bluuebunny/crossref_metadata_2025 huggingface dataset:
San Agustín sobre la experiencia divina del alma
Authors: Zwollo Laela , Eguiarte B. Enrique A. ,   Order of Augustinian Recollects
Published: April 2022

St. Augustine expounds his theory of intellectual vision in book XII of The literal meaning of Genesis. This involves the sight of the mind's eye which operates in the upper echelon of the human soul. My paper deals with how intellectual vision relates to Augustine’s doctrine of imago Dei, or his interpretation of the verses Genesis 1:27: God created man in his own image. The imago Dei, located in every human intellect, progressively acquires a resemblance to God by gathering knowledge from divine Light. This doctrine furnishes the potential of a divine, epistemological experience in the form of a uisio intellectualis.
Las cartas de Agustín ‘Ad Donatistas’, y su importancia en la controversia antidonatista
Authors: Buenacasa Pérez Carles ,   Order of Augustinian Recollects
Published: April 2022

The purpose of this paper is to explain how, until the Conference of Carthage in 411, Augustin granted great importance to the letters as a direct and quick manner to focus his communication and debate with Donatists. He wisely used the letter to address both the Donatist plebs and the aristocrats and the schismatic bishops. In his letters, Augustine displayed a very detailed sort of arguments (historical, scriptural, theological, etc.) to achieve that followers of Donatism apostate from their schismatic faith. In fact, Augustine anticipated in his letters the arguments that he will develop largely in his treaties. After the Conference of Carthage in 411, a new shift in Augustinian epistolary strategy arose. Besides interrupting his correspondence with the Donatist bishops -now legally heretics- he will address no further letter to the Donatist people with the only exception of the synodal letter 141, read in 412 by Augustine on behalf of the Council of Zerta. From then on, Augustine did not use the epistolar format for the debate anymore, and he only used it in order to spread the verdict of condemnation of Donatism by Flavius Marcellinus.
El concepto de ‘corazón’ en Agustín de Hipona
Authors: Demura Kazuhiko , Anoz José ,   Order of Augustinian Recollects
Published: April 2022

In this paper I will survey Augustine’s concept of heart, cor in Latin, mostly focusing on his 390s works and sermons, and try to clarify how his characteristic concept of heart was discovered and developed in his philosophical investigation and pastoral experience. I hope it should shed light on Augustine’s anthropology (especially his understanding of interiority and spirituality) and its effectiveness in reforming his congregations in North Africa.
1 Tm 1,15: ¿‘humanus sermo’ o ‘fidelis sermo’? Sermón agustiniano 174 y su cristología
Authors: Eelen Alicia , Anoz José ,   Order of Augustinian Recollects
Published: April 2022

Abstract: Augustine’s y. 174 is traditionally dated around 413 (Kunzelmann 1931; Verbraken 1976). This dating has been confirmed by Hombert (2000). His main argument is based on Augustine’s use of humanus sermo instead of fidelis sermo, when quoting 1Tim. 1:15. According to Hombert, Augustine first adopted the faulty reading humanus sermo, but, after realizing this reading was mistaken, switched to the correct phrase fidelis sermo. Thus, when establishing a timeline using the switch to fidelis sermo as a reference point, the preaching of y. 174 must be placed, according to Hombert, before the sermons quoting 1 Tim 1:15 with the words fidelis sermo, such as s. 175-176, which are traditionally dated around 413-414. However, as Hombert remarks himself, this timeline has to be used with precaution. He mentions Dolbeau 30 as a counterexample. This sermon is traditionally dated 416, but still contains humanus sermo, instead of fidelis sermo. Since Augustine still uses humanus sermo after the supposed correction to fidelis sermo, I will argue that we cannot automatically assume that his use of humanus sermo in 5.174 originates in his ignorance of the correct reading. Moreover, 5. 174 provides us with Information on Augustine’s Christology, paying much attention to Christ’s humanity. I will show that in this specific Christological context, the phrase humanus sermo is more functional than fidelis sermo and that Augustine’s use of this reading could, thus, just be motivated by the fact that he wanted to explicitly state his Christological views.
Bioethics and Non-Consequentialism
Authors: Kershnar Stephen ,   Philosophy Documentation Center
Published: April 2022

The various features of bioethics center around a person’s right to decide what happens to her body and what she may do with it. This is true for patients and medical professionals. Our intuitions concerning rights in bioethics are similar to our intuitions concerning rights in other areas. Consider, for example, rights concerning movement, privacy, religion, sex, speech, and thought. Intuitively, these rights are consistent with one another, trump other moral considerations, and can be lost. If people were to own themselves, this would provide a unified explanation of what justifies other rights, what particular rights people have, why these particular rights are consistent with one another, and why these particular rights have certain features, such as trumping utility. Here I explore whether people own themselves.
Condensation of Ede1 promotes the initiation of endocytosis
Authors: Kozak Mateusz , Kaksonen Marko
Published: April 2022

