the underlying distribution that generated the sample observations, it can be highly unstable in the context of skewed distributions. To cope with this problem, we propose an efficient estimator of the population mean based on the concept of conditional bias of a unit, which can be viewed as a measure of its influence. The idea is to reduce the impact of the sample units that have a large influence. The resulting estimator depends on a cut‐off value. We suggest selecting the cut‐off value that minimizes the maximum absolute estimated conditional bias with respect to the proposed estimator. An estimator of the mean square error is also presented. An empirical investigation comparing several estimators in terms of relative bias and relative efficiency suggests that the proposed estimator and the estimator of its mean square error perform well for a wide class of distributions.
Pharmacokinetics of Deutetrabenazine and Tetrabenazine: Dose Proportionality and Food Effect
Authors: Schneider Frank , Stamler David , Bradbury Margaret , Loupe Pippa S. , Hellriegel Edward , Cox Donna S. , Savola Juha‐Matti , Gordon Mark Forrest , Rabinovich‐Guilatt Laura
Published: October 2020

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α‐dihydrotetrabenazine (α‐HTBZ) and β‐dihydrotetrabenazine (β‐HTBZ). One study was an open‐label 2‐part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open‐label 5‐way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high‐fat meal. Both studies confirmed longer half‐lives for active metabolites and lower peak‐to‐trough fluctuations for the sum of the metabolites (total [α+β]‐HTBZ) following deutetrabenazine compared with tetrabenazine (3‐ to 4‐fold and 11‐fold, respectively) in steady‐state conditions. Deutetrabenazine doses estimated to provide total (α+β)‐HTBZ exposure comparable to tetrabenazine 25 mg were 11.4‐13.2 mg. Food had no effect on exposure to total (α+β)‐HTBZ, as measured by AUC. Although the total (α+β)‐HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.
A Pyridine‐Acetylene‐Aniline Oligomer: Saccharide Recognition and Influence of this Recognition Array on the Activity as Acylation Catalyst
Authors: Ohishi Yuki , Takata Toshikazu , Inouye Masahiko
Published: October 2020

In order to create new functions of foldamer‐type hosts, various kinds of recognition arrays are expected to be developed. Here, a pyridine‐acetylene‐aniline unit is presented as a new class of a saccharide recognition array. The conformational stabilities of this array were analyzed by DFT calculation, and suggested that a pyridine‐acetylene‐aniline oligomer tends to form a helical structure. An oligomer of this array was synthesized, and its association for octyl β‐D‐glucopyranoside was confirmed by 1H NMR measurements. UV/Vis, circular dichroism, and fluorescence titration experiments revealed its high affinity for octyl glycosides in apolar solvents (Ka=104 to 105 M−1). This oligomer was relatively stable under basic conditions, and therefore this array was expected to be applied to the derivatization of saccharides. A 4‐(dialkylamino)pyridine attached pyridine‐acetylene‐aniline oligomer proved to catalyze the acylation of the octyl glucoside.
Videotherapy and therapeutic alliance in the age of COVID‐19
Authors: Simpson Susan , Richardson Lisa , Pietrabissa Giada , Castelnuovo Gianluca , Reid Corinne
Published: October 2020

The arrival of the coronavirus (COVID‐19) pandemic has confronted us with a global and unprecedented challenge of community‐wide psychological distress alongside reduced access to therapeutic services in the traditional face‐to‐face format, due to the need to self‐isolate. This previously unimagineable set of circumstances provides a unique opportunity, and indeed an imperative, for videotherapy to fulfil its potential in addressing mental health and well‐being needs from a distance. Historically, the uptake of videotherapy has been hindered by psychotherapist expectations of inferior therapeutic alliance and outcomes, in spite of considerable research evidence to the contrary. Research suggests that videotherapy provides a powerful pathway for clients to experience enhanced opportunities for self‐expression, connection and intimacy. This more neutral therapeutic ‘space’ provides clients with multifarious opportunities for self‐awareness, creative experience and collaboration, with potentially a greater sense of agency over their own experience. This paper explores ways in which videotherapy can lead to a revitalisation of the concept of the therapeutic relationship, in order to meet the challenges associated with COVID‐19. A number of specific considerations for videotherapy adaptations and etiquette in the midst of COVID‐19 are described.
Photoinduced Electron Transfer in Axially Coordinated Supramolecular Zinc Tetrapyrrole Bis(styryl)BODIPY Donor‐Acceptor Conjugates
Authors: Benitz Alejandro , Thomas Michael B. , de Silva Imesha , Nesterov Vladimir N. , Verbeck Guido F. , D'Souza Francis
Published: October 2020

