bluuebunny/crossref_metadata_2025 huggingface dataset:
Defisiensi Vitamin B12: Tinjauan Aspek Fisiologi dan Dampak Spesifik terhadap Ginjal Vitamin B12 Deficiency: Insight of Physiological Aspect and the Specific Impact to the Kidney
Authors: Amani Patwa
Published: February 2022

Defisiensi vitamin B12 (VB12) saat ini masih merupakan masalah kesehatan masyarakat di seluruh dunia baik negara maju maupun berkembang. Selain karena kurangnya intake, terdapat berbagai penyebab terjadinya defisiensi VB12 yang berkaitan dengan fisiologi absorbsi dan utilisasi seluler vitamin B12. Dampak dari defisiensi VB12 bukan saja terjadi pada sistem hematologi yang secara klasik sudah diketahui, namun memiliki dampak pada berbagai sistem tubuh salah satunya organ ginjal. Beberapa laporan kasus menunjukan adanya hubungan antara kelainan gen yang terlibat dalam proses absorbsi vitamin B12 dengan penyakit ginjal progresif kronis. Review ini bertujuan membahas defisiensi VB12 yang ditinjau dari aspek fisiologi serta dampak khususnya pada organ ginjal.
PENGARUH LATIHAN LINGKUP GERAK SENDI AKTIF RESISTIF TERHADAP FLEKSIBILITAS OTOT SERVIKAL
Authors: Putri Mustika Anggiane , Anjani Safira Fatimah , Lutfie Syarief Hasan
Published: February 2022

Latar Belakang: Perkembangan teknologi yang pesat mengubah pola hidup manusia. Kini penggunaan gawai di seluruh dunia rata-rata 3-5 jam per hari. Hal tersebut dapat menimbulkan masalah pada tulang belakang berupa penurunan fleksibilitas leher akibat postur yang dipertahankan dalam waktu yang lama. Latihan lingkup gerak sendi aktif resistif diharapkan dapat memperbaiki dan menjaga fleksibilitas leher. Metode: Penilitian ini dilakukan dengan desain penelitian eksperimental menggunakan model one group pre test and post test without control. Jumlah subyek penelitian sebanyak 14 orang yang dipilih melalui random sampling dan sesuai dengan kriteria inkulsi. Informed consent telah diperoleh dari seluruh subyek penelitian. Durasi penelitian selama 4 minggu dan perlakuan yang diberikan berupa latihan lingkup gerak sendi aktif resistif leher yang dilakukan sebanyak 3 kali dalam seminggu. Data merupakan hasil dari pengukuran fleksibilitas leher menggunakan goniometer universal yang dilakukan sebelum dan sesudah latihan. Hasil: Uji statistik menggunakan uji t berpasangan dan uji wilcoxon. Nilai signifikansi pada lingkup gerak sendi leher fleksi 0.000, ekstensi 0.046, lateral fleksi kanan 0.020, lateral fleksi kiri 0.011, rotasi kanan 0.021, rotasi kiri 0.001. Kesimpulan: Terdapat  peningkatan bermakna fleksibilitas otot leher pada lingkup gerak sendi leher (fleksi, lateral fleksi kanan dan kiri, rotasi kanan dan kiri) antara sebelum dan sesudah latihan LGS aktif resistif. ABSTRACTBackground: Rapid technological development changes the pattern of human life. Now the use of devices around the world is on average 3-5 hours per day. This can cause problems in the spine in the form of decreased neck flexibility due to posture that is maintained for a long time. Active resistive range of motion exercise is expected to improve and maintain neck flexibility. Method: This study was conducted with an experimental design using one group model pre-test and post-test without control. The number of subjects was 14 who were selected through random sampling and in accordance with the inclusion criteria. Informed consent was obtained from all the subjects. The duration of the study is 4 weeks and the intervention is carried out 3 times a week. Data is the result of measurement of neck flexibility using a universal goniometer which is done before and after the intervention. Results: Statistical test using paired t-test and Wilcoxon test. Significance value in 0.000 flexion range of motion, extension 0.046, right lateral flexion 0.020, left lateral flexion 0.011, right rotation 0.021, left rotation 0.001.Conclusion: There are significant differences in neck muscle flexibility in the entire range of motion (flexion, extension, right and left lateral flexion, right and left rotation) between before and after an active resistive range of motion exercise
FEATURES OF THE INTERACTION OF THE ANTENNA AND HEAD BLOCKS OF THE TWO-BLOCK INERTIAL PENETRATOR DURING THE INTRODUCTION OF THE STUDIED CELESTIAL BODY INTO THE GROUND
Authors:   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Leun E. V. , Polyakov A. A. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Zaschirinsky S. A. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Shakhanov A. E. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Nesterin I. M. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Sysoev V. K. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia, Khmel D. S. ,   NPO Lavochkina JSC, Khimki, Moscow region, Russia
Published: February 2022