Clathrin-mediated endocytosis is initiated by a network of weakly interacting proteins through a poorly understood mechanism. Ede1, the yeast homolog of mammalian Eps15, is an early-arriving endocytic protein and a key initiation factor. In the absence of Ede1, most other early endocytic proteins lose their punctate localization and endocytic uptake is decreased. We show that in yeast cells, cytosolic concentration of Ede1 is buffered at a critical level. Excess amounts of Ede1 form large condensates which recruit other endocytic proteins and exhibit properties of phase-separated liquid droplets. We demonstrate that the central region of Ede1, containing a coiled-coil and a prion-like region, is essential for both the condensate formation and the function of Ede1 in endocytosis. The functionality of Ede1 mutants lacking the central region can be partially rescued by an insertion of heterologous prion-like domains. Conversely, fusion of a heterologous lipid-binding domain with the central region of Ede1 can promote clustering into stable plasma membrane domains. We propose that the ability of Ede1 to form condensed networks supports the clustering of early endocytic proteins and promotes the initiation of endocytosis.
Factors related to overweight and obese populations maintaining metabolic health
Authors: Lin Yi-Hsuan , Chang Hsiao-Ting , Tseng Yen-Han , Chen Harn-Shen , Chiang Shu-Chiung , Chen Tzeng-Ji , Hwang Shinn-Jang
Published: April 2022

Background

For people who are overweight or obese, maintaining a metabolically healthy status can decrease the risks of developing cardiovascular diseases and Type 2 diabetes. Despite this, only a limited amount of research has discussed the metabolically healthy overweight and obesity (MHOO) population in Asia and the factors associated with them maintaining their metabolic health.

Methods

This study enrolled 195 MHOO participants from communities in northern Taiwan during 2009–2010 (baseline). Of the 195 participants, 89 completed the follow-up assessment after a median follow-up time of nine years. Body type was determined by body mass index (BMI, kg/m2). We defined overweight as a BMI ≥ 24 kg/m2 and <27 kg/m2 and defined obese as a BMI ≥ 27 kg/m2. Metabolic health was defined as the absence of cardiometabolic diseases and the presence of ≤1 of the cardiometabolic risk factors, namely hypertension, hyperglycemia, hypertriglyceridemia, and low serum high-density lipoprotein cholesterol. Metabolic health, BMI, and other covariates were evaluated at both baseline and follow-up. Generalized estimating equations (GEE) models were used to analyze the factors associated with maintenance of metabolic health during the follow-up period.

Results

At baseline, the mean age of the study participants was 47.4 (SD 5.3) years and 46 (51.7%) of the participants were women. There were 51 (57.3%) individuals who maintained their metabolic health status at the time of the nine-year follow-up. The detrimental factors pertaining to metabolic health included older age, longer duration until follow-up, BMI ≥ 27 kg/m2, and increase in waist circumference. No significant relationships were observed between sociodemographic factors and lifestyle factors, such as sex, level of education, cigarette smoking, alcohol consumption, and physical activity, and sustained metabolic health among MHOO individuals.

Conclusions

To maintain metabolic health and prevent negative changes in health status, control of bodyweight and waist circumference should remain a priority for MHOO individuals even when there are no metabolic disorders present.
Expression and promoter analysis of MEP pathway enzyme-encoding genes in Pinus massoniana Lamb
Authors: Zhu Peihuang , Chen Yu , Wu Fan , Meng Miaojing , Ji Kongshu
Published: April 2022

The methylerythritol phosphate (MEP) pathway provides the universal basic blocks for the biosynthesis of terpenoids and plays a critical role in the growth and development of higher plants. Pinus massoniana is the most valuable oleoresin producer tree with an extensive terrestrial range. It has the potential to produce more oleoresin with commercial value, while being resistant to pine wood nematode (PWN) disease. For this study, eleven MEP pathway associated enzyme-encoding genes and ten promoters were isolated from P. massoniana. Three PmDXS and two PmHDR existed as multi-copy genes, whereas the other six genes existed as single copies. All eleven of these MEP enzymes exhibited chloroplast localization with transient expression. Most of the MEP genes showed higher expression in the needles, while PmDXS2, PmDXS3, and PmHDR1 had high expression in the roots. The expressions of a few MEP genes could be induced under exogenous elicitor conditions. The functional complementation in a dxs-mutant Escherichia coli strain showed the DXS enzymatic activities of the three PmDXSs. High throughput TAIL PCR was employed to obtain the upstream sequences of the genes encoding for enzymes in the MEP pathway, whereby abundant light responsive cis-elements and transcription factor (TF) binding sites were identified within the ten promoters. This study provides a theoretical basis for research on the functionality and transcriptional regulation of MEP enzymes, as well as a potential strategy for high-resin generation and improved genetic resistance in P. massoniana.
Clinicoepidemiological Profile of Otorhinolaryngological Diseases among Patients Aged 5-15 YearsA Retrospective Study
Authors: Mili Mohan Kumar , Saikia Asha , Sarmah Monikuntal , Phookan Jyotirmoy , Saikia Naba Jyoti
Published: April 2022

