bluuebunny/crossref_metadata_2025 huggingface dataset:
Process design of a fully integrated continuous biopharmaceutical process using economic and ecological impact assessment
Authors: Ding Chaoying , Ardeshna Hiren , Gillespie Christopher , Ierapetritou Marianthi
Published: September 2022

Continuous biomanufacturing is a promising alternative to current batch operation as it offers benefits in terms of improved productivity, product quality, and reduced footprint. This study aims to build a fully integrated continuous platform for monoclonal antibody (mAb) production incorporating novel technologies (like intensified seed expansion and continuous high cell density perfusion operations, single‐pass tangential flow filtration, and single‐use technologies) as well as media and buffer preparation steps. Economic assessment is performed on the basis of the total cost of goods (COGs), which is $102.2/g in the base‐case scenario with a bioreactor scale of 500 L. E‐factor is used as an environmental indicator and the result shows that 4865.6kg of process water and 11.1 kg of consumables are required to produce 1 kg mAbs. After the development and analysis of the benchmark process, scenario analysis is performed to assess the impacts of the bioreactor scale (60–2000 L) and upstream titers (1.12–2.08 g/L) on the process economics as well as on the environmental footprint. With the increase of bioreactor scale and mAb titer, the operating COGs per unit product decrease. Moreover, increasing the mAb titer is more favorable in terms of the ecological impacts. To investigate the production capacity, the upstream production is increased and the downstream bottlenecks are determined. It is found that only the multicolumn chromatographic (MCC) operations become the process bottleneck and the order of the MCC unit operation that becomes the process bottleneck depends on capacity utilization for that step. Finally, a new platform is built with the integration of membrane chromatography and the two designed processes are compared in terms of economic and ecological impacts.
Scalable manufacturing platform for the production of PEGylated heme albumin
Authors: Savla Chintan , Palmer Andre F.
Published: September 2022

Cell‐free heme, which was previously shown to have adverse effects on the innate immune system, does not induce inflammation when bound to a protein carrier via overexpression of the enzyme heme‐oxygenase 1 (HO‐1). Studies in mouse macrophage cell culture and human endothelial cells have confirmed HO‐1 catalyzed breakdown of protein bound heme into biliverdin, iron, and carbon monoxide (CO), which elicits anti‐inflammatory effects. However, to fully realize the anti‐inflammatory therapeutic effects of heme, a colloidally stable heme protein carrier must be developed. To accomplish this goal, we incorporated multiple heme molecules into human serum albumin (HSA) via partial unfolding of HSA at basic pH followed by refolding at neutral pH, and subsequently conjugated the surface of the heme‐HSA complex with polyethylene glycol (PEG) to stabilize heme‐HSA. Quantification studies confirmed that a maximum of 5−6 hemes could be bound to HSA without precipitation or degradation of heme‐HSA. Dynamic light scattering, size exclusion‐high performance liquid chromatography (SEC‐HPLC), and matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF) mass spectrometry confirmed the increase in hydrodynamic diameter and molecular weight (MW), respectively, upon PEGylation of heme‐HSA. Furthermore, PEG‐heme‐HSA was stable upon exposure to different pH environments, freeze‐thaw cycles, and storage at 4°C. Taken together, we devised a synthesis and purification platform for the production of PEGylated heme‐incorporated HSA that can be used to test the potential anti‐inflammatory effects of heme in vivo.
Metabolic minimap of anaerobic digestion for undergraduate biochemistry courses
Authors: Shen Jian , Jin Wenxiong , Chen Chang
Published: September 2022