Photoinduced electron transfer (PET) in newly assembled dyads formed via metal‐ligand axial coordination of phenylimidazole‐functionalized bis(styryl)BODIPY (BODIPY(Im)2) and zinc tetrapyrroles, that is, zinc tetratolylporphyrin (ZnP), zinc tetra‐t‐butyl phthalocyanine (ZnPc) and zinc tetra‐t‐butyl naphthalocyanine (ZnNc), in non‐coordinating o‐dichlorobenzene (DCB) is investigated using both steady‐state and time‐resolved transient absorption techniques. The structure of the BODIPY(Im)2 was identified by using single crystal X‐ray structural analysis. The newly formed supramolecular dyads were fully characterized by spectroscopic, computational and electrochemical methods. The binding constants measured from optical absorption spectral studies were in the range of ∼104 M−1 for the first zinc tetrapyrrole binding and suggested that the two imidazole entities of bis(styryl)BODIPY behave independently in the binding process. The energy level diagram established using spectral and electrochemical studies suggested PET to be thermodynamically unfavorable in the ZnP‐bearing complex while for ZnPc‐ and ZnNc‐bearing complexes such a process is possible when zinc tetrapyrrole is selectively excited. Consequently, occurrence of efficient PET in the latter two dyads was possible to establish from femtosecond transient absorption studies wherein the electron transfer products, that is, the radical cation of zinc tetrapyrrole and the radical anion of BODIPY(Im)2, was possible to spectrally identify. From target analysis of the transient data, time constants of circa 3 ns for ZnPc⋅+:BODIPY⋅− and circa 0.5 ns for ZnNc⋅+:BODIPY⋅− were obtained indicating persistence of the radical ion‐pair to some extent. The electron acceptor property of bis(styryl)BODIPY in donor‐acceptor conjugates is borne out from the present study.
Severe delayed pulmonary toxicity following PD‐L1–specific CAR‐T cell therapy for non‐small cell lung cancer
Authors: Liu Heping , Ma Yuxiang , Yang Chaopin , Xia Shangzhou , Pan Qiuzhong , Zhao Hongyun , Fang Wenfeng , Chen Xi , Zhang Yang , Zou Benyan , Li Qiuyuan , Wan Yang , Chen Hao , Tang Yan , Zhao Jingjing , Weng Desheng , Xia Liming , Zhang Li , Xia Jianchuan
Published: October 2020

Objectives

This phase I study aimed to evaluate the antitumor effect and safety of programmed death‐ligand‐1 (PD‐L1)–targeting autologous chimeric antigen receptor T (CAR‐T) cells for patients with non‐small cell lung cancer (NSCLC).

Methods

Programmed death‐ligand‐1–specific CAR‐T cells were generated using lentiviral transduction. Four patients with NSCLC were recruited, but only one patient was finally involved. CAR‐T cells were infused on three different days (total dose during therapy, 1 × 106 CAR‐T cells kg−1 body weight). The date on which the patient received the first CAR‐T cell infusion was designated as Day 0.

Results

Circulating CAR‐T cells accounted for 3.30% of the patient’s peripheral blood T cells detected by FACS analysis during the first follow‐up (Day +29). The chest CT scan showed subtle tumor shrinkage (stable disease). On Day +43, the patient developed pyrexia without any known causes and dyspnoea that rapidly deteriorated to respiratory failure in 3 days. The chest X‐ray and CT scan showed bilateral extensive pulmonary infiltration in addition to the tumor silhouette on the left upper lung. The interleukin (IL)‐6 levels in serum dramatically increased (> 100‐fold). The patient was immediately transferred to the ICU where he received oxygen and intravenous infusions of tocilizumab and methylprednisolone. His symptoms rapidly improved and the pulmonary inflammation gradually resolved.

Conclusion

The clinical manifestations and test findings for this patient with NSCLC might represent unique clinical manifestations of solitary organ damage secondary to PD‐L1–specific CAR‐T cell therapy. The differential diagnosis, underlying mechanism and prevention and treatment strategies for such complications have also been discussed.
Transient inconsistency between population density and fisheries yields without bycatch species extinction
Authors: Chen Renfei
Published: October 2020

Recent studies have demonstrated the great advantages of marine reserves in solving bycatch problems by maintaining the persistence (i.e., avoid extinction) of endangered species without sacrificing the fisheries yields of target species. However, transient phenomena rather than equilibrium states of population dynamics still require further research. Here, with a simple and general model, the transient dynamics of the target fish species are investigated under management which minimizes extinction risk of the bycatch species. An interesting finding is that fisheries yields can strongly fluctuate even if population density both inside and outside marine reserve only slightly varies (or vice versa), leading to transient inconsistency between the population densities and fisheries yields. This finding suggests that population density dynamics of the target fish species cannot be used to predict the transient phenomena of fisheries yields (or vice versa) in fisheries management. However, the unpredictability can be receded as the sensitivity analyses show that a large marine reserve size and low escapement rate can shorten the transient duration.