Introduction: Ear, nose and throat diseases are some of the common causes of absenteeism among the school going children and can contribute to various co-morbidities. The most common among the Ear, Nose, Throat (ENT) diseases in school going children is hearing impairment due to ear wax or different types of otitis media which can be prevented with early detection and intervention. Upper respiratory tract infections also predispose a child to complications such as tonsillitis, sinusitis along with otitis media that can lead to morbidities like hearing impairment and learning disability. Aim: To determine the prevalence of ear, nose and throat diseases among the school going children and their clinicoepidemiological profile. Materials and Methods: This retrospective study was carried out in a tertiary care centre, Assam Medical College and Hospital, Dibrugarh, Upper Assam, India during the period of January 2019 to December 2019. Study included all the 1525 children within age group of 5-15 years attending the ENT Outpatient Department (OPD). Data was obtained from the outdoor register and the history sheets. Data collected was age, sex, religion and distribution of diseases according to site. Number of children having ear, nose, throat or neck diseases were calculated using Microsoft Excel software 2013, version 15.0. Results: Majority of the cases studied were found to be in the age group of 5-10 years (54.1%). ENT diseases were more common in boys (54.2%) than in girls (45.8%). Diseases of the ear (55.9%) were most common, followed by oral cavity and throat (19.3%), nose and Paranasal Sinus (PNS) (18.2%) and neck (6.6%). The most common diseases in ear were Chronic Suppurative Otitis Media (CSOM) and presence of earwax, while sinusitis and allergic rhinitis were more prevalent in diseases of nose and PNS. Pharyngitis and tonsillitis were more commonly found among the diseases of oral cavity and throat. Conclusion: These diseases are a major burden in the school going children resulting in their absence from school, low academic and extracurricular performance and other outdoor activities. Keeping an eye on this aspect, a structured and systematic school health program can be designed in collaboration with state health system, so that it can be properly followed up and needed treatment can be initiated with the help of state government cost.
Acute Necrotising Pancreatitis in a Patient with Situs Inversus TotalisA Rare Case Report
Authors: Muddasetty Rohith , Chinnusamy Kolandasamy , Raju Prabhakaran , Chidambaranathan Sugumar , Lakshmanamoorthy Naganathbabu Obla
Published: April 2022

Situs inversus totalis is a rare congenital anomaly occurring in one per 4000-20000 live births. It can present in early life due to gut rotation abnormality, however majority of them are asymptomatic and identified later in life when they undergo imaging for other reasons. Although acute pancreatitis is a common disease in young adults, presence of situs inversus alters the approach for necrosectomy when it is necessary. The author reports a 29-year-old male patient who had acute necrotising pancreatitis and incidentally found to have situs inversus totalis. Since the patient required drainage of necrotic collection there was a change in approach to right flank region rather than the routine left flank. This case was reported to emphasise on identification of situs anomalies and need to alter surgical approach.
Extraction, Phytochemical Screening and Antioxidant Potential of Hydroalcoholic Extract of Aerial Parts of Bauhinia variegata
Authors: Jain Amit Kumar , Loksh Kavita R.
Published: April 2022

The goals of this research are to screen phytochemicals, perform thin layer chromatography, assess the quantity of phenolic and flavonoid compounds, and measure the antioxidant potential of Bauhinia variegata. The well-known test methodology available in the literature was used to determine the qualitative analysis of various phytochemical elements as well as the quantitative analysis of total phenol and flavonoids. The hydro alcoholic extract of Bauhinia variegata aerial parts was investigated for qualitative and quantitative analyses, as well as antioxidant activity using an in vitro model, namely the 1,1-diphenyl, 2-picryl hydrazyl (DPPH) assay. The presence of phenols and flavonoids was discovered by phytochemical research. The total phenolic and flavonoid content of Bauhinia variegata hydroalcoholic extract was 1.454 and 1.112mg/100mg, respectively. Ascorbic acid, which was employed as a control, was also assessed for comparison. In the investigated models, the extract demonstrated dose-dependent free radical scavenging activity. Bauhinia variegata aerial parts For the DPPH technique, hydroalcoholic extract had an IC50 value of 60.22g/ml, which was close to that of ascorbic acid (IC50=17.68g/ml). The IC50 value for the hydrogen peroxide technique was determined to be 76.97g/ml, which compares favourably to ascorbic acid (IC50=18.69g/ml). The current study discusses the phytochemical profile, antioxidant activity, and TLC of Bauhinia variegata, which will be employed for medical purposes in the future.
A roadmap for sustaining biodiversity and ecosystem services through joint conservation and restoration of northern drainage basins
Authors: Heino Jani , Koljonen Saija
Published: April 2022

1. Freshwater ecosystems and their biota are more seriously threatened than their marine and terrestrial counterparts. A solution to halt increasing negative impacts of anthropogenic development would be to reconsider the basics of nature conservation (i.e. protection of pristine and near‐pristine areas) and restoration (i.e. returning an impacted site to as natural condition as possible) through inclusion of the knowledge on abiotic and biotic dynamics of rivers draining pristine catchments. In boreal and Arctic regions, such comparisons are still possible because in addition to harbouring strongly modified drainage basins, some of the most natural drainage basins are also situated in these high‐latitude areas.