As a representative catabolic reaction that widely exists in nature, anaerobic digestion (AD) exhibits great value regarding the global carbon cycle, renewable energy development, and environmental protection. Such an important biochemical reaction was ignored before and should be introduced into the teaching and textbooks of undergraduate biochemistry courses. However, students may face obstructions when learning AD theories since the metabolic pathways in AD are very complex. To solve these problems, an instructive metabolic minimap of the AD reaction was designed, including its reaction stages, reaction pathways, substrates, and enzymes. Furthermore, the interrelationships between aerobic catabolism (AEC) and anaerobic catabolism (ANC) were also summarized by combining the catabolic pathways of typical biological macromolecules. In this paper, AD theories were first replenished into undergraduate biochemistry courses by metabolic minimap, which not only provided valuable supports for the practical teaching of AD in undergraduate biochemistry courses, but also acted as an important reference for students in biology‐related majors and biochemistry teachers.
Successful thrombolytic therapy is associated with increased granulocyte CD15 expression and reduced stroke‐induced immunosuppression
Authors: Béres‐Molnár Katalin Anna , Czeti Ágnes , Takács Ferenc , Barna Gábor , Kis Dániel , Róka Gabriella , Folyovich András , Toldi Gergely
Published: September 2022

Objectives

Stroke‐induced immunosuppression (SIIS) increases the risk of poststroke infections. We aimed to determine whether failed versus successful thrombolytic therapy (TT) resulted in SIIS‐associated changes in peripheral granulocyte markers at 1 week following the insult.

Methods

We collected peripheral blood samples from 19 patients with acute ischemic stroke undergoing TT within 6 h after the onset of their first symptoms and 7 days after the insult. Age‐matched controls were sampled on one occasion. We compared the expression of CD15 and CD64 on monocytes, granulocytes, and lymphocytes using flow cytometry.

Results

The proportion of granulocytes and CD15+ granulocytes was comparable between controls and stroke patients at both time points. While the proportion of CD15bright granulocytes was also comparable, the mean fluorescence intensity (MFI) of CD15 on this subset was reduced in stroke patients by day 7 but was overall higher at both time points compared to controls. The MFI of CD15 on granulocytes was lower in stroke patients with failed TT than in those with successful TT 1 week after the insult.

Conclusions

Our current results indicate that TT may not only acutely reduce the systemic inflammatory response following stroke but may also play a role in reversing SIIS at a later stage following the insult, as reflected by the higher expression of the CD15 marker on granulocytes following successful TT.
Implementation of a psychological treatment outcomes evaluation system for young people at Uruguay's National Health System: Using CORE‐OM
Authors: Dogmanas Denisse , Arias María Alejandra , Gago Fiorella , de Álava Laura , Roussos Andres
Published: September 2022

Routine outcome measurement is an important practice to improve the quality of mental health services. Since 2011, it has been mandatory for health services to offer psychotherapy in Uruguay's National Health System. Adolescents and young people are a priority population. The lack of information about the functioning and the effectiveness of the mental health services focused on youth is an obstacle to assess and, as a consequence, to improve the services. The objective of this study was to evaluate the implementation of a system to establish the characteristics and outcomes of psychological treatment received by young people at services provided by Uruguay's National Health System. The present study was the first of its kind to examine the outcomes of psychotherapy offered in mental health services. A pre‐post design in a naturalistic setting was used. Sixty‐nine participants, aged 16 to 24 years, and 26 therapists from four health services participated. Sociodemographic and clinical questionnaires, the Clinical Outcome Routine Evaluation‐Outcome Measure (CORE‐OM; Evans et al., 2002) and a semi‐structured interview were applied to assess the perception of change. CORE‐OM results portrayed a decrease in psychological distress. Interview data helped to better understand the perception of change. A high number of dropouts revealed the need for the services to use strategies to prevent early dropouts in young users. The CORE‐OM appears to be a valuable tool. Barriers for outcomes system implementations are discussed and may prove useful to other countries where there is a lack of an outcome‐oriented clinical culture.
Cocoa Pod Husk: A High‐Pectin Source with Applications in the Food and Biomedical Fields
Authors: Barrios‐Rodríguez Yeison Fernando , Salas‐Calderón Karen Tatiana , Orozco‐Blanco Dayana Alejandra , Gentile Piergiorgio , Girón‐Hernández Joel
Published: September 2022

