bluuebunny/crossref_metadata_2025 huggingface dataset:
Deeply Rooted: Maximizing the Strengths of a Historically Black University and Community‐based Participatory Research to Understand Environmental Stressors and Trauma among Black Youth
Authors: Mance GiShawn A. , Rodgers Caryn R.R. , Roberts Debra , Terry Amanda
Published: August 2020

This paper explores a partnership between an HBCU (Historically Black Colleges and Universities) and a community to understand trauma given the high rates of reported violence among youth locally. The accumulative stress of living in high‐stress, high‐poverty environments coupled with the normative developmental tasks of adolescence is thought to place these youths at risk for negative mental and physical outcomes (Murry et al., 2011). The current research uses a community‐based participatory research (CBPR) approach and developmental lens to better understand environmental stressors and subsequent trauma among Black youth. Specifically, the paper describes the recruitment, engagement, and equitable partnership between a youth advisory board (YAB), university research team, and community agencies advisory board (CAB). The current work is part of a larger research study designed to explore environmental stressors, coping, and social supports for Black youth residing in low‐resource urban communities. The broad objective of the research is to develop a trauma‐informed community intervention to improve adolescent mental health. The initial phase of this university–community research, which entails the YAB, CAB, and university discussion groups, is outlined in this paper. Community engagement and trust are key factors described in the literature when collaborating with communities of color. These themes were reiterated by research partners in this study. The research team created coding terms to identify themes from YAB and CAB transcript data, respectively. YAB themes regarding stressors centered around financial strain, anger, and loss/violence. CAB themes regarding adolescent mental health and resources centered around trauma, trust, and sustainability. Initial steps to utilize the themes identified thus far are described. The unique advantages of an HBCU and CBPR to address mental health disparities in ethnic minority communities are also highlighted.
An additional case of Néstor‐Guillermo progeria syndrome diagnosed in early childhood
Authors: Fisher Heather G. , Patni Nivedita , Scheuerle Angela E.
Published: August 2020

Néstor‐Guillermo progeria syndrome (NGPS; OMIM 614008) is characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudosenile facial appearance, and normal cognitive development. In contrast to other progeria syndromes, NGPS is associated with a longer lifespan and higher risk for developing severe skeletal abnormalities. It is an autosomal recessive condition caused by biallelic pathogenic variants in BANF1. There are two previously reported patients with NGPS, both Spanish with molecular diagnoses made in adulthood and having the same homozygous pathogenic variant c.34G > A; p.Ala12Thr. Presented here is a 2 year, 8 month old girl with short stature, poor weight gain, sparse hair, and dysmorphic facial features reminiscent of premature aging. Whole exome sequencing identified the same c.34G > A homozygous pathogenic variant in BANF1 as reported in the previous patients. This is the first reported case of a child and is supporting evidence for this recurrent loss of function variant.
The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates
Authors: Méjécase Cécile , Kozak Igor , Moosajee Mariya
Published: August 2020

Genetic eye diseases are phenotypically and genetically heterogeneous, affecting 1 in 1,000 people worldwide. This prevalence can increase in populations where endogamy is a social preference, such as in Arab populations. A retrospective consecutive cohort of 91 patients from 74 unrelated families affected with non‐syndromic and syndromic inherited eye disease presenting to the ocular genetics service at Moorfields Eye Hospitals United Arab Emirates (UAE) between 2017 and 2019, underwent clinically accredited genetic testing using targeted gene panels. The mean ± SD age of probands was 27.4 ± 16.2 years, and 45% were female (41/91). The UAE has a diverse and dynamic population, and the main ethnicity of families in this cohort was 74% Arab (n = 55), 8% Indian (n = 6) and 7% Pakistani (n = 5). Fifty‐six families (90.3%) were genetically solved, with 69 disease‐causing variants in 40 genes. Fourteen novel variants were detected with large deletions in CDHR1 and TTLL5, a multiexon (1–8) duplication in TEAD1 and 11 single nucleotides variants in 9 further genes. ABCA4‐retinopathy was the most frequent cause accounting for 21% of cases, with the confirmed UAE founder mutation c.5882G>A p.(Gly1961Glu)/c.2570T>C p.(Leu857Pro) in 25%. High diagnostic yield for UAE patients can guide prognosis, family decision‐making, access to clinical trials and approved treatments.
Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non‐profit foundation
Authors: Mansfield Brian C. , Yerxa Benjamin R. , Branham Kari H.
Published: August 2020

The Foundation Fighting Blindness is a 50‐year old 501c(3) non‐profit organization dedicated to supporting the development of treatments and cures for people affected by the inherited retinal diseases (IRD), a group of clinical diagnoses that include orphan diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease, among others. Over $760 M has been raised and invested in preclinical and clinical research and resources. Key resources include a multi‐national clinical consortium, an international patient registry with over 15,700 members that is expanding rapidly, and an open access genetic testing program that provides no cost comprehensive genetic testing to people clinically diagnosed with an IRD living in the United States. These programs are described with particular focus on the challenges and outcomes of establishing the registry and genetic testing program.
A General Strategy for Hollow Metal‐Phytate Coordination Complex Micropolyhedra Enabled by Cation Exchange
Authors: Chen Meiling , Peng Chenxi , Su Yaoquan , Chen Xue , Zhang Yuezhou , Wang Yu , Peng Juanjuan , Sun Qiang , Liu Xiaowang , Huang Wei
Published: August 2020