2. A suitable approach for simultaneous planning of joint river conservation and restoration would be to (i) examine how well different kinds of rivers are covered by existing protected area networks and (ii) to restore parts of degraded rivers to facilitate colonization by aquatic and riparian organisms that have found havens in existing protected areas. This joint approach is a two‐way road, as conservation and restoration benefit from each other by allowing river networks to facilitate movements of organisms and matter, thereby mimicking natural riverine meta‐systems in anthropogenically modified drainage basins, with restored sites acting as stepping‐stones between protected areas.

3. We argue that existing policy instruments should consider the fact that river ecosystems are spatially and temporally dynamic meta‐systems. These characteristics should be given due attention in conservation and restoration rather than relying on a static approach where a snap‐shot classification of river reaches is thought to be enough without considering underlying ecological dynamics. Taking ecological dynamics into account would contribute to sustainable management and maintenance of biodiversity and ecosystem services.
Motion modeling from 4D MR images of liver simulating phantom
Authors: Kavaluus Henna , Koivula Lauri , Salli Eero , Seppälä Tiina , Saarilahti Kauko , Tenhunen Mikko
Published: April 2022

Background and purpose

A novel method of retrospective liver modeling was developed based on four‐dimensional magnetic resonance (4D‐MR) images. The 4D‐MR images will be utilized in generation of the subject‐specific deformable liver model to be used in radiotherapy planning (RTP). The purpose of this study was to test and validate the developed 4D‐magnetic resonance imaging (MRI) method with extensive phantom tests. We also aimed to build a motion model with image registration methods from liver simulating phantom images.

Materials and methods

A deformable phantom was constructed by combining deformable tissue‐equivalent material and a programmable 4D CIRS‐platform. The phantom was imaged in 1.5 T MRI scanner with T2‐weighted 4D SSFSE and T1‐weighted Ax dual‐echo Dixon SPGR sequences, and in computed tomography (CT). In addition, geometric distortion of the 4D sequence was measured with a GRADE phantom. The motion model was developed; the phases of the 4D‐MRI were used as surrogate data, and displacement vector fields (DVF's) were used as a motion measurement. The motion model and the developed 4D‐MRI method were evaluated and validated with extensive tests.

Result

The 4D‐MRI method enabled an accuracy of 2 mm using our deformable phantom compared to the 4D‐CT. Results showed a mean accuracy of <2 mm between coordinates and DVF's measured from the 4D images. Three‐dimensional geometric accuracy results with the GRADE phantom were: 0.9‐mm mean and 2.5 mm maximum distortion within a 100 mm distance, and 2.2 mm mean, 5.2 mm maximum distortion within a 150 mm distance from the isocenter.

Conclusions

The 4D‐MRI method was validated with phantom tests as a necessary step before patient studies. The subject‐specific motion model was generated and will be utilized in the generation of the deformable liver model of patients to be used in RTP.
Hidden Local Symmetry Breaking in Silver Diamondoid Compounds is Root Cause of Ultralow Thermal Conductivity
Authors: Xie Hongyao , Bozin Emil S. , Li Zhi , Abeykoon Milinda , Banerjee Soham , Male James P. , Snyder G. Jeffrey , Wolverton Christopher , Billinge Simon J. L. , Kanatzidis Mercouri G.
Published: April 2022

Typically, conventional structure transitions occur from a low symmetry state to a higher symmetry state upon warming. In this work, an unexpected local symmetry breaking in the tetragonal diamondoid compound AgGaTe2 is reported, which, upon warming, evolves continuously from an undistorted ground state to a locally distorted state while retaining average crystallographic symmetry. This is a rare phenomenon previously referred to as emphanisis. This distorted state, caused by the weak sd3 orbital hybridization of tetrahedral Ag atoms, causes their displacement off the tetrahedron center and promotes a global distortion of the crystal structure resulting in strong acoustic–optical phonon scattering and an ultralow lattice thermal conductivity of 0.26 W m−1 K−1 at 850 K in AgGaTe2. The findings explain the underlying reason for the unexpectedly low thermal conductivities of silver‐based compounds compared to copper‐based analogs and provide a guideline to suppressing heat transport in diamondoid and other materials.
Bacteria‐Elicited Specific Thrombosis Utilizing Acid‐Induced Cytolysin A Expression to Enable Potent Tumor Therapy
Authors: Qin Wenjun , Xu Wenxuan , Wang Longyu , Ren Debao , Cheng Yibin , Song Wen , Jiang Tao , Ma Lixin , Zhang Cheng
Published: April 2022

Given the special microenvironment of solid tumors, live microorganisms have emerged as drug delivery vehicles and therapeutic agents. Here, an acid‐induced therapeutic platform is constructed using attenuated Escherichia coli to express the cytolysin A protein. The bacteria can target and colonize tumor tissues without causing notable host toxicity. Bacterial infection can disrupt blood vessels and trigger thrombosis in tumor tissues, resulting in the cut‐off of nutrient supply to tumor cells and the arrest of tumor growth. The expression of cytolysin A induced by the acidic tumor microenvironment further strengthens thrombosis and provides a complementary therapeutic option due to its pore‐forming function. In a xenograft mouse tumor model, this strategy reduces tumor proliferation by 79% and significantly prevents tumor metastasis, thus paving a new avenue for bacteria‐based tumor therapy.
Elucidating the Rate‐Limiting Processes in High‐Temperature Sodium‐Metal Chloride Batteries
Authors: Landmann Daniel , Svaluto‐Ferro Enea , Heinz Meike V. F. , Schmutz Patrik , Battaglia Corsin
Published: April 2022