Cocoa liquor, butter, and powder represent derived products from a small portion of the fruits, compared with the cocoa pod husk (CPH) which accounts for ∼ 70 % of fresh weight. CPH, improperly disposed in plantations, can cause diseases threatening worldwide chocolate production. However, this biomass can be a potential source of bioactive compounds aligned with the circular economy. An overview on the different methods for extracting pectin, resulting in variable extraction yields with a critical discussion on the obtained physicochemical characteristics, is presented. Additionally, the potential applications of the extracted pectin for food and biomedical application are discussed, including thickener, stabilizer, excipient, drug‐release modifier, macrophage activator, etc. Despite these potential outputs, new extraction methods need to be considered for improving efficiency and sustainability. Finally, potential approaches are introduced that can help to minimize the environmental impact, making the extraction cost‐ and time‐efficient, and, therefore, more ssustainable for a further successful translation to industry.
Extended treatment with (1→3)(1→6)‐β‐d‐glucan (Botryosphaeran) reduces obesity and its comorbidities in high‐fat/high‐sugar diet‐fed rats
Authors: Ribeiro Mariana Costa , Silva Amadeu Zattoni da , Giordani Morenna Alana , Lira Cleberson , Luvizotto Renata de A. M. , Nascimento André F. , Queiroz Diogo Albino de , Dekker Robert F. H. , Barbosa‐Dekker Aneli M. , de Queiroz Eveline Aparecida Isquierdo Fonseca
Published: September 2022

Obesity is associated with other diseases such as diabetes and cancer. Botryosphaeran, a fungal (1→3)(1→6)‐β‐d‐glucan, is described to present antimutagenic, hypoglycemic, hypocholesterolemic, and antitumor activities when administered by gavage over 15 days in rats and mice. Thus, the present study aims to analyze the metabolic effects of Botryosphaeran (12 mg/kg body weight/day) treatment over 30 days in obese Wistar male rats. Obesity was induced in the rats by a high‐fat/high‐sugar diet for 8 weeks. Control rats received a standard diet. On the 5th week, Botryosphaeran treatment commenced. Groups: control, obese, and obese+Botryosphaeran 30 days. In the 8th week, obesity was characterized. Feed intake, glucose and lipid profiles, glucose tolerance, and insulin sensitivity were analyzed. Obese rats showed accumulation of visceral adipose tissue, reduction of muscle mass, glucose intolerance, insulin resistance, hyperglycemia, and dyslipidemia. Botryosphaeran effectively reduced weight gains and the accumulation of retroperitoneal adipose tissue, corrected the levels of glucose, triglycerides, and very low‐density lipoprotein‐cholestrol, and improved insulin sensitivity. Treatment for 30 days was effective in maintaining the beneficial effects demonstrated by this β‐glucan when administered for 15 days without promoting side effects. Treatment with (1→3)(1→6)‐β‐
d‐glucan presented anti‐obesogenic and beneficial metabolic effects in Wistar rats; important for the treatment of obesity and its comorbidities.
Effective Iodine Capture Behavior by a Censer‐shaped Macrocycle in Vapor Phase and Aqueous Solution
Authors: Jiao Jianmin , Xie Wang , Li Yumei , Lin Chen , Jiang Juli , Wang Leyong
Published: September 2022

Iodine capture is of great significance for disposal of the hazardous radioactive iodine. CTX[P(O)Ph], one kind of censer‐shaped macrocycle cyclotrixylohydroquinoylene (CTX) derivatives, was applied as an efficient iodine adsorbent. It showed satisfactory iodine adsorption capacity in vapor phase and could be reused without obvious adsorption capacity loss. Besides, the adsorbent could also uptake iodine in water. Fortunately, two iodine loading CTX[P(O)Ph] crystal structures were obtained under different conditions to explore the mechanism of iodine adsorption. This work provides a relatively rare example of iodine adsorption by macrocycle. It is promising that the results with crystal information might be meaningful for exploring and designing new kinds of iodine adsorbents.
Efficient Photoredox Cycles to Control Perylenediimide Self‐Assembly**
Authors: Chen Chunfeng , Valera Jorge S. , Adachi Takuji B. M. , Hermans Thomas M.
Published: September 2022