The ability to incorporate functional metal ions (Mn+) into metal–organic coordination complexes adds remarkable flexibility in the synthesis of multifunctional organic–inorganic hybrid materials with tailorable electronic, optical, and magnetic properties. We report the cation‐exchanged synthesis of a diverse range of hollow Mn+‐phytate (PA) micropolyhedra via the use of hollow Co2+‐PA polyhedral networks as templates at room temperature. The attributes of the incoming Mn+, namely Lewis acidity and ionic radius, control the exchange of the parent Co2+ions and the degree of morphological deformation of the resulting hollow micropolyhedra. New functions can be obtained for both completely and partially exchanged products, as supported by the observation of Ln3+(Ln3+=Tb3+, Eu3+, and Sm3+) luminescence from as‐prepared hollow Ln3+‐PA micropolyhedra after surface modification with dipicolinic acid as an antenna. Moreover, Fe3+‐ and Mn2+‐PA polyhedral complexes were employed as magnetic contrast agents.
Hydroxamic Acids Immobilized on Resins (HAIRs): Synthese von Dual‐Target‐HDAC‐Inhibitoren und HDAC‐PROTACs
Authors: Sinatra Laura , Bandolik Jan J. , Roatsch Martin , Sönnichsen Melf , Schoeder Clara T. , Hamacher Alexandra , Schöler Andrea , Borkhardt Arndt , Meiler Jens , Bhatia Sanil , Kassack Matthias U. , Hansen Finn K.
Published: August 2020

Multi‐Target‐Wirkstoffe stellen in der modernen Tumortherapie einen vielversprechenden Ansatz dar. Basierend auf dem bekannten Synergismus zwischen Histon‐Deacetylase‐Inhibitoren (HDACi) und alkylierenden Zytostatika präsentieren wir in dieser Arbeit die Entwicklung von alkylierenden HDACi, welche aus einer Pharmakophor‐Verknüpfungsstrategie hervorgegangen sind. Für die Synthese haben wir ein Protokoll entwickelt, bei dem Hydroxamsäuren an Festphasenharze immobilisiert und als vielseitig anwendbare Bausteine für die Synthese von funktionalisierten HDACi verwendet wurden. Verbindung 3 n zeigt eine signifikant bessere Induktion der Apoptose, Caspase‐3/7‐Aktivierung und Erzeugung von DNA‐Schäden als die Summe der biologischen Aktivitäten der einzelnen Pharmakophore. Um die Vielseitigkeit unserer beladenen Harze zu demonstrieren, wurde dieses Konzept auf die Synthese eines HDAC‐PROTAC 4 übertragen. Western‐Blot‐Experimente bestätigten, dass PROTAC 4 den Abbau von HDACs effizient induziert.
LaOCl‐Coupled Polymeric Carbon Nitride for Overall Water Splitting through a One‐Photon Excitation Pathway
Authors: Lin Yuan , Su Wenyue , Wang Xuxu , Fu Xianzhi , Wang Xinchen
Published: August 2020

It is a challenge to explore photocatalytic materials for sunlight‐driven water splitting owing to the limited choice of a single semiconductor with suitable band energy levels but with a minimized band gap for light harvesting. Here, we report a one‐photon excitation pathway by coupling polymeric carbon nitride (PCN) semiconductor with LaOCl to achieve overall water splitting. This artificial photosynthesis composite catalyzes the decomposition of H2O into H2 and O2, with evolution rates of 22.3 and 10.7 μmol h−1, respectively. The high photocatalytic performance of PCN/LaOCl can be ascribed to the simultaneously accomplished reduction and oxidation of water on LaOCl and PCN domains, respectively, as well as the fast charge separation and migration induced by the interfacial electric field related to LaOCl modification. This study provides new insights on the development of composite photocatalysts for pure water splitting based on polymer‐based materials via charge modulation.
Damage and Repair in Informational Poly(N‐substituted urethane)s
Authors: Mondal Tathagata , Charles Laurence , Lutz Jean‐François
Published: August 2020

The degradation and repair of uniform sequence‐defined poly(N‐substituted urethane)s was studied. Polymers containing an ω‐OH end‐group and only ethyl carbamate main‐chain repeat units rapidly degrade in NaOH solution through an ω→α depolymerization mechanism with no apparent sign of random chain cleavage. The degradation mechanism is not notably affected by the nature of the side‐chain N‐substituents and took place for all studied sequences. On the other hand, depolymerization is significantly influenced by the molecular structure of the main‐chain repeat units. For instance, hexyl carbamate main‐chain motifs block unzipping and can therefore be used to control the degradation of specific sequence sections. Interestingly, the partially degraded polymers can also be repaired; for example by using a combination of N,N′‐disuccinimidyl carbonate with a secondary amine building‐block. Overall, these findings open up interesting new avenues for chain‐healing and sequence editing.
Enantiospecific Solid Solution Formation Triggers the Propagation of Homochirality
Authors: Baglai Iaroslav , Leeman Michel , Wurst Klaus , Kellogg Richard M. , Noorduin Willem L.
Published: August 2020