Sodium‐metal chloride batteries are considered a sustainable and safe alternative to lithium‐ion batteries for large‐scale stationary electricity storage, but exhibit disadvantages in rate capability. Several studies identify metal‐ion migration through the metal chloride conversion layer on the positive electrode as the rate‐limiting step, limiting charge and discharge rates in sodium‐metal chloride batteries. Here the authors present electrochemical nickel and iron chlorination with planar model electrodes in molten sodium tetrachloroaluminate electrolyte at 300 °C. It is discovered that, instead of metal‐ion migration through the metal chloride conversion layer, it is metal‐ion diffusion in sodium tetrachloroaluminate which limits chlorination of both the nickel and iron electrodes. Upon charge, chlorination of the nickel electrode proceeds via uniform oxidation of nickel and the formation of NiCl2 platelets on the surface of the electrode. In contrast, the oxidation of the iron electrodes proceeds via localized corrosion attacks, resulting in nonuniform iron oxidation and pulverization of the iron electrode. The transition from planar model electrodes to porous high‐capacity electrodes, where sodium‐ion migration along the tortuous path in the porous electrode can become rate limiting, is further discussed. These mechanistic insights are important for the design of competitive next‐generation sodium‐metal chloride batteries with improved rate performance.
Engineering Interfacial Band Bending over ZnIn2S4/SnS2 by Interface Chemical Bond for Efficient Solar‐Driven Photoelectrochemical Water Splitting
Authors: Li Shengnan , Meng Linxing , Tian Wei , Li Liang
Published: April 2022

Developing a simple and effective strategy to modulate the energy band bending of heterojunction photoelectrodes is pivotal in terms of photoelectrochemical (PEC) water splitting. Herein, it is demonstrated that the introduction of the interfacial InOSn chemical bonds at the ZnIn2S4/SnS2 interface regulates the band bending of ZnIn2S4/SnS2 heterojunction photoanodes, reverses the charge transport direction, and reduces the oxygen evolution reaction (OER) overpotential. Detailed analysis indicates that the interfacial InOSn bond makes band adaptation to promote carrier separation and transfer through ultraviolet photoelectron spectrometry, hydroxyl radical production tests, and surface photovoltage measurements. Due to the special nanosheet morphology with exposed edges of the heterojunction interface, the InOSn bonds are partially exposed, which can reduce the OER overpotential and boost the surface injection efficiency according to the PEC impedance spectroscopy and density functional theory calculations. The synergistic modulation of InOSn bond yields a photocurrent of 4.57 mA cm−2 at 1.23 V (vs reversible hydrogen electrode, AM 1.5 G) and a low onset potential of −0.14 VRHE. This work provides a new solution for energy band regulation to improve the performance of heterojunction photoelectrodes for PEC water splitting.
Nonmetal (S or Se)‐Bridged Core Shell Electrodes for Promoting Electrochemical Performance
Authors: Wang Jiawei , Sun Mingshuai , Zhang Xubin , Wang Fumin , Song Jian , Zhang Weike , Wang Zheng , Li Mingzhao
Published: April 2022

To meet strategic applications, rational design of advanced electrochemical materials would solve the poor electrochemical performance of core‐shell electrodes caused by the weak interfacial interaction between core and shell. Herein, two novel core‐shell electrodes LCCH‐S@PBAs and LCCH‐Se@PBAs are fabricated with a nonmetal (S or Se) bridging the core and shell. Electrochemical tests show that the as‐synthesized electrodes, especially LCCH‐S@PBAs, present higher mass‐specific capacitance with 10.1 C cm−2 at 1 mA cm−2, which is much better than that of PBA‐based homologs. Experimental results and theoretical calculations show that the bridging S or Se in the interface, not only tune electronic nature of the d‐states of metal ions in core and shell, but also form ionic bonds (M1(LCCH)‐S‐M2(PBAs) and M1(LCCH)‐Se‐M2(PBAs)) which facilitates the transmission of electrons, thus making a substantial enhancement of electrochemical performance via a dynamically more favorable pathway. The comparison with LCCH‐C@PBAs, in which the rGO is connected with core and shell by Van der Waals’ forces, also suggests the outstanding role of ionic bonds for electrochemical performance. This work proves that nonmetal bridging structures make a great contribution for enhanced electrochemical performance and demonstrates the large space to modulate the nonmetal bridging status for core‐shell structures in electrochemical materials.
Urgent cytoreduction for newly diagnosed acute myeloid leukemia patients allows acquisition of pretreatment genomic data and enrollment on investigational clinical trials
Authors: Kim Kunhwa , Konopleva Marina , DiNardo Courtney D. , Borthakur Gautam , Loghavi Sanam , Tang Guilin , Daver Naval , Pemmaraju Naveen , Jabbour Elias , Rausch Caitlin R. , Yilmaz Musa , Sasaki Koji , Short Nicholas J. , Jain Nitin , Brandt Mark , Pierce Sherry , Garcia‐Manero Guillermo , Ravandi Farhad , Kantarjian Hagop , Kadia Tapan M.
Published: April 2022