В статье обсуждаются вопросы внедрении в грунт исследуемого небесного тела двухблочного инерциального пенетратора, состоящего из антенного и головного блоков. Показано, что при ударном внедрении в грунт небесного тела такого пенетратора без отделения антенного блока от головного создание канала устойчивой радиосвязи возможно при образовании кратера c большим углом раскрытия с формой от конусообразного до полусферического. Для существенного снижения скорость сближения антенного блока с небесным телом и возникающей соответствующей перегрузки наиболее перспективно высокоскоростное отделение, например, за счет отстрела антенного блока от головного.
INCREASING THE FIRE AND EXPLOSION SAFETY OF ELECTRICAL RCT DEVICES POWERED BY OPTICAL RADIATION TRANSMITTED BY OPTICAL FIBER
Authors:   JSC ", Leun E. V. ,   NPO Lavochkina"
Published: February 2022

Статья посвящена вопросам питания электрических устройств РКТ оптическим излучением, передаваемым оптическим волокном. Основное внимание уделено повышению пожаровзрывобезопасносности (ПВБ) и увеличению передаваемой мощности сигнала. Среди способов достижения этого рассматриваются возможности механического упрочения волокон, их дублирования, формирования полностью замкнутых волоконно-оптических каналов, спиральной закрутки оптических волокон и контроля текущего уровня трещинообразования. Обсуждаются вопросы практической реализации предложенных технических решений.
Ants of the genus Leptogenys Roger, 1861 (Hymenoptera: Formicidae, Ponerinae) from Nepal
Authors:   Central Department of Zoology, Institute of Science and Technology, Tribhuvan University, Nepal, Subedi I.P. , Budha P.B. ,   Central Department of Zoology, Institute of Science and Technology, Tribhuvan University, Nepal, Yamane Sk.
Published: February 2022

Six species of the genus Leptogenys Roger, 1861 are reported from Nepal. Leptogenys laeviceps (Smith, 1857), stat. ressur. is raised to species status. Lepto¬genys birmana Forel, 1900, L. chinensis (Mayr, 1870), L. dentilobis Forel, 1900, L. kitteli Mayr, 1870, and L. laeviceps (Smith, 1857) are recorded from Nepal for the first time. A key based upon the worker caste is provided for all Nepalese species. A map of the distribution of Leptogenys species in Nepal is presented.
Psychometric Assessment of SpiDiscI: Spiritual Distress Scale for Palliative Care Patients in India
Authors: Gielen Joris , Kashyap Komal , Singh Suraj Pal , Bhatnagar Sushma , Chaturvedi Santosh K.
Published: February 2022

Objectives:

Spirituality has an impact on the quality of life of palliative care patients and it influences the way in which they experience their disease. Spiritual distress is a common issue among palliative care patients in India that is best assessed through a tool specifically designed for them. This study presents the findings of a psychometric assessment of SpiDiscI: a 16-item spiritual distress scale for Hindi speaking palliative care patients in India.

Materials and Methods:

This study used a non-experimental cross-sectional sample survey design. 400 cancer patients undergoing pain treatment at the pain and palliative care unit of a tertiary cancer hospital in New Delhi enrolled in the study and completed the study’s questionnaire. The questionnaire contained a section on demographic information, a numerical rating scale (NRS) for pain, SpiDiscI, FACIT-Sp-12, and WHOQOL-BREF. A subset of 50 patients with stable pain completed SpiDiscI a 2nd time 2 weeks after the first administration of the scale to assess test-retest reliability.

Results:

The scale’s internal consistency is very good (Cronbach’s Alpha 0.85). Spiritual distress scores ranged from 0 to 93.8 (mean 37.1, SD 23.6). Significant negative correlations between SpiDiScI and both FACIT-Sp-12 (R = –0.16, P = 0.001) and WHOQOL-BREF (R = –0.27, P < 0.001) confirmed convergent validity. There was no significant association with NRS pain scores (R = 0.06, P = 0.224). The highly significant association (R = 0.75, P < 0.001) of the scores on assessments 2 weeks apart confirmed test-retest reliability.

Conclusion:

SpiDiScI is a reliable and valid measure to assess spiritual distress in research among Hindi speaking palliative care patients in India.
Landslide Susceptibility Mapping using Frequency Ratio, a case study of Vythiriblock in Wayanad, the northern part of Kerala, India
Authors: Vinayan Midhuna , Grurugnanam B. , Bairavi S.
Published: February 2022