Propagation of homochirality plays a crucial role in the discussion on the origin of life. We investigated the role of structurally related enantiopure additives in chiral symmetry breaking during reactive crystallizations. We demonstrate that symmetry breaking can be driven towards the same absolute configuration as the additive if this additive forms an enantiospecific solid solution with the racemate. We observe two antagonistic processes: enantiospecific growth inhibition directs symmetry breaking to the opposite enantiomer following “the rule of reversal”, and enantiospecific solid solution formation that favors homochiral outcome. During continuous grinding, contributions of solid solution formation override contributions of enantiospecific growth inhibition, directing the process towards the absolute configuration of the additive. Collectively, our findings offer a potential mechanism for the propagation of homochirality.
A Robust Mixed‐Lanthanide PolyMOF Membrane for Ratiometric Temperature Sensing
Authors: Feng Tongtong , Ye Yingxiang , Liu Xiao , Cui Hui , Li Zhiqiang , Zhang Ying , Liang Bin , Li Huanrong , Chen Banglin
Published: August 2020

Temperature sensors play a significant role in biology, chemistry, and engineering, especially those that can work accurately in a noninvasive manner. We adopted a photoinduced post‐synthetic copolymerization strategy to realize a membranous ratiometric luminescent thermometer based on the emissions of two lanthanide ions. This novel mixed‐lanthanide polyMOF membrane exhibits not only the integrity and temperature sensing behaviour of the Ln‐MOF powder but also excellent mechanical properties, such as flexibility, elasticity, and processability. Moreover, the polyMOF membrane shows remarkable stability under harsh conditions, including high humidity, strong acid and alkali (pH 0–14), which allowed the mapping of temperature distributions in extreme circumstances. This work highlights a simple strategy for polyMOF membrane formation and pushes forward the further practical application of Ln‐MOF‐based luminescent thermometers in various fields and conditions.
Duale Emission: Klassen, Mechanismen und Bedingungen
Authors: Behera Santosh Kumar , Park Soo Young , Gierschner Johannes
Published: August 2020

Dual emittierende (DE‐)Verbindungen finden starkes Interesse in den Material‐ and Biowissenschaften; allerdings fehlt eine systematische Zusammenfassung der zugrundeliegenden Prozesse. Diese erfolgt hier durch eine Klassifizierung der DE‐Phänomene, wobei zwischen Prozessen unterschieden wird, die einerseits auf nur einem Emitter mit zwei emittierenden Zuständen oder andererseits auf zwei unbhängigen Emittern oder zwei korrelierten Emittern beruhen. Danach werden die für die Materialwissenschaften relevanten DE‐Mechnismen beschrieben, wobei die elektronischen und geometrischen Bedingungen herausgearbeitet werden, unter denen sie erfolgen; die weiterführende Literatur, auf die verwiesen wird, soll einen genaueren Einblick in die mechanistischen Aspekte der DE‐Prozesse und einen Überblick über die Substanzklassen und ihre Anwendungen geben. Indem Zweideutigkeiten vermieden werden und auf Fehlinterpretationen hingewiesen wird, mag diese Übersicht die weitere gezielte Entwicklung von DE‐Materialien fördern.
Ein einfach koordiniertes Silizium(II)‐Kation: Ein kristallines “Supersilylen”
Authors: Hinz Alexander
Published: August 2020

Einfach koordinierte Silizium(II)‐Kationen werden als reaktive Ambiphile angesehen, die die typische hohe Lewis‐Acidität von Siliziumkationen mit Nucleophilie durch die Gegenwart eines freien Elektronenpaars am selben Atom vereinigen. Nun wurde ein Carbazolderivat als Substituent genutzt, um Salze mit einem einfach koordinierten Silizium(II)‐Kation [RSi]+, (R=sterisch anspruchsvoller Carbazolylsubstituent), durch Halogenidabstraktion von einem basenfreien Iodosilylen mit Ag[Al(OtBuF)4] darzustellen. Trotz der sterischen Abschirmung beweist das Silylenyliumkation [RSi]+ hohe Reaktivität. Es wurde gezeigt, dass durch Umsetzung mit einem Amin drei Bindungen am Siliziumatom in einer Reaktion gebildet werden können, was mit dem Konzept eines “Supersilylens” einhergeht. Das so durch oxidative Addition einer NH‐Bindung an [RSi]+ erhaltene Silyliumion [RSi(H)NR′2]+ (in der Oxidationsstufe SiIV) ist noch acider als das Silylenyliumion (SiII), da kein freies Elektronenpaar am Siliziumatom mehr vorhanden ist.
Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
Authors: Sinatra Laura , Bandolik Jan J. , Roatsch Martin , Sönnichsen Melf , Schoeder Clara T. , Hamacher Alexandra , Schöler Andrea , Borkhardt Arndt , Meiler Jens , Bhatia Sanil , Kassack Matthias U. , Hansen Finn K.
Published: August 2020

Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases.
Dual Emission: Classes, Mechanisms, and Conditions
Authors: Behera Santosh Kumar , Park Soo Young , Gierschner Johannes
Published: August 2020

There has been much interest in dual‐emission materials in the past few years for materials and life science applications; however, a systematic overview of the underlying processes is so‐far missing. We resolve this issue herein by classifying dual‐emission (DE) phenomena as relying on one emitter with two emitting states (DE1), two independent emitters (DE2), or two correlated emitters (DE3). Relevant DE mechanisms for materials science are then briefly described together with the electronic and/or geometrical conditions under which they occur. For further reading, references are given that offer detailed insight into the complex mechanistic aspects of the various DE processes or provide overviews on materials families or their applications. By avoiding ambiguities and misinterpretations, this systematic, insightful Review might inspire future targeted designs of DE materials.
A Mono‐Substituted Silicon(II) Cation: A Crystalline “Supersilylene”
Authors: Hinz Alexander
Published: August 2020