Photoreduction of perylenediimide (PDI) derivatives has been widely studied for use in photocatalysis, hydrogen evolution, photo‐responsive gels, and organic semiconductors. Upon light irradiation, the radical anion (PDI⋅−) can readily be obtained, whereas further reduction to the dianion (PDI2−) is rare. Here we show that full 2‐electron photoreduction can be achieved using UVC light: 1) in anaerobic conditions by ‘direct photoreduction’ of PDI aggregates, or 2) by ‘indirect photoreduction’ in aerobic conditions due to acetone ketyl radicals. The latter strategy is also efficient for other dyes, such as naphthalenediimide (NDI) and methylviologen (MV2+). Efficient photoreduction on the minute time‐scale using simple LED light in aerobic conditions is attractive for use in dissipative light‐driven systems and materials.
Carbon2Chem® – A Key Building Block for Climate Protection
Authors: Deerberg Görge , Oles Markus , Schlögl Robert
Published: September 2022

No abstract.
Experimental investigation of liquid–liquid flow in an inclined pipe using dimensionless numbers
Authors: Yousefirad Sasan , Shad Saeed , Nejati Hamed , Zivar Davood
Published: September 2022

Two‐phase flow is a common phenomenon in the energy industry, where flow patterns significantly affect heat transfer and pressure drop in different systems. However, there is no unique or comparable flow map because of its dependency on dimensional parameters. Therefore, an analysis using dimensionless numbers makes the results comprehensive. To do so, a series of liquid–liquid flow experiments (1296 experiments) were conducted in a transparent pipe at the different velocities of the phases. The flow patterns were captured using a high‐speed camera. The experiments were performed at eight different inclinations within the range of −20 to +20 degrees. Six flow patterns are observed at different inclinations; stratified flow with mixing at the interface (STMI), dispersion of water in oil (Dw/o), dispersion of oil in water (Do/w), dual continuous (DC), slug, and wavy stratified (WST), where the first five flow patterns are presented in the upward flow and the two last flow patterns disappear in some of the downward flow. The pattern of boundaries for each flow pattern in the upward flow shows dependency on inclination, while in the downward flow condition, a rather general format can be applied to most of the patterns. The analysis illustrates that gravity and buoyancy forces are the dominating forces in the system compared to other forces, such as viscous, inertia, and interfacial tension, which are due to the inclination of the pipe.
Modulation of Conformational Transition of Polypeptides under Slightly Acidic Environment†
Authors: Li Jie , Zhang Jiajie , Long Qi , Guo Weisheng , Xiong Menghua
Published: September 2022

Comprehensive Summary

Controlling the conformational transition of polypeptides under slightly acidic environment is challenging. Herein, we report a class of pH‐responsive helix‐to‐coil conformationally transitionable polypeptides (pCTPs) by simply conjugating tertiary amine groups (TAs) to polylysine. Their conformation is highly dependent on the charge state of TAs, showing a helical structure when most TAs are deprotonated and a non‐helical structure when majority of TAs are protonated. The conformational transition pH can be modulated by tuning the hydrophobicity of TAs and the incorporation of hydrophobic monomers at a pH range of 7.2 to 6.0. Such pCTP showed a vesicle‐to‐micelle transition when their conformation transformed from helix to coil, facilitating controlled drug release. Our study provided an approach to control the conformational transition of polypeptides under slightly acidic condition.
Design and Application of m‐Hydroxybenzyl Alcohols in Regioselective (3 + 3) Cycloadditions of 2‐Indolymethanols†
Authors: Shi Yi‐Cheng , Yan Xin‐Yu , Wu Ping , Jiang Song , Xu Ran , Tan Wei , Shi Feng
Published: September 2022