Landslides are common and disastrous events in India's Western Ghats during the rainy season and various factors influence the occurrence of landslides. The present research aims to establish landslide susceptibility zones to control landslide hazards and risk effectively. Landslides occurred in the entire area of the Wayanad district. The study was carried out in vythiri taluk to do detailed surveys using remote sensing and GIS, GPS and field investigation. A total of 162 landslide locations are used to develop a landslide susceptibility map of this area. Landslide susceptibility map of this area was done by using the frequency ratio (FR) model. The landslide susceptibility map is based on factors that affect directly or indirectly land subsidence process. There are twelve landslide influencing factors taken for this study: Slope, Aspect, Land use/land cover, Rainfall, Vegetation, Soil, Distance to lineament, Distance to the road, Elevation, Curvature, Geomorphology and Lithology. The resulting landslide susceptibility map shows that 3.6 % of the region is in a low susceptible zone, 40.5 % is in a moderate susceptible zone, 49 % is in a high susceptible zone and 6.9 % is in a very high susceptible zone to landslides. According to this model, the area under the curve (AUC) for the success rate is 75.3 %. This study would support the relevant authorities in identifying potential risks in particular parts which could be used for landslide mitigation activities as construction development in the region increases.
Key Role of Ionic Liquids in the Cleaner and Greener Synthesis of Lactams
Authors: Srivastava Nitin
Published: February 2022

The antibiotics like cephalosporin, penicillin etc. contain lactams as the main component. Due to increase in bacterial resistance to antibiotics, there is a need of synthesis of novel β-lactam agents that are stable to β-lactamase and have high potency on broad spectrum. Besides this β-lactams also decrease the cholesterol in blood plasma. They are potent anticancer agents and enzyme inhibiting substances. Ionic liquids have been found to be versatile greener solvents employed for the synthesis of lactams with many other advantages in comparison to traditional media. They are said to be “tailored solvents” whose many properties like solubility, viscosity, refractive index density can be managed as per the requirement of the reaction by tuning the size of atoms involved in the ionic liquids. The review envisages the development of sustainable synthesis of lactams using various ionic liquids and emphasizes the research in this area for the development of better synthetic methods.
Spectral analysis and kinetic studies of enzymatic delignification of kraft wood pulp by xylanase
Authors: Pradeep K.R. , Narasimhan T.G. , Krishna Prasad R. , Udaya Bhaskar Reddy Ragula
Published: February 2022

The traditional bleaching methods used chlorine as bleaching agent which produced large amount of chlorinated organic compounds including dioxins which are persistent environmental pollutants. The alternate methods using peroxides and enzymes were developed to achieve total chlorine free bleaching. The xylanase enzyme was used as bleaching agent in this study. The delignification study was performed to evaluate the optimum conditions required for obtaining minimum kappa number of the pulp to remove maximum lignin from the wood fibres. The interactions of various factors such as pulp consistency, enzyme dosage and temperature were studied. The best conditions for enzymatic bleaching obtained were 10% consistency, 50 IU of enzyme dosage and 52oC in the range studied. The predicative mathematical models were developed for enzymatic bleaching. The activation energy for xylanase delignification of paper pulp was 13.989kJ/mol. The significant functional groups in bleached pulp samples were analysed using Fourier transform infrared spectroscopy and the surface morphology of pulp fibres was studied using Scanning electron microscopy images.
Technical calculation of crusher parameters for grain grinding using negative temperature
Authors: Кишкилев С.В. , Антимонов С.В. , Попов В.П. , Белов А.Г. , Соловых С.Ю.
Published: February 2022

Для измельчения зернового сырья широко используют различные виды дробилок, сфера применения которых намного шире области зернопереработки. Наиболее часто применяют машины ударного принципа действия благодаря простоте конструкции, надёжности в работе и удобству обслуживания при эксплуатации. Однако при измельчении значительная часть энергии затрачивается непроизводительно, при этом не обеспечивается однородный гранулометрический состав, возможно переизмельчение зерна и образование пылевидной фракции. Рабочие органы дробилок подвержены интенсивному износу и нуждаются в частой замене, что приводит к удорожанию эксплуатации и обслуживания измельчителей. С целью повышения качества продукта, создания конкурентоспособного оборудования и технологических линий для переработки зернового сырья необходимо научно-техническое обоснование новых эффективных методов и технологий проектирования, создания и модернизации процессов, машин, агрегатов и их эксплуатации для переработки зернового сырья. Цель исследования — обосновать предлагаемую конструкцию дробилки, оборудованной системой замораживания зернового сырья, на примере технического расчета комплекса параметров, характеризующих её работу. Предлагаемая конструкция позволяет регулировать количество охлаждающего реагента, необходимого для достижения заданной температуры сырья при проведении процесса дробления. Приведённый технический расчёт комплекса параметров усовершенствованной роторной дробилки, оборудованной системой замораживания зернового сырья, позволяет определить геометрические размеры камеры дробления и рабочих органов, а также количество охлаждающего агента, необходимого для достижения заданной температуры сырья при проведении процесса дробления зернового сырья.