Mono‐coordinated silicon(II) cations are predicted to be reactive ambiphiles, combining the typically high Lewis acidity of silicon cations with nucleophilicity due to the presence of an electron pair at the same atomic centre. Here, a carbazole‐derived scaffold was used to isolate salts with a mono‐coordinated silicon(II) cation, [RSi]+ (R=bulky carbazolyl substituent), by halide abstraction from a base‐free halosilylene, RSiI, with Ag[Al(OtBuF)4]. Despite the bulk of the carbazolyl moiety, the silylenylium cation [RSi]+ retains high reactivity. It was shown to react with an amine to form three bonds at the silicon atom in one reaction which conforms with the notion of a “supersilylene”. The resulting silylium cation [RSi(H)NR′2]+ (in the formal oxidation state SiIV) obtained by oxidative addition of an NH bond at [RSi]+ is even more acidic than the silylenylium cation (SiII) due to the absence of a lone pair of electrons the silicon atom.
Screening of Bombyx mori brain proteins interacting with protein tyrosine phosphatase of BmNPV
Authors: Wang Guobao , Na Shuang , Qin Li
Published: August 2020

In this study, glutathione‐S‐transferase pull‐down combined with mass spectrometry techniques were used to identify the candidate proteins interacting with protein tyrosine phosphatase of the Bombyx Mori nucleopolyhedrovirus in the B. mori (BmNPV‐PTP) brain. A total of 36 proteins were identified from BmNPV‐PTP coprecipitate samples by searching the NCBI_Bombyx Mori database with the original mass spectrum data. Among those proteins, the interaction between BmNPV‐PTP and B. mori cyclophilin A may accelerate the apoptosis of certain nerve cells involved in regulating behavior, and thus may be an inducer of enhanced locomotor activity (ELA). After the BmNPV invasion, BmNPV‐PTP binding to peripheral‐type benzodiazepine receptors may initiate a series of abnormal cascades of the nervous system, which results in abnormal hyperactive behavior in B. mori. Besides this, vacuolar ATP synthase catalytic subunit A, annexin, and several enzymes for energy conversion were identified, which may play a role in enhancing viral entry and infectivity and provide energy for enhancing the locomotor activity of B. mori. In general, the results of this study will facilitate the understanding of the molecular mechanisms underlying the ELA of B. mori larva induced by BmNPV.
Synthesis of novel 4,5‐dihydropyrrolo[1,2‐a]quinoxalines, pyrrolo[1,2‐a]quinoxalin]‐2‐ones and their antituberculosis and anticancer activity
Authors: Makane Vitthal B. , Vamshi Krishna Eruva , Karale Uattam B. , Babar Dattatraya A. , Kalari Saradhi , Rekha Estharla M. , Shukla Manjulika , Kaul Grace , Sriram Dharmarajan , Chopra Sidharth , Misra Sunil , Rode Haridas B.
Published: August 2020

A facile strategy was developed for the synthesis of biologically important 4,5‐dihydropyrrolo[1,2‐a]quinoxalines and pyrrolo[1,2‐a]quinoxalin]‐2‐ones by treating 2‐(1H‐pyrrol‐1‐yl)anilines with imidazo[1,2‐a]pyridine‐3‐carbaldehyde or isatin, using amidosulfonic acid (NH3SO3) as a solid catalyst in water at room temperature. The protocol has been extended to electrophile ninhydrin. The catalyst could be recycled for six times without the loss of activity. The compounds were evaluated for their antituberculosis, antibacterial, and anticancer activities. It is worth noting that compounds 3d and 3e demonstrated a minimum inhibitory concentration value of 6.25 µM against Mycobacterium tuberculosis H37Rv, whereas compounds 3d, 3g, 5d, 5e, and 5i showed a remarkable inhibition of A549, DU145, HeLa, HepG2, MCF‐7, and B16‐F10 cell lines, respectively. Staphylococcus aureus was inhibited by compounds 5b, 5e, 5d, 5g, and 5l at 32 µg/ml.
Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin–Resistant Kawasaki Disease
Authors: Koné‐Paut Isabelle , Tellier Stéphanie , Belot Alexandre , Brochard Karine , Guitton Corinne , Marie Isabelle , Meinzer Ulrich , Cherqaoui Bilade , Galeotti Caroline , Boukhedouni Nadja , Agostini Helene , Arditi Moshe , Lambert Virginie , Piedvache Céline
Published: August 2020

Objective

Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)– and steroid‐resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin‐1 in patients with IVIG‐resistant KD.

Methods

Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient’s body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C‐reactive protein (CRP) levels.

Results

Seventy‐five percent of patients in the intention‐to‐treat group and 87.5% in the per‐protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1–99.8%) of physician evaluations and on 100% (95% CI 73.5–100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7–81.3%]) and 6 of 12 patients (50% [95% CI 21.1–78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred.