Comprehensive Summary

A new class of m‐hydroxybenzyl alcohols has been designed as competent three‐carbon building blocks and achieved their application in 2‐indolylmethanol‐involved regioselective (3 + 3) cycloadditions under the catalysis of Brønsted acids. By this appoach, a series of indole‐fused six‐membered cycloadducts have been synthesized in overall good yields (up to 98%) with excellent regioselectivity (all >95: 5 rr), thus affording a powerful method for the construction of indole‐fused six‐membered rings. Moreover, a catalytic asymmetric version of this (3 + 3) cycloaddition has been preliminarily investigated, which revealed the potential of the reaction for constructing chiral indole‐fused six‐membered rings in an enantioselective manner. This work not only has accomplished the first design of m‐hydroxybenzyl alcohols as competent reactants, but also represents the first application of m‐hydroxybenzyl alcohols as three‐carbon building blocks in cycloadditions. In addition, this work provides a good example for regioselective and C3‐nucleophilic (3 + 3) cycloadditions of 2‐indolylmethanols, which will substantially enrich the chemistry of 2‐indolylmethanols.
2‐Difluoromethoxy‐Substituted Estratriene Sulfamates: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Steroid Sulfatase Inhibition
Authors: Dohle Wolfgang , Asiki Hannah , Gruchot Wojciech , Foster Paul A. , Sahota Havreen K. , Bai Ruoli , Christensen Kirsten E. , Hamel Ernest , Potter Barry V. L.
Published: September 2022

2‐Difluoromethoxyestratriene derivatives were designed to improve potency and in vivo stability of the drug candidate 2‐methoxyestradiol (2ME2). Compound evaluation in vitro against the proliferation of MCF‐7 and MDA MB‐231 breast cancer cells, as inhibitors of tubulin polymerisation and also steroid sulfatase (STS) both in cell lysates and in whole cells, showed promising activities. In antiproliferative assays 2‐difluoromethoxyestradiol was less potent than 2ME2, but its sulfamates were often more potent than their corresponding non‐fluorinated analogues. The fluorinated bis‐sulfamate is a promising antiproliferative agent in MCF‐7 cells (GI50 0.28 μM) vs the known 2‐methoxyestradiol‐3,17‐O,O‐bissulfamate (STX140, GI50 0.52 μM), confirming the utility of our approach. Compounds were also evaluated in the NCI 60‐cell line panel and the fluorinated bis‐sulfamate derivative displayed very good overall activities with a sub‐micromolar average GI50. It was a very potent STS inhibitor in whole JEG‐3 cells (IC50 3.7 nM) similar to STX140 (4.2 nM) and additionally interferes with tubulin assembly in vitro and colchicine binding to tubulin. An X‐ray study of 2‐difluoromethoxy‐3‐benzyloxyestra‐1,3,5(10)‐trien‐17‐one examined conformational aspects of the fluorinated substituent. The known related derivative 2‐difluoromethyl‐3‐sulfamoyloxyestrone was evaluated for STS inhibition in whole JEG‐3 cells and showed an excellent IC50 of 55 pM.
Synthesis and Vasorelaxant Activity of Nitrate−Coumarin Derivatives
Authors: Matos Maria João , Uriarte Eugenio , Seoane Nuria , Picos Aitor , Gil‐Longo José , Campos‐Toimil Manuel
Published: September 2022

Due to the need for new chemical entities for cardiovascular diseases, we have synthesized a new series of nitrate−coumarins and evaluated their vasorelaxant activity in contraction‐relaxation studies using rat aorta rings precontracted with phenylephrine or by depolarization with a high concentration of potassium chloride. Four of the new compounds were able to relax smooth vascular muscle with a similar profile and potency to glyceryl trinitrate (IC50=12.73 nM) and sodium nitroprusside (IC50=4.32 nM). Coumarin‐7‐yl‐methyl nitrate (4), the best compound within the series, was able to relax smooth vascular muscle in the low nanomolar range (IC50=1.92 nM). The mechanisms of action have been explored, being the activation of sGC and the opening of K+ channels involved. Our studies indicate that the new nitrate derivatives are reversible and not deleterious for aortic rings, suggesting that these compounds have a potential interest for the development of new and highly efficient vasodilator drugs.
Berberine ameliorates pulmonary inflammation in mice with influenza viral pneumonia by inhibiting NLRP3 inflammasome activation and gasdermin D‐mediated pyroptosis
Authors: An Chen , Wu Yanmin , Wu Jun , Liu Huanwei , Zhou Siyao , Ge Dongyu , Dong Ruijuan , You Leiming , Hao Yu
Published: September 2022