Different types of grinders are used for grain grinding as well as for other materials. Crushers are the most common due to their simple design, reliability and ease of maintenance. However, energy consumption is often inefficient while the mass of produced particles is non-uniform. Sometimes grain is overgrinded and a dusty fraction is formed. Working units of crushers require frequent replacement increasing maintenance costs. To improve product quality as well as design competitive equipment and technological lines for grain processing it is necessary to analyze new effective methods and technologies for designing, development and improvement of processes, machines and operation. The aim was to validate crusher design equipped with grain freezers via technical calculation of the number of crusher parameters. The presented design enables the adjustment of cooling agent quantity to provide the required material temperature when grinding. The given technical calculation of the impact rotary crusher parameters can aid to determine the crushing chamber size as well as of other working units.
CQA Transformer Models in the Home Improvement Domain
Authors: Maia Macedo , Endres Markus
Published: February 2022

To find answers for subjective questions about many topics through Q\&A forums, questioners and answerers can cooperatively help themselves by sharing their doubts or answers based on their background and life experiences. These experiences can help machines redirect questioners to find better answers based on community question-answering models. This work proposes a comparative analysis of the pairwise community answer retrieval models in the home improvement domain considering different kinds of user question context information. Community Question-Answering (CQA) models must rank candidate answers in decreasing order of relevance for a user question. Our contribution consists of transformer-based language models using different kinds of user information to accurate the model generalisation. To train our model, we propose a proper CQA dataset in the home improvement domain that consists of information extracted from community forums, including question context information. We evaluate our approach by comparing the performance of each baseline model based on rank-aware evaluation measures.
Engineering transient dynamics of artificial cells by stochastic distribution of enzymes
Authors: van Hest Jan C. , Song Shidong , Mason Alexander , Post Richard , de Corato Marco , Mestre Rafael , Yewdall Amy , Cao Shoupeng , van der Hofstad Remco , Sanchez Samuel , Abdelmohsen Loai
Published: February 2022

Random fluctuations are inherent to all complex molecular systems. Although nature has evolved mechanisms to control stochastic events to achieve the desired biological output, reproducing this in synthetic systems represents a significant challenge. Here we present an artificial platform that enables us to exploit stochasticity to direct motile behavior. We found that enzymes, when confined to the fluidic polymer membrane of a core-shell coacervate, were distributed stochastically in time and space. This resulted in a transient, asymmetric configuration of propulsive units, which imparted motility to such coacervates in presence of substrate. This mechanism was confirmed by stochastic modelling and simulations in silico. Furthermore, we showed that a deeper understanding of the mechanism of stochasticity could be utilized to modulate the motion output. Conceptually, this work represents a leap in design philosophy in the construction of synthetic systems with life-like behaviors.
Principle of Chirality Hierarchy in Three-Blade Propeller Systems
Authors: Liu Shubin
Published: February 2022

There are different kinds of molecular chirality, such as zero-dimensional point chirality, one-dimensional axial chirality, 2D planar chirality, and 3D chirality. When they coexist in one system, such as in helical structures of proteins and DNA, they form a chirality hierarchy. Earlier, we showed that the chirality propensity of a lower level in a hierarchy is dictated by that of a higher level and henceforth proposed the Principle of Chirality Hierarchy. In this work, we confirm the validity of this principle in the three-blade propeller molecular system. We consider different choices for the three components of a propeller and systematically investigate the dependence of the stereoisomeric energy difference on these choices. Our results show that the preference of the 0D chirality of a functional group in the propeller system is determined by the 1D chirality, and homochirality is also a remarkable feature for this system. We also unveiled that there exists positive cooperativity and electrostatic interactions play the dominant role in determining the stereoisomeric stability difference while the roles for exchange-correlation and steric effects are minor but indispensable. The establishment and confirmation of the Principle of Chirality Hierarchy from this work should find important applications in asymmetric synthesis, macromolecular assembly, and many others.
Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease
Authors: Wan Shunzhou , Bhati Agastya , Wade Alexander , Alfe Dario , Coveney Peter
Published: February 2022

Although researchers have been working tirelessly since the COVID-19 outbreak, so far only two drugs – remdesivir and ronapreve – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput x-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CLpro). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CLpro. The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug−protein binding, in turn shedding light on the design and discovery of potential drugs.
Efficient Synthesis and Functionalization of 3-Bromo Naphtho[2,3b]thiophene
Authors: Burke Emily , Welsh Erin , Robertson Katherine , Speed Alexander
Published: February 2022

Naphtho[2,3b]thiophene is a linear sulfur containing polycyclic aromatic hydrocarbon. Naphtho[2,3b]thiophene and its derivatives are commonly accessed by a Bradsher cyclization. Synthesis of the Bradsher cyclization substrate typically requires harsh conditions, including several oxidation state changes. Here we report an improved, multigram synthesis of 3-bromonaphtho[2,3b]thiophene, exploiting a copper-catalyzed cross coupling to prepare the Bradsher substrate in 3 steps from commercial materials while minimizing redox reactions. Modification of the naphthothiophene scaffold in the 3-position has not previously been reported. In this work, the 3-bromonaphthothiophene is further functionalized via lithium-halogen exchange, with the key finding being a specific order of addition in lithiation is required to avoid undesired rearrangement reactions. A small yet versatile set of derivatives, including a naphthothiophene-containing chiral amine are prepared.
Immobilized Polythiophene-fullerene on Surfaces: Beyond Photovoltaics
Authors: Samanta Debasis , Ramar Periyamuthu , Aishwarya B.V
Published: February 2022