Conclusion

Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG‐refractory KD.
Synergistic Roles of Macrophages and Neutrophils in Osteoarthritis Progression
Authors: Hsueh Ming‐Feng , Zhang Xin , Wellman Samuel S. , Bolognesi Michael P. , Kraus Virginia B.
Published: August 2020

Objective

To evaluate the role of immune cells and their effector cytokines in the pathogenesis and progression of knee osteoarthritis (OA) in matched OA synovial fluid (SF) and synovial tissue samples.

Methods

Cells from matched samples of synovial tissue and SF acquired from individuals undergoing total knee replacement for OA (n = 39) were characterized for immune cell–associated surface markers and intracellular cytokine expression using polychromatic flow cytometry. Additional individuals with radiographic knee OA (Kellgren/Lawrence severity grades ≥1) who had available etarfolatide (inflammatory cell) imaging (n = 26) or baseline and 3‐year data on progression of radiographic knee OA (n = 85) were also assessed. SF cytokine concentrations in all cohorts were evaluated for associations with synovial tissue and SF cell phenotypes and severity of radiographic knee OA.

Results

Macrophages (predominant in the synovial tissue, 53% of total cells) and neutrophils (predominant in the SF, 26% of total cells) were the major immune cell populations identified in the OA knee joints, exhibiting expression of or association with transforming growth factor β1 (TGFβ1) and elastase, respectively, in the SF. Expression levels of TGFβ1 and elastase were significantly associated with severity of radiographic knee OA. Baseline SF concentrations of TGFβ1 and elastase along with radiographic knee OA severity scores were predictive of knee OA progression, with areas under the receiver operating characteristic curves of 0.810 (for TGFβ1), 0.806 (for elastase), and 0.846 (for both TGFβ1 and elastase combined), with greater stability of prediction when both markers were utilized.

Conclusion

Our findings demonstrate the hitherto underappreciated role of neutrophils in the sterile inflammatory process and progression of OA. Two soluble mediators, SF elastase and TGFβ1, are strong predictors of knee OA progression, reflecting a synergistic role of neutrophil and macrophage populations in the pathogenesis and worsening of OA that could potentially be utilized to identify patients who may have a greater risk of more rapid disease progression.
Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open‐Label, Randomized Study
Authors: Quartier Pierre , Alexeeva Ekaterina , Constantin Tamàs , Chasnyk Vyacheslav , Wulffraat Nico , Palmblad Karin , Wouters Carine , I. Brunner Hermine , Marzan Katherine , Schneider Rayfel , Horneff Gerd , Martini Alberto , Anton Jordi , Wei Xiaoling , Slade Alan , Ruperto Nicolino , Abrams Ken ,   the Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group
Published: August 2020

Objective

To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA).

Methods

The study was designed as a 2‐part phase IIIb/IV open‐label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study.

Results

In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified.

Conclusion

Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin‐1 inhibition appears necessary to maintain this response.
A Diaminodiacid (DADA) Strategy for the Development of Disulfide Surrogate Peptides
Authors: Qi Yun‐Kun , Qu Qian , Bierer Donald , Liu Lei
Published: August 2020

Disulfide bond‐containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid‐phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA‐based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA‐based disulfide surrogates are described.
Sequestering Ability of a Synthetic Chelating Agent towards Copper(II) and Iron(III): A Detailed Theoretical and Experimental Analysis
Authors: Ritacca Alessandra G. , Malacaria Luana , Algieri Vincenzo , De Nino Antonio , Russo Nino , Furia Emilia , Maiuolo Loredana , Sicilia Emilia
Published: August 2020

In the continuous effort to identify selective chelators towards bioavailable and toxic metal ions, the potential selectivity of a novel N,O chelating ligand, recently synthesized and claimed to be able to bind to Cu(II) ions forming stable complexes while leaving unaltered the level of essential metal ions, was scrutinized using a combined theoretical and experimental approach. A multistep synthetic procedure was used to synthesize the ligand, whose chelating properties along with the stability of the complexes formed binding Cu(II) and, for comparison, Fe(III) ions were evaluated using potentiometric measurements and UV‐Vis spectroscopy. DFT analysis allowed to disclose the structural characteristics of the formed complexes. In the plethora of all the possible structures, a selection of the most reliable ones was achieved by means of a stringent comparison between experimental and simulated UV‐Vis spectra. The outcomes of the present investigation demonstrate that the Cu(II) sequestering ability of the ligand is smaller than that towards Fe(III). The strategy used here should allow to check the propensity of ligands in selectively binding metal ions.
Ruthenium‐Hydride Assisted Remarkable Diversity Towards Non‐Spectator Feature of Benzodifuroxan
Authors: Dey Sanchaita , Panda Sanjib , Lahiri Goutam Kumar
Published: August 2020

The present article demonstrates that ruthenium‐hydride [RuII(H)(Cl)(CO)(PPh3)3] mediated diverse functionalization modes of benzodifuroxan (BDF) encompassing two furoxan rings. Hydride transfer from the metal precursor facilitated multiple cascade reactions involving unsymmetrical cleavage of the furoxan rings of BDF, leading to the one‐pot formation of a series of ruthenium (II) coordinated functionalized ligands exhibiting bidentate κ2‐N,O, κ2‐N,N′ and bis‐bidentate μ‐bis(κ2‐N,O) modes. Further, a moderately stable intermediate species was also encountered in the reaction sequence in which the transformed deoxygenated ligand coordinated to the metal ion via the rarely manifested furazan ring (κ2‐N,N′′ mode). The products were authenticated by their single‐crystal X‐ray structures and other spectroscopic/analytical techniques. Redox non‐innocence of the functionalized ligands in the complexes was illustrated by spectroelectrochemistry (cyclic voltammmetry, UV‐Vis. and EPR) in conjunction with DFT/TD‐DFT calculations. Mechanistic outline for the facile ring opening processes of BDF including interconversions of complexes (e. g. reductive ring opening) were also addressed.
Zum Einsatz von ZFSV im Fernwärmeleitungsbau
Authors: Weidlich Ingo
Published: August 2020