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18–89), there was no significant difference in short‐ and long‐term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30‐ and 60‐day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70–1.37, p = .879). Results were unchanged after stratification by age (< or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial.
Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25
Authors: Barbier Mathieu , Bahlo Melanie , Pennisi Alessandra , Jacoupy Maxime , Tankard Rick M. , Ewenczyk Claire , Davies Kayli C. , Lino‐Coulon Patricia , Colace Claire , Rafehi Haloom , Auger Nicolas , Ansell Brendan R. E. , van der Stelt Ivo , Howell Katherine B. , Coutelier Marie , Amor David J. , Mundwiller Emeline , Guillot‐Noël Lena , Storey Elsdon , Gardner R. J. McKinlay , Wallis Mathew J. , Brusco Alfredo , Corti Olga , Rötig Agnès , Leventer Richard J. , Brice Alexis , Delatycki Martin B. , Stevanin Giovanni , Lockhart Paul J. , Durr Alexandra
Published: April 2022

Objective

Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus.

Methods

Whole‐exome and whole‐genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology.

Results

The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1‐domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double‐stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response.

Interpretation

This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022;92:122–137
Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi‐Purpose Asymmetric Organocatalysts
Authors: Scharinger Fabian , Pálvölgyi Ádám Márk , Weisz Melanie , Weil Matthias , Stanetty Christian , Schnürch Michael , Bica‐Schröder Katharina
Published: April 2022

Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi‐purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza‐Michael‐initiated cyclizations, as well as for a novel Robinson‐like Michael‐initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.
Promoted catalytic potential in sulfides oxidation and biological screening of green Pd (II) and Co (II) complexes of salicylidene isatin hydrazone ligand
Authors: Adam Mohamed Shaker S. , Makhlouf Mohamed M. , Mohamed Mamdouh A. , Desoky M. Mohamad Ahmed
Published: April 2022

Mononucleating complexes of isatin hydrazone sodium sulfonate ligand (HLn) with palladium (II) and cobalt (II) ions: The complexes were synthesized within 1:1 and 2:1 molar ratio of HLn with Pd2+and Co2+ion in PdLn and Co (Ln)2, respectively. The catalytic reactivity of both complexes was examined in the oxidation of sulfides (diphenyl sulfide, dps, and methylphenyl sulfide, mps) using hydrogen peroxide under aerobic conditions. Oxoproducts, dipheylsufoxide, dpo, and methyl phenyl sulfoxide, mpo, are the chemoselective products with detection of large amounts of the unselective further oxidation products of dioxoproducts (dipheylsufone, dpn, and methylphenyl sulfone, mpn). The homogenous catalyst of Co (Ln)2revealed more efficient action compared to that of PdLn depending on the high electrochemical reversible potential of the central metal ion in the catalytic reaction within the electron and/or oxygen transfer system.

Exploring the importance of the M2+ion in the coordinated ligand, the bio‐reactivity of HLn, PdLn, and Co (Ln)2was illustrated within some commonly well‐known bacteria and fungi strains. Additionally, they were involved as anticancer reagents against some human cancer cell lines in vitro. Both metal complexes presented high inhibited action versus the growth of the studied microorganism and cancer. The interaction effect of Pd2+and Co2+ions in their pincer complexes was tested with calf thymus DNA spectroscopically and via the viscosity changes.
Cardioprotective effect of silymarin nanoemulsion on 5‐fluorouracil‐induced cardiotoxicity in rats
Authors: Safarpour Soheila , Safarpour Samaneh , Moghadamnia Ali A. , Kazemi Sohrab , Ebrahimpour Anahita , Shirafkan Fatemeh , Mansoori Razieh , Golchoobian Ravieh
Published: April 2022

5‐Fluorouracil (5‐FU)‐associated cardiotoxicity has been ranked as the second most common cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. In the present study, we investigated the protective impacts of silymarin (SIL) and silymarin nanoemulsion (SLN) against cardiotoxicity caused by 5‐FU in rats. Thirty male Wistar rats were divided into six groups as follows: control, SLN (5 mg/kg), SIL (5 mg/kg), 5‐FU + SLN, 5‐FU + SIL, and 5‐FU. Cardiotoxicity was induced by a single intraperitoneal injection of 5‐FU (100 mg/kg). The control group received an intraperitoneal injection (ip) of normal saline and the treatment groups received ips of SIL and SLN for 14 days. 5‐FU resulted in significant cardiotoxicity, represented by an increase in the serum levels of cardiac enzymes and malondialdehyde, as well as cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) expression, and histopathological degeneration. 5‐FU treatment also induced a decrease in body weight, total antioxidant capacity (TAC), and catalase values. Evaluation of electrocardiographic parameters in 5‐FU‐treated rats showed increases in the ST segment, QRS duration, and RR interval. Treatment with SIL and SLN reduced oxidative stress, cardiac enzymes, histopathological degeneration, and the expression of TNF‐α and COX‐2 in cardiac tissue. Our results demonstrated that treatment with SIL and SLN significantly improved cardiotoxicity induced by 5‐FU in rats.
The Conundrum of Lung Disease and Drug Hypersensitivity‐like Reactions in Systemic Juvenile Idiopathic Arthritis
Authors: Binstadt Bryce A. , Nigrovic Peter A.
Published: April 2022