Surfaces coated with polythiophene-fullerene, particularly poly(3-hexylthiophene)-Phenyl-C61-butyric acid methyl ester (P3HT-PCBM) emerged as a gold standard for fabrication of photovoltaic devices of bulk heterojunction type. Since, photocatalytic dye degradation has a similar initiation mechanism driven by electron-hole production under sunlight, the surface was used as a reusable photocatalytic "chip" to degrade polluting organic dyes. Detailed investigations were carried out on various factors affecting the efficacy
A microbial sulfoquinovose monooxygenase pathway that enables sulfosugar assimilation
Authors: Sharma Mahima , Lingford James , Petricevic Marija , Snow Alexander , Zhang Yunyang , Jarva Michael , Mui Janice , Scott Nichollas , Saunders Eleanor , Mao Runyao , Epa Ruwan , da Silva Bruna , Pires Douglas , Ascher David , McConville Malcolm , Davies Gideon , Williams Spencer , Goddard-Borger Ethan
Published: February 2022

Breakdown of the sulfosugar sulfoquinovose (SQ, 6-deoxy-6-sulfoglucose), produced by photosynthetic organisms, is an important component of the biogeochemical carbon and sulfur cycles. Here, we reveal a new pathway for SQ degradation involving oxidative desulfurization to release sulfite and complete breakdown of the carbon skeleton of this sugar to support the growth of the plant pathogen Agrobacterium tumefaciens. SQ or its glycoside sulfoquinovosyl glycerol are imported by an ABC transporter system with associated SQ binding protein. A sulfoquinovosidase cleaves the SQ glycoside and a flavin mononucleotide-dependent sulfoquinovose monooxygenase acts in concert with an NADH-dependent flavin reductase to release sulfite and form 6-oxo-glucose. A short-chain dehydrogenase/reductase oxidoreductase reduces 6-oxo-glucose to glucose, allowing it to enter primary metabolism. Structural and biochemical studies provide detailed insights into the binding and recognition of key species along the reaction coordinate. This sulfoquinovose monooxygenase pathway is distributed across alphaproteobacteria and especially within the rhizobiales. This metabolic strategy...
Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinans bearing multiple effective residues (TriMER) library
Authors: Saitoh Tsuyoshi , Amezawa Mao , Horiuchi Jumpei , Nagumo Yasuyuki , Yamamoto Naoshi , Kutsumura Noriki , Oshita Ryuichiro , Tokuda Akihisa , Irukayama-Tomobe Yoko , Ogawa Yasuhiro , Ishikawa Yukiko , Hasegawa Emi , Sakurai Takeshi , Uchida Yasuo , Sato Tetsu , Gouda Hiroaki , Tanimura Ryuji , Yanagisawa Masashi , Nagase Hiroshi
Published: February 2022

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a high degree of three-dimensional properties, leading to a novel small-scale focused library based on 1,3,5- trioxazatriquinane. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (–)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) could serve as a privileged structure for G-protein coupled receptors (GPCRs) and the TriMER library approach might be useful for the hit discovery process targeting other GPCRs not only opioid and orexin receptors.
Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene
Authors: Gohil Khyati , Kazmi M. Zain , Williams Florence
Published: February 2022

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.
Reaction of irbesartan with nitrous acid produces irbesartan oxime derivatives, rather than N-nitrosoirbesartan
Authors: Lin Jinsheng , Zhou Qiang , Jia Ru , Liu Wentao , Hou Huacui , Ma Jian , Li Dan , Chen Nuo , Chen Wenbin , Ye Jian , Hu Wenping , Zhu Wenquan , Li Min
Published: February 2022

In October 2021, a number of batches of irbesartan and irbesartan hydrochlorothiazide finished products were recalled from the US market, due to the presence of unacceptable level of the probably carcinogenic nitrosamine N-nitrosoirbesartan. Nevertheless, there is no revealing of the exact structure of this hypothetical N-nitrosoirbesartan. In the current study, we performed a set of 10 reactions of irbesartan with nitrous acid under various conditions and found no trace of this hypothetical N-nitrosoirbesartan by a sensitive and accurate LC-MS method with limit of detection (LOD) of 30 ppb. With the use of LC-PDA/UV-high resolution MSn as well as 1D/2D NMR, the reaction products formed are found to be the two isomeric oxime derivatives of irbesartan, with the Z-isomer as the predominant product. Furthermore, no trace of this hypothetical N-nitrosoirbesartan can be detected in representative commercial batches of irbesartan. Despite of the fact that in silico evaluation suggests that the two irbesartan oximes may be controlled as regular impurities, analysis of representative irbesartan commercial batches by the LC-MS method indicates that the oximes are not detected (LOD: 30 ppb).
Signal-Processing and Adaptive Prototissue Formation in Metabolic DNA Protocells
Authors: Samanta Avik , Hörner Maximilian , Liu Wei , Weber Wilfried , Walther Andreas
Published: February 2022