Zeitweise fließfähige selbstverdichtende Verfüllbaustoffe (ZFSV) sind Verfüllbaustoffe aus Böden und Baustoffen, die nur unter dem Einfluss der Schwerkraft in Hohlräume fließen und nach einem definierten Zeitraum den Anwendungen entsprechende physikalische Eigenschaften aufweisen. Im Leitungsbau kommen ZFSV zum Einsatz, um bei der offenen Bauweise den Graben zu verfüllen. Vorbehalte gegenüber der Übertragbarkeit vorhandener Berechnungsmethoden für die Rohrstatik und die dauerhafte Gewährleistung der Wiederaushubfestigkeit führten zu einem bis heute andauernden Akzeptanzproblem dieser Verlegemethode im Fernwärmeleitungsbau. Da sich Fernwärmeleitungen nach der Installation infolge eines thermischen Belastungskollektivs im Betrieb ausdehnen, interagieren diese Leitungen immer mit dem anstehenden Bettungsmaterial. Mit dem vorliegenden Aufsatz wird ein Einblick in den Stand des Wissens gegeben und ein vereinfachter Berechnungsansatz vorgeschlagen, der neben deutlich komplexeren Modellen steht und daher die Möglichkeit bietet, aufgrund der Einfachheit Akzeptanzprobleme zu überwinden.
International variation in managing locally advanced or recurrent rectal cancer: prospective benchmark analysis
Authors: Denost Q , Solomon M , Tuech J-J , Ghouti L , Cotte E , Panis Y , Lelong B , Rouanet P , Faucheron J-L , Jafari M , Lefevre J H , Rullier E , Heriot A , Austin K , Lee P , Brown W , Maillou-Martinaud H , Savel H , Quintard B , Broc G , Saillour-Glénisson F
Published: August 2020

Background

Tumour extension beyond the mesorectal plane (ymrT4) occurs in 5–10 per cent of patients with rectal cancer and 10 per cent of patients develop locally recurrent rectal cancer (LRRC) after primary surgery. There is global variation in healthcare delivery for these conditions.

Methods

An international benchmark trial of the management of ymrT4 tumours and LRRC was undertaken in France and Australia between 2015 and 2017. Heterogeneity in management and operative decision-making were analysed by comparison of surgical resection rates, blinded intercountry reading of pelvic MRI, quality-of-life assessment and qualitative evaluations.

Results

Among 154 patients (97 in France and 57 in Australia), 31·8 per cent had ymrT4 disease and 68·2 per cent LRRC. The surgical resection rates were 88 and 79 per cent in France and Australia respectively (P = 0·112). The concordance in operative planning was low (κ = 0·314); the rate of pelvic exenteration was lower in France than Australia both in clinical practice (36 of 78 versus 34 of 40; P < 0·001) and in theoretical conditions (10 of 25 versus 50 of 57; P = 0·002). The R0 resection rate was lower in France than Australia for LRRC (25 of 49 versus 18 of 21; P = 0·007) but not for ymrT4 tumours (21 of 26 versus 15 of 15; P = 0·139). Morbidity rates were similar. Patients who underwent non-exenterative procedures had higher scores on the mental functioning subscale at 12 months (P = 0·047), and a lower level of distress at 6 months (P = 0·049). Qualitative analysis highlighted five categories of psychosocial factors influencing treatment decisions: patient, strategy, specialist, organization and culture.

Conclusion

This international benchmark trial has highlighted the differences in worldwide treatment of locally advanced and LRRC. Standardized care should improve outcomes for these patients.
MiR‐5683 suppresses glycolysis and proliferation through targeting pyruvate dehydrogenase kinase 4 in gastric cancer
Authors: Miao Yongchang , Li Qing , Sun Guangli , Wang Lu , Zhang Diancai , Xu Hao , Xu Zekuan
Published: August 2020

Gastric cancer (GC) is one of the most deadly malignancies at global scale, and is particularly common in eastern Asia. MicroRNA‐5683 (miR‐5683) was confirmed to be downregulated in GC by analyzing data from the Cancer Genome Atlas. We packaged miR‐5683‐mimics and miR‐5683‐inhibitors into lentivirus vectors and transfected them into GC cells. MiR‐5683 expression and possible target genes were detected by employing quantitative real‐time polymerase chain reaction. In vitro, cell proliferation and apoptosis were analyzed using CCK‐8, colony formation assay, and flow cytometric assay. We verified the direct interaction between miR‐5683 and the possible downstream target gene pyruvate dehydrogenase kinase 4 (PDK4) through luciferase reporter assay. The role of miR‐5683 in vivo was explored by injecting stably transfected GC cells subcutaneously into nude mice. Here we show that miR‐5683 was downregulated in GC and the decreased level of miR‐5683 enhances GC cell proliferation and impairs apoptosis. Tumor oncogene PDK4, which is associated with GC overall survival and disease‐free survival, has been identified as the target gene of miR‐5683. Besides, we demonstrate that the inhibition of miR‐5683 promotes glycolysis by upregulating the PDK4 expression, thus leading to GC progression. Our study determines that miR‐5683 represses GC glycolysis and progression through targeting PDK4. MiR‐5683 overexpression may thus become a new treatment strategy for GC.
Tetrandrine sensitizes nasopharyngeal carcinoma cells to irradiation by inducing autophagy and inhibiting MEK/ERK pathway
Authors: Wang Jun , Yao Zhouzhou , Lai Xiaoping , Bao Hongwei , Li Yue , Li Shuaixiang , Chang Lihong , Zhang Gehua
Published: August 2020