An unusual form of lung disease has begun to affect some children with systemic juvenile idiopathic arthritis (JIA), coincident with increasing utilization of interleukin‐1 (IL‐1) and IL‐6 antagonists. Many children with systemic JIA–associated lung disease (SJIA‐LD) have a history of clinical and laboratory features resembling drug reaction with eosinophilia and systemic symptoms (DRESS), a presentation now convincingly associated with HLA–DRB1*15. Treatment of DRESS typically requires drug discontinuation, a daunting prospect for clinicians and families who rely upon these agents. Here we review SJIA‐LD and its associated DRESS‐like phenotype. We suggest an alternative explanation, the cytokine plasticity hypothesis, proposing that IL‐1 and IL‐6 blockers modulate the milieu in which T cells develop, leading to a pathologic immune response triggered through exposure to common microbes, or to other exogenous or endogenous antigens, rather than to the drugs themselves. This hypothesis differs from DRESS in mechanism but also in clinical implications, predicting that control of pathogenic T cells could permit continued use of IL‐1 and IL‐6 antagonists in some individuals. The spectrum posed by these two hypotheses provides a conceptual framework that will guide investigation into the pathogenesis of SJIA‐LD and may open up new therapeutic avenues for patients with systemic JIA.
Unravelling Charge Carrier Mobility in d0‐Metal‐based Spinels
Authors: Dillenz Manuel , Sotoudeh Mohsen , Glaser Clarissa , Janek Jürgen , Groß Axel , Euchner Holger
Published: April 2022

Enabling high Mg ion mobility, spinel‐type materials are promising candidates for cathode or solid electrolyte applications. To elucidate the factors governing the observed high mobility of multivalent ions, periodic DFT calculations of various charge carriers (A=Li, Na, K, Mg, Ca, Zn and Al) in the ASc2S4 and ASc2Se4 spinel compounds were performed, resulting in the identification of a Brønsted‐Evans‐Polanyi‐type scaling relation for the migration barriers of the various charge carriers. Combining this scaling relation with the derivation of a descriptor, solely based on easily accessible observables, constitutes a conceptual framework to investigate ion mobility in d0‐metal‐based spinel chalcogenides with significantly reduced computational effort. This approach was exemplarily verified for various d0‐metal‐based spinel chalcogenide compounds AB2X4 (B=Sc, Y, Ga, In, Er and Tm; X=O, S and Se) and led to the identification of d0‐metal‐based CaB2O4 spinels as promising compounds possibly enabling high Ca ion mobility.
Chemiluminescence assay for kanamycin based on target recycling strategy
Authors: Yu Liyuan , Zhang Xiaoqian , Jin Daobin , Lou Fangxu , Zhao Jikuan , Hun Xu
Published: April 2022

A chemiluminescence (CL) sensing strategy for kanamycin residue detection in fish samples was established based on luminol‐functionalized gold nanoparticles as CL nanoprobe materials combined with DNA hairpin structure and carboxyl‐modified magnetic beads. Relying on nucleic acid amplification technology, the system can successfully realize the recycling of kanamycin, so that the biosensor can release a large number of luminol‐functionalized gold nanoparticles with excellent CL performance even at a low residual levels of kanamycin. The biosensor strategy showed a good linear relationship with kanamycin in the range 0.09–130 nM, the detection limit was as low as 0.04 nM. This method proves the excellent performance of the sensing strategy and provides a low‐cost and high‐sensitivity CL analysis strategy for the detection of kanamycin and even other antibiotics.
Development of a versatile, uniform, and stable initiator layer by the functionalization of a polydopamine/polyethyleneimine film
Authors: Jeong Jaehoon , Bisht Himani , Ryu Sanghyun , Hong Daewha
Published: April 2022

Polymer brush surfaces have various interesting applications; however, to facilitate their formation on surfaces, an initiator ad‐layer is required in advance. In this study, we developed a versatile initiator film that simultaneously meets the standards of uniformity and stability using a simple surface coating strategy. In brief, co‐deposition of dopamine and polyethyleneimine formed a polydopamine/polyethyleneimine (pDP) film, which was then acylated with external α‐bromoisobutyryl bromide. The resultant initiator film, pDP functionalized with initiator (pDPI), showed a homogeneous surface morphology and resisted harsh solvent conditions. The subsequent surface‐initiated polymerization from the developed pDPI initiator layer also formed a thick polymer brush.
Impact of thresholding on the consistency and sensitivity of diffusion MRI‐based brain networks in patients with cerebral small vessel disease
Authors: De Brito Robalo Bruno M. , Vlegels Naomi , Leemans Alexander , Reijmer Yael D. , Biessels Geert Jan
Published: April 2022

Introduction

Thresholding of low‐weight connections of diffusion MRI‐based brain networks has been proposed to remove false‐positive connections. It has been previously established that this yields more reproducible scan–rescan network architecture in healthy subjects. In patients with brain disease, network measures are applied to assess inter‐individual variation and changes over time. Our aim was to investigate whether thresholding also achieves improved consistency in network architecture in patients, while maintaining sensitivity to disease effects for these applications.