Viral pneumonia is a common complication caused by Influenza A virus infection and is characterized by severe pulmonary inflammation. A previous study showed that berberine (BBR) significantly ameliorated the pulmonary inflammation in mice with influenza viral pneumonia but its underlying mechanism is not entirely understood. In this study, we reproduced the mouse model of influenza viral pneumonia through intranasal infection of A/Puerto Rico/8/34 (H1N1), to further investigate the anti‐inflammatory mechanism of BBR based on nucleotide‐binding oligomerization domain‐like receptor protein (NLRP) 3 inflammasome activation and Gasdermin D (GSDMD)‐mediated pyroptosis. Consistent with MCC950 (10 mg/kg, a specific NLRP3 inflammasome inhibitor), BBR (10 mg/kg) obviously improved the weight loss and survival rate of infected mice, alleviated their pulmonary inflammation, and suppressed the accumulation of tumor necrosis factor and interleukin (IL)‐6 in lungs without obvious inhibition on viral multiplication (hemagglutinin titer and nucleoprotein messenger RNA). Moreover, BBR (10 mg/kg) reduced the expressions of NLRP3, apoptosis‐associated speck‐like protein containing a CARD (ASC), and cysteinyl aspartate‐specific proteinase (Caspase)1 (Caspase1 precursor [Pro‐caspase1] + Caspase1p20 subunit) and the ratio of Caspase1p20 subunit to Caspase1, thus inhibiting the NLRP3 inflammasome activation and resulting in the decreased contents of mature IL‐1β and IL‐18 in lungs. The GSDMD expression (GSDMD precursor [Pro‐GSDMD] + GSDMD‐N terminal [NT]) and the ratio of GSDMD‐NT to GSDMD were also declined by BBR (10 mg/kg). These evidence indicate that BBR may ameliorate pulmonary inflammation in mice with influenza viral pneumonia through inhibiting NLRP3 inflammasome activation, as well as depressing GSDMD‐mediated pyroptosis via declining GSDMD expression and restraining NLRP3 inflammasome‐mediated GSDMD activation.
Synthesis and evaluation of [177Lu]Lu‐labeled porphyrin loaded PAMAM dendrimer: Impact on tumor uptake and pharmacokinetics
Authors: Kumar Naveen , Guleria Mohini , Chakraborty Avik , Amirdhanayagam Jeyachitra , Bannore Trupti Upadhye , Damle Archana , Sarma Haladhar D. , Das Tapas
Published: September 2022