Radioresistance was the main reason for local recurrence and metastasis of nasopharyngeal carcinoma. Tetrandrine is reported as an antitumor drug via inducing cell cycle arrest and apoptosis. In this study, the radiosensitization effects of maximum noncytotoxic doses of tetrandrine in nasopharyngeal carcinoma were analyzed both in vitro and in vivo, using MTT assay, western blot, TUNEL, and HE staining. It was found that the maximum dose of tetrandrine inhibited the phosphorylation of ERK and MEK induced by irradiation, and significantly enhanced irradiation‐induced cell growth inhibition in nasopharyngeal carcinoma cells CNE1, CNE2, and C666‐1. The ERK activator and overexpression of ERK reversed the radiosensitization effect of tetrandrine. About 50 mg/kg of tetrandrine which was used as the maximum noncytotoxic dose of tetrandrine in vivo, enhanced the radiosensitivity of the xenograft tumor and increased the apoptosis rate of the xenograft tumor cells caused by irradiation, while did not raise the side effect of the treatment. Moreover, tetrandrine increased autophagy in nasopharyngeal carcinoma cells. These results suggested that the maximum noncytotoxic dose of tetrandrine sensitized nasopharyngeal carcinoma to irradiation by inhibiting MEK/ERK pathway and inducing autophagy.
Immunosuppressive role of CD11b+CD33+HLA‐DR− myeloid‐derived suppressor cells‐like blast subpopulation in acute myeloid leukemia
Authors: Hyun Shin Young , Na Eun Jung , Jang Ji Eun , Chung Haerim , Kim Soo Jeong , Kim Jin Seok , Kong Jee Hyun , Shim Kwang Yong , Lee Jong In , Min Yoo Hong , Cheong June‐Won
Published: August 2020

Objective

Myeloid‐derived suppressor cells (MDSCs) facilitate tumor growth and development by suppressing T cell function; however, their role in acute myeloid leukemia (AML) remains unclear. Here, we investigated the immunosuppressive role and prognostic value of blasts with an MDSC‐like phenotype.

Methods

CD11b+CD33+HLA‐DR− MDSC‐like blasts from bone marrow mononuclear cells of patients with AML were analyzed. To investigate their T cell‐suppressing function, MDSC‐like blasts were isolated using flow cytometry and co‐cultured with CD8+ cytotoxic T cells and NB4 leukemic cells. Treatment outcomes were then compared between the MDSC‐like blasts low (≤9.76%) and high (>9.76%) groups to identify clinical significance.

Results

MDSC‐like blasts showed higher expression of arginase‐1 and inducible nitric oxide synthase. Isolated MDSC‐like blasts significantly suppressed CD8+ T cell proliferation induced by phytohemagglutinin A. NB4 cell proliferation was significantly suppressed upon co‐culture with CD8+ cytotoxic T cells and partially restored upon co‐culture with MDSC‐like blasts. Patients with high MDSC‐like blasts at diagnosis showed substantially shorter overall survival and leukemia‐free survival relative to low MDSC‐like blasts patients, with subgroup analysis showing statistically significant differences in patients not receiving allogeneic hematopoietic stem cell transplantation.

Conclusion

We demonstrated that MDSC‐like blasts drive AML‐specific immune‐escape mechanisms by suppressing T cell proliferation and restoring T cell‐suppressed NB4 cell proliferation, with clinically higher fractions of MDSC‐like blasts at diagnosis resulting in poor prognosis.
Identification of small molecule drugs and development of a novel autophagy‐related prognostic signature for kidney renal clear cell carcinoma
Authors: Xing Qianwei , Ji Chengjian , Zhu Bingye , Cong Rong , Wang Yi
Published: August 2020