Methods

We applied fixed‐density and absolute thresholding on brain networks in patients with cerebral small vessel disease (SVD, n = 86; ≈24 months follow‐up), as a clinically relevant exemplar condition. In parallel, we applied the same methods in healthy young subjects (n = 44; scan–rescan interval ≈4 months) as a frame of reference. Consistency of network architecture was assessed with dice similarity of edges and intraclass correlation coefficient (ICC) of edge‐weights and hub‐scores. Sensitivity to disease effects in patients was assessed by evaluating interindividual variation, changes over time, and differences between those with high and low white matter hyperintensity burden, using correlation analyses and mixed ANOVA.

Results

Compared to unthresholded networks, both thresholding methods generated more consistent architecture over time in patients (unthresholded: dice = .70; ICC: .70–.78; thresholded: dice = .77; ICC: .73–.83). However, absolute thresholding created fragmented nodes. Similar observations were made in the reference group. Regarding sensitivity to disease effects in patients, fixed‐density thresholds that were optimal in terms of consistency (densities: .10–.30) preserved interindividual variation in global efficiency and node strength as well as the sensitivity to detect effects of time and group. Absolute thresholding produced larger fluctuations of interindividual variation.

Conclusions

Our results indicate that thresholding of low‐weight connections, particularly when using fixed‐density thresholding, results in more consistent network architecture in patients with longer rescan intervals, while preserving sensitivity to disease effects.
Transfer of continuous manufacturing process principles for mAb production in a GMP environment: A step in the transition from batch to continuous
Authors: Botelho Ferreira Kevin , Benlegrimet Asma , Diane Gabriel , Pasquier Victor , Guillot Raphael , De Poli Marc , Chappuis Loïc , Vishwanathan Nandita , Souquet Jonathan , Broly Hervé , Bielser Jean‐Marc
Published: April 2022

Implementation of continuous in lieu of batch upstream processing (USP) and downstream process (DSP) for the production of recombinant therapeutic protein is a significant paradigm change. The present report describes how the first kilograms of monoclonal antibody were produced with equipment originally designed for batch operations while using continuous manufacturing processes and principles. Project timelines for the delivery of clinical material have driven this ambition and helped the transition. Nevertheless, because of equipment availability, a tradeoff between the envisaged continuous downstream process (cDSP) operations and the ones described in this article had to be taken. A total of 2.1 kg of monoclonal antibody were produced in two GMP runs for clinical trials. For USP, a 200‐L single‐use pilot scale bioreactor was upgraded to enable perfusion operation. DSP steps were designed to be easily transferable to cDSP for later clinical or commercial productions. An in‐line conditioning buffer preparation strategy was tested in a discontinuous way to prove its efficiency and the purification cascade was structured in parallel to the continuous collection of antibody‐containing cell culture supernatant. This strategy will avoid any process change when later moving to the continuous equipment that is currently under qualification. Alignment between small‐scale references runs and the GMP runs in terms of productivity and quality confirmed that the presented approach was valid. Thus, we demonstrate that existing fed‐batch infrastructure can be adapted to continuous manufacturing without significant additional investments. Such approach is useful to evaluate next‐generation manufacturing processes before making large investments.
Did court dismiss student's negligence claim?
Authors: Lyerly Eric
Published: April 2022

Jane Doe was an Allegheny College student residing in an on‐campus residence hall. The residence hall had nine entrances accessible via proximity access cards and/or student identification cards.
Review recent rulings involving campus security
Authors: Lyerly Eric
Published: April 2022

An overview of the key topics faced by campus administrators with citations to noteworthy cases, statutes, regulations, and additional sources.
Four‐Component Ugi Reaction for Optical Chirality Sensing and Surface Nanoengineering of Chiral Self‐Assemblies
Authors: Liu Bingyu , Gao Junjie , Hao Aiyou , Xing Pengyao
Published: April 2022

Using green chemistry to control chirality at hierarchical levels as well as chiroptical activities endows with new opportunities to the development of multiple functions. Here, the four‐component Ugi reaction is introduced for the general and precise optical chirality sensing of amines as well as the surface nanoengineering of chiral soft self‐assemblies. To overcome the relatively weak Cotton effects, direct synthesis of a folded peptide structure on a rotatable ferrocene core with axial chirality was accomplished from chiral amine, 1,1’‐ferrocenyl dicarboxylic acid, formaldehyde and isocyanide. Enhanced Cotton effects benefiting from the folded structure allow for the precise and quantitative sensing of natural and synthetic chiral amines covering alkyl, aromatic amines and amino acid derivatives. In addition, aqueous reaction enables the modification of amine‐bearing dye to microfibers self‐assembled from π‐conjugated amino acids. Surface dye‐modification via Ugi reaction barely changes the pristine morphology, showing non‐invasive properties in contrast to dye staining, which is applicable in soft nano/microarchitectures from self‐assembly. This work which combines the four‐component Ugi reaction to enable precise ee% detection and surface nanoengineering of soft chiral assemblies sheds light on the advanced application of green chemistry to chirality science.