The objective of the present work is to evaluate the ability of the radiolabeled PAMAM dendrimers (polyamidoamine) towards facilitating the delivery of an in‐house synthesized porphyrin derivative in the tumorous lesions to evaluate their candidature for possible application in endo‐radionuclide therapy. For this, PAMAM particles were conjugated with a porphyrin derivative namely, 5,10,15,20‐tetrakis‐(4‐carboxymethyleneoxyphenyl)porphyrin (STAP), synthesized in‐house following a two‐step reaction. The average number of porphyrin molecules loaded per PAMAM particle was evaluated using ultraviolet‐visible spectrophotometry and was found to be approximately 2. STAP conjugated PAMAM particles were further conjugated with p‐NCS‐benzyl‐DOTA (subsequently referred as DOTA) to facilitate radiolabeling with 177Lu. On an average, two p‐NCS‐benzyl‐DOTA molecules were observed to be attached per PAMAM‐STAP particle. DOTA‐PAMAM‐STAP conjugate was radiolabeled with 177Lu with a final radiochemical purity of >95%, which was determined by paper chromatography using two different mobile phases viz. 0.1 M sodium citrate buffer (pH 5.0) and 10 mM DTPA. Biological behavior of [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate was investigated in fibrosarcoma bearing Swiss mice model wherein accumulation of radiolabeled particles was observed in liver, GIT, spleen, and kidneys at 3 h post‐administration. However, accumulated activity exhibited rapid clearance from majority of the organs at 24 h post‐administration. [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate exhibited an appreciable uptake in tumor mass [6.09 ± 1.22 percentage injected activity/organ (% IA/organ)] at 3 h post‐administration (p.i.) which was found to reduce to 1.05 ± 0.13 % IA/organ at 24 h post‐administration. The results obtained in biodistribution studies were further corroborated through scintigraphic imaging performed in the same animal model. Despite of an appreciable accumulation in tumor mass, the lower retention of the [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate therein, at longer time point (24 h p.i.) may limit its possible potential as a radio‐therapeutic agent and indicates towards need for further structural manoeuvring to attain favorable in vivo performance.
Blood–brain barrier permeable benzylpiperidin‐4‐yl‐linked benzylamino benzamides as dual cholinesterase inhibitors
Authors: Banoo Razia , Nuthakki Vijay K. , Abdullaha Mohd , Sharma Mohit , Bharate Sandip B.
Published: September 2022

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder involving various pathological events. The existing options for managing the disease utterly rely on cholinesterase (ChE) inhibitors. In recent years, the dual inhibition of ChEs as a potential AD therapeutics has substantially attracted the attention of medicinal chemists. Recently, we reported benzyl piperidinyl‐linked methoxy‐naphthamides as dual ChE inhibitors. Herein, we investigated the peripheral anionic binding site‐binding methoxy‐naphthamide fragment that yielded benzyl piperidinyl‐linked benzyl aminobenzamide as another class of dual ChE inhibitors. The 3,5‐dimethoxy benzyl aminobenzamide, 8c1, exhibits inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with half‐maximal inhibitory concentration values of 0.61 and 2.04 µM, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed‐type mode of inhibition for AChE and BChE with ki values of 0.14 and 0.46 µM, respectively. The derivative 8c1 crosses the blood–brain barrier as indicated by the Pe value of 14.34 × 10−6cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self‐aggregation of amyloid‐β. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.
An integrative insight into the diversity, distribution, and biogeography of the freshwater endemic clade of the Ponticola syrman group (Teleostei: Gobiidae) in the Caucasus biodiversity hotspot
Authors: Zarei Fatah , Esmaeili Hamid Reza , Sadeghi Reza , Schliewen Ulrich K. , Kovačić Marcelo , Abbasi Keyvan , Gholamhosseini Ali
Published: September 2022