The fundamental life-defining processes in living cells, such as replication, division, adaptation, and tissue formation, take place via intertwined metabolic reaction networks orchestrating downstream signal processing in a confined, crowded environment with high precision. Hence, it is crucial to understand and reenact some of these functions in wholly synthetic cell-like entities (protocells) to envision designing soft-materials with life-like traits. Herein, we report on a programmable all-DNA protocell (PC) composed of a liquid DNA interior and a hydrogel-like shell, harboring DNAzyme active sites in the interior whose catalytic bond-cleaving activity leads to a downstream phenotype change in the protocells, as well as triggers prototissue formation. In this regard, we coupled several tools of DNA nanoscience, such as RNA cleavage, dynamic strand displacement reactions, and multivalent palindromic interactions, in a synchronize pathway so that the input signal can be processed inside the protocells and generate downstream cues giving rise to metabolic adaptive behavior. For example, the compartmentalized DNAzyme catalyzes the bond-cleavage of a substrate that releases a DNA strand in situ to trigger a strand displacement reaction at the shell of the protocells leading to a change in color resembling a “phenotype-like” change in cells, and finally to establish communication with other protocells via multivalent interactions.
Non-Hermitian Cavity Quantum Electrodynamics - Configuration Interaction Singles Approach for Polaritonic Structure with ab initio Molecular Hamiltonians
Authors: McTague Jonathan , Foley Jonathan
Published: February 2022

We combine {ab initio molecular electronic Hamiltonians with a cavity quantum electrodynamics model for dissipative photonic modes and apply mean-field theories to the ground- and excited-states of resulting polaritonic systems. In particular, we develop a restricted Hartree-Fock theory for the mean-field ground-state and a non-Hermitian configuration interaction singles theory for mean-field excited-states of the molecular system strongly interacting with a photonic mode, and apply these methods to several paradigmatic polaritonic systems. We leverage the Psi4Numpy framework to yield open-source and accessible reference implementations of these methods.
Mono-alkyl Phosphinic Acids as Ligands in Nanocrystal Synthesis
Authors: Dhaene Evert , Smet Philippe F. , De Buysser Klaartje , De Roo Jonathan
Published: February 2022

Surfactants play a crucial role in the synthesis of colloidal nanocrystals. Nevertheless, only a handful molecules are currently used, oleic acid being the most typical example. Here, we show that mono-alkyl phosphinic acids are an interesting surfactant class with a reactivity that is intermediate between carboxylic acids and phosphonic acids. We first present the synthesis of n-hexyl, 2-ethylhexyl, n-tetradecyl, n-octadecyl, and oleyl phosphinic acid. These compounds are suitable surfactants during high-temperature nanocrystal synthesis (240-300°C). In contrast to phosphonic acids, they do not form poly anhydride gels. Consequently, CdSe quantum dots synthesized with octadecylphosphinic acid are conveniently purified, and are free from background scattering in UV-Vis. The CdSe nanocrystals have a very low polydispersity and a photoluminescence quantum yield up to 18%, without additional shell. Furthermore, we could synthesize CdSe and CdS nanorods using phosphinic acid ligands and found a remarkable purity (i.e. without tetrapod impurities). We conclude that the reactivity towards TOP-S and TOP-Se precursors decreases in the series: cadmium carboxylate > cadmium phosphinate > cadmium phosphonate. By introducing a third and intermediate class of surfactants, we enhance the versatility of surfactant-assisted syntheses.
Anisotropic strength behavior of single-crystal TATB
Authors: Kroonblawd Matthew , Steele Brad , Nelms Matthew , Fried Laurence , Austin Ryan
Published: February 2022

High-rate strength behavior plays an important role in the shock initiation of high explosives, with plastic deformation serving to localize heat into hot spots and as a mechanochemical means to enhance reactivity. Recent simulations predict that detonation-like shocks produce highly reactive nanoscale shear bands in the layered crystalline explosive TATB (1,3,5-triamino-2,4,6-trinitrobenzene), but the thresholds leading to this response are poorly understood. We utilize molecular dynamics (MD) to simulate the high-rate compressive stress-strain response of TATB, with a focus on understanding flow behavior. The dependence of strength on pressure and loading axis (crystal orientation) is explored. The deformation mechanisms fall broadly into two categories, with compression along crystal layers activating a buckling/twinning mode and compression normal to the layers producing nanoscale shear bands. Despite the complexity of the underlying mechanisms, the crystal exhibits relatively straightforward stress-strain curves. Most of the crystal orientations studied show rapid strain softening following the onset of yielding, which settles to a steady flow state. Trajectories are analyzed using five metrics for local states and structural order, but most of these metrics yield similar distributions for these deformation mechanisms. On the other hand, a recently proposed measure of intramolecular strain energy is found to most cleanly distinguish between these mechanisms, while also providing a plausible connection with mechanochemically accelerated decomposition kinetics. Localization of intramolecular strain energy is found to depend strongly on crystal orientation and pressure.
A Low-cost Sulfate-based All Iron Redox Flow Battery
Authors: Yu Sicen , Yue Xiujun , Holoubek John , Xing Xing , Pan Eric , Pascal Tod , Liu Ping
Published: February 2022