Abnormal autophagic levels have been implicated in the pathogenesis of multiple cancers, however, its role in tumors is complex and has not yet been explored clearly. Hence, we aimed to explore the prognostic values of autophagy‐related genes (ARGs) for kidney renal clear cell carcinoma (KIRC). Differentially expressed ARGs and transcription factors (TFs) were identified in KIRC patients obtaining from the The Cancer Genome Atlas (TCGA) database. Then, networks between TFs and ARGs, gene ontology functional annotations and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were conducted. Next, we performed consensus clustering, COX regression analysis and Lasso regression analysis to identify the prognostic ARGs. Finally, an individual prognostic index (PI, riskScore) was established. Based on TCGA cohort and ArrayExpress cohort, Survival analysis, ROC curve, independent prognostic analysis, and clinical correlation analysis were also performed to evaluate this PI. Based on differentially expressed ARGs, KIRC patients were successfully divided into two clusters (P = 5.916e‐04). AS for PI, it was constructed based on 11 ARGs and significantly classified KIRC patients into high‐risk group and low‐risk group in terms of OS (P = 4.885e‐15 for TCGA cohort, P = 6.366e‐03 for ArrayExpress cohort). AUC of its ROC curve reached 0.747 for TCGA cohort and 0.779 for ArrayExpress cohort. What's more, this PI was proven to be a valuable independent prognostic factor in both univariate and multivariate COX regression analysis (P < .001). Prognostic nomograms were also performed to visualize the relationship between individual predictors and survival rates in patients with KIRC. By means of connectivity map database, emetine, cephaeline and co‐dergocrine mesilate related to ARGs were found to be negatively correlated with KIRC. This study provided an effective PI for KIRC and also displayed networks between TFs and ARGs. KIRC patients were successfully divided into two clusters based on differentially expressed ARGs. Besides, small molecule drugs related to ARGs were also identified for KIRC.
In‐hospital stroke after transcatheter aortic valve implantation: A UK observational cohort analysis
Authors: Myat Aung , Buckner Luke , Mouy Florence , Cockburn James , Baumbach Andreas , Banning Adrian P. , Blackman Daniel J. , Curzen Nick , MacCarthy Philip , Mullen Michael , de Belder Mark , Cox Ian , Kovac Jan , Brecker Stephen , Turner Mark , Khogali Saib , Malik Iqbal S. , Alsanjari Osama , Redwood Simon , Prendergast Bernard , Trivedi Uday , Robinson Derek , Ludman Peter , de Belder Adam , Hildick‐Smith David
Published: August 2020

Objectives

We sought to identify baseline demographics and procedural factors that might independently predict in‐hospital stroke following transcatheter aortic valve implantation (TAVI).

Background

Stroke is a recognized, albeit infrequent, complication of TAVI. Established predictors of procedure‐related in‐hospital stroke; however, remain poorly defined.

Methods

We conducted an observational cohort analysis of the multicenter UK TAVI registry. The primary outcome measure was the incidence of in‐hospital stroke.

Results

A total of 8,652 TAVI procedures were performed from 2007 to 2015. There were 205 in‐hospital strokes reported by participating centers equivalent to an overall stroke incidence of 2.4%. Univariate analysis showed that the implantation of balloon‐expandable valves caused significantly fewer strokes (balloon‐expandable 96/4,613 [2.08%] vs. self‐expandable 95/3,272 [2.90%]; p = .020). After multivariable analysis, prior cerebrovascular disease (CVD) (odds ratio [OR] 1.51, 95% confidence interval [CI 1.05–2.17]; p = .03), advanced age at time of operation (OR 1.02 [0.10–1.04]; p = .05), bailout coronary stenting (OR 5.94 [2.03–17.39]; p = .008), and earlier year of procedure (OR 0.93 [0.87–1.00]; p = .04) were associated with an increased in‐hospital stroke risk. There was a reduced stroke risk in those who had prior cardiac surgery (OR 0.62 [0.41–0.93]; p = .01) and a first‐generation balloon‐expandable valve implanted (OR 0.72 [0.53–0.97]; p = .03). In‐hospital stroke significantly increased 30‐day (OR 5.22 [3.49–7.81]; p < .001) and 1‐year mortality (OR 3.21 [2.15–4.78]; p < .001).

Conclusions

In‐hospital stroke after TAVI is associated with substantially increased early and late mortality. Factors independently associated with in‐hospital stroke were previous CVD, advanced age, no prior cardiac surgery, and deployment of a predominantly first‐generation self‐expandable transcatheter heart valve.
Characterization of differences between microwave and traditional thermal sterilization to prevent fungal spoilage during storage of high‐moisture paddy rice
Authors: Tian Tian , Zhang Bin , Chen Shangbing , Tao Tingting , Liu Qiang , Liu Bing , Yuan Jian , Ding Chao
Published: August 2020

Background and objectives

Characteristic difference between microwave (MW; 2.45 GHz, 1.5 W/g) and traditional thermal (TT; water bath, 100°C) sterilization on representative fungi (Aspergillus candidus, Aspergillus glaucus, Penicillium chrysogenum, Alternaria alternata, and Fusarium nivale) on high‐moisture paddy rice was evaluated by observing heat absorption of rice surface, fungal mortality, growth, and cell permeation.

Findings

Using MW (2.45 GHz, 1.5 W/g) can inhibit the growth of fungi, such as Aspergillus candidus. Under our experimental conditions, MW radiation was effective for safe storage of high‐moisture rice with fungal mortality of 95%. Fungal dehydrogenase activities after MW treatment were nearly 50% lower than fungal dehydrogenase activities after TT. Both MW and TT at the same temperature (60°C) can inhibit the growth of fungal spores. However, MW had better inhibitory effect, which is conducive to the safe storage of high‐moisture paddy rice.

Conclusions

Microwave and TT sterilization destroy fungal cell, causing substantial cell leakage and death. MW is more destructive to organisms on high‐moisture paddy rice than TT, which may be due to the nonthermal effects of MW.

Significance and novelty

Compared with TT, MW has better sterilization and could prevent fungal contamination in high‐moisture paddy rice storage and other cereals.