Freshwater habitats of the Caucasus biodiversity hotspot represent a center of endemism for the gobiid genus Ponticola Iljin, 1927. Hitherto, large‐scale molecular studies, owing to restricted taxon and geographical sampling, have failed to give an elaborate picture of diversity and evolutionary history of these species. Here, to contribute to filling this gap, we assessed taxonomic diversity, phylogeography and evolutionary history for the south Caspian populations of Ponticola presently classified as P. iranicus and P. patimari, using an integrative taxonomic approach comprising an entire geographic range sampling, and analyses of mitochondrial DNA haplotypes, the head lateral line system, otolith shape, and meristic and morphometric variation. All freshwater samples of the P. syrman group belong to a monophyletic clade with two main subclades: a small subclade confined to the upper Sefidroud sub‐basin including the type locality of P. iranicus and a large subclade with three geographically constrained haplogroups (Hg1, Hg2, and Hg3), comprising the rest of the distribution. Hg1 showed an eastern distribution including the type locality of P. patimari, while Hg2 and Hg3 are sister groups with central and western‐central distributions, respectively. The freshwater clade diverged from P. syrman during the Tyurkyanian low stand (~150 m b.s.l. lasting ~0.1 Myr), while the divergence of P. iranicus and P. patimari and radiations within P. patimari took place during the Bakunian high stand (up to 50 m a.s.l. lasting ~378–480 kya). Species delimitation analyses indicated two distinct species, corresponding to each main subclade. Although the otolith shape and lateral line analyses did not reflect with phylogeographic pattern, PCA and DFA plots of meristic and morphometric data showed a clear separation of the two major subclades corresponding to P. iranicus and P. patimari, suggesting the presence of significant morphological variation meriting formal taxonomic recognition. Overall, our findings (i) reveal the presence of two freshwater endemic species in the P. syrman group, and pending further investigation, hypothesize the presence of a third cryptic species; (ii) revise and document a narrow distributional range and low diversity for P. iranicus, in contrast to a wider distributional range and high diversity for P. patimari; (iii) suggest that the climatic oscillations of the Pleistocene were associated with the cladogenesis within the P. syrman group; and (iv) allowed for the recognition of conservation units and proposition of management measures.
Trichlorosilyl Anions of p‐Block Elements – New Applications for Simple Molecules
Authors: Böhme Uwe , Riedel Sophie
Published: September 2022

Recently several trichlorosilyl anions of main group elements have been isolated and characterized. Since 2015 anions [E(SiCl3)n]−, which are stabilized solely by trichlorosilyl groups, have been prepared with E=B, C, Si, Ge, P, S. These compounds have long been overlooked due to their high reactivity. This disadvantage is also an advantage, since the high reactivity makes these anions useful as reagents in a number of transformations. Anions of this kind have been used so far in substitution reactions, as superacids, and weakly coordinating anions. This review summarizes present methods for the synthesis of these compounds. Possible applications and future developments are outlined.
Acid‐Promoted Carbon‐Carbon Triple Bond Cleavage of Ynones for the Synthesis of Benzo[d]oxazoles/Benzo[d]thiazoles and 1‐Arylethan‐1‐ones
Authors: Guo Zi‐Yi , Li Ke‐Ru , Li Hang , Wang Xu , Zhang Ji‐Tan , Xie Mei‐Hua
Published: September 2022

A synchronous synthesis of benzo[d]oxazoles/benzo [d]thiazoles and 1‐arylethan‐1‐ones enabled by acid‐promoted C−C triple bond cleavage of ynones is disclosed. This reaction was accomplished with good tolerance of various functional groups and aminophenols/aminobenzenethiols to access the corresponding products, especially some structurally special 1‐arylethan‐1‐ones, in moderate to good yield. Furthermore, the readily accessible synthesis of some biologically active molecules has highlighted the synthetic utility of this strategy.
Fabrication and Characterization of Sulphur‐doped Graphitic Carbon Nitride Nanosheets as a Highly Selective and Ultrasensitive Electrochemical Sensor for Detection of 2,4‐Dinitrophenol in Real Gym Supplements
Authors: Pratibha  , Kumar Nikhil , Kapoor Atul , Rajput Jaspreet Kaur , Singh Dinesh , Varnika
Published: September 2022

Herein, an effective template assisted calcination procedure has been adopted to synthesize the Sulphur‐doped graphitic carbon nitride (SXGCN). Furthermore, the SXGCN/GCE was then utilized for the electrochemical determination of 2,4‐Dinitrophenol (2,4‐DNP). It has been inferred that among the variously prepared SXGCN (x=0 %, 20 %, 40 %, 60 %, 80 %, and 100 %), S80GCN afforded the excellent electrochemical response for detection of 2,4‐DNP. The synthesized SXGCN/GCE (x=80 %) demonstrates with a low detection limit of 0.9083 μM with linear range of 1–90 μM. Furthermore, the practical application of this sensor was successfully proved by detecting spiked 2,4‐dinitrophenol in a real gym supplements sample.
A Comparative Study of Voltammetric vs Impedimetric Immunosensor for