Redox flow batteries (RFBs) are promising choices for stationary electric energy storage. Nevertheless, commercialization is impeded by high-cost electrolyte and membrane materials. Here, we report a low-cost all-iron RFB that features inexpensive FeSO4 electrolytes, microporous membrane along with a glass fiber separator. The addition of 0.1 м 1-ethyl-3-methylimidazolium chloride (EMIC) overcomes the low solubility of FeSO4 in water which is raised to 2.2 м. DFT calculations demonstrate that EMI+ can strengthen the interaction between sulfate anions and water molecules. This electrolyte composition also allows both anode and cathode reactions to operate without actively maintaining a pH gradient between them, thus eliminating the need for expensive ion exchange membranes. The all-iron RFB demonstrates stable operation at a current density of 20 mA cm−2 for more than 800 cycles via a simple, periodic regeneration process. Furthermore, the system cost of FeSO4/EMIC RFBs is projected to be $ 50 per kWh due to its low-cost active materials and the inexpensive microporous membrane. This low-cost, high-concentration all-iron RFB is a promising stationary energy‐storage system for storing renewable energy.
Role of anionic backbone in NHC-stabilized coinage metal complexes: New precursors for atomic layer deposition
Authors: Boysen Nils , Philip Anish , Rogalla Detlef , Karppinen Maarit , Devi Anjana
Published: February 2022

Cu and Ag precursors that are volatile, reactive, and thermally stable are currently of high interest for their application in atomic layer deposition (ALD) of thin metal films. In pursuit of new precursors for coinage metals namely Cu and Ag, a series of new N-heterocyclic carbene (NHC) based Cu(I) and Ag(I) complexes were synthesized. Modifications in the substitution pattern of diketonate-based anionic backbones led to five monomeric Cu complexes and four closely related Ag complexes with the general formula [M(tBuNHC)(R)] (M = Cu, Ag; tBuNHC = 1,3-di-tert-butyl-imidazolin-2-ylidene; R = diketonate). Thermal analysis indicated that most of the Cu complexes are thermally stable and volatile compared to the more fragile Ag analogs. One of the promising Cu precursors was evaluated for the ALD of nanoparticulate Cu metal films using hydroquinone as the reducing agent at appreciably low deposition temperatures (145–160 °C). This study highlights the considerable impact of the employed ligand sphere on the structural and thermal properties of metal complexes that are relevant for vapor phase processing of thin films.
Development and Evaluation of a Synthetic Opioid Targeted Gas Chromatography Mass Spectrometry (GC-MS) Method
Authors: Sisco Edward , Burns Amber , Moorthy Arun
Published: February 2022

A method for the targeted confirmation of synthetic opioids and related compounds observed in forensic seized drug analysis was developed and evaluated. Investigated settings included column type, flow rate, temperature program, inlet temperature, source temperature, and tune type. It was evaluated against a suite of 222 synthetic opioids and related compounds, and successfully differentiated all but four compound pairs based on retention time or mass spectra. Compared to a general confirmatory method, the targeted method was up to 25 times more sensitive and provided at least a two-fold increase in retention time differences. Analysis of case extracts successfully demonstrated utility of the method and showed no instance of carryover, although the high polarity column required wider retention time windows than other columns.
Chemoinformatic Characterization of Synthetic Screening Libraries Focused on Epigenetic Targets
Authors: Flores-Padilla E. Alexis , Juárez-Mercado K. Eurídice , Naveja José J. , Kim Taewon D. , Miranda-Quintana Ramón Alain , Medina-Franco José L.
Published: February 2022

The importance of epigenetic drug and probe discovery is on the rise. This is not only paramount to identify and develop therapeutic treatments associated with epigenetic processes but also to understand the underlying epigenetic mechanisms involved in biological processes. To this end, chemical vendors have been developing synthetic compound libraries focused on epigenetic targets to increase the probabilities of identifying promising starting points for drug or probe candidates. However, the chemical contents of these data sets, the distribution of their physicochemical properties, and diversity remain unknown. To fill this gap and make this information available to the scientific community, we report a comprehensive analysis of eleven libraries focused on epigenetic targets containing more than 50,000 compounds. We used well-validated chemoinformatics approaches to characterize these sets, including novel methods such as automated detection of analog series and visual representations of the chemical space based on Constellation Plots and Extended Chemical Space Networks. This work will guide the efforts of experimental groups working on high-throughput and medium-throughput screening of epigenetic-focused libraries. The outcome of this work can also be used as a reference to design and describe novel focused epigenetic libraries.
Stable isotope phosphate labelling of diverse metabolites is enabled by a family of 18O-phosphoramidites
Authors: Haas Thomas , Mundinger Stephan , Qiu Danye , Jork Nikolaus , Ritter Kevin , Dürr-Mayer Tobias , Ripp Alexander , Saiardi Adolfo , Schaaf Gabriel , Jessen Henning
Published: February 2022

Stable isotope labelling is state-of-the-art in quantitative mass spectrometry, yet often accessing the required standards is cumbersome and very expensive. As 18O can be derived from heavy water (H218O), it is comparably cheap and particularly suited for labelling of phosphorylated compounds, provided the introduction is straight-forward and phosphate neutral loss in the ion source can be avoided. Here, a unifying synthetic concept for 18O-labelled phosphates is presented, based on a family of modified 18O2‑phosphoramidite reagents. This flexible toolbox offers access to major classes of biologically highly relevant phosphorylated metabolites as their isotopologues including - but not limited to - nucleotides, inositol phosphates, -pyrophosphates, and inorganic polyphosphates. 18O-enrichment ratios >95% and good yields are obtained consistently in gram-scale reactions, while enabling late-stage labelling. We demonstrate the utility of the 18O labelled inositol phosphates and pyrophosphates by assignment of these metabolites from different biological matrices, such as mammalian cell lysates, slime mold and plant samples. We demonstrate that phosphate neutral loss is negligible in an analytical setup employing capillary electrophoresis electrospray ionization triple quadrupole mass spectrometry.
Total Synthesis of Himastatin
Authors: D'Angelo Kyan , Schissel Carly , Pentelute Bradley , Movassaghi Mohammad
Published: February 2022

The synthesis and study of antibiotic natural products with unique structures and mechanisms of action represents a proven strategy to combat the public health crisis posed by antibiotic-resistant bacteria. The natural product himastatin is an antibiotic with an unusual homodimeric structure that presents a significant synthetic challenge. We report the concise total synthesis of himastatin by a newly developed final-stage dimerization strategy that was inspired by a detailed consideration of its biogenesis. Combining our bio-inspired dimerization approach with a modular synthesis enabled expedient access to a number of designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.
Can Electric Field be a Descriptor of Catalytic Activity? A Case Study on Chorismate Mutase
Authors: Siddqui Shakir Ali , Dubey Kshatresh
Published: February 2022

The current theoretical perception of enzymatic activity is highly reliant on the determination of activation energy of the reactions which is often calculated using a computational demanding quantum mechanical calculation. With the ever-increasing use of bioengineering techniques that produce too many variants of the same enzyme, a fast and accurate way to study the relative efficiency of enzymes is a need of time. Here, we propose the electric field (EF) of the enzyme along the reaction axis as a descriptor for the enzymatic activity using an example of Chorismate Mutase in its native and several variants (R90A, R90G, and R90K/C88S). The study shows a linear correlation between the calculated enzymatic EF and enzymatic activity of all complexes. The MD simulations of the Michaelis complex and the transition state analog (TSA) show a stabilizing force on TSA due to the enzymatic EF. The QM/MM and QM-only DFT calculations with the presence of External Electric Field (EEF) oriented along the reaction axis show that the electric can increase the dipole moment of the TS, thereby, stabilizing it and thus lowers the activation energy.
Colorimetric detection on paper analytical device using machine learning
Authors: Khanal Bidur , Pokhrel Pravin , Khanal Bishesh , Giri Basant
Published: February 2022

Paper-based analytical devices (PADs) employing colorimetric detection and smartphone images have gained wider acceptance in a variety of measurement applications. The PADs are primarily meant to be used in field settings where assay and imaging conditions greatly vary resulting in less accurate results. Recently, machine learning (ML) assisted models have been used in image analysis. We evaluated a combinations of four ML models - logistic regression, support vector machine, random forest, and artificial neural network, and three image color spaces - RGB, HSV, and LAB for their ability to accurately predict analyte concentrations. We used images of PADs taken at varying lighting conditions, with different cameras, and users for food color and enzyme inhibition assays to create training and test datasets. Prediction accuracy was higher for food color than enzyme inhibition assays in most of the ML model and colorspace combinations. All models better predicted coarse level classification than fine grained concentration labels. ML models using sample color along with a reference color increased the models’ ability in predicting the result in which the reference color may have partially factored out the variation in ambient assay and imaging conditions. The best concentration label prediction accuracy obtained for food color was 0.966 when using ANN model and LAB colorspace. The accuracy for enzyme inhibition assay was 0.908 when using SVM model and LAB colorspace. Appropriate model and colorspace combinations can be useful to analyze large numbers of samples on PADs as a powerful low-cost quick field-testing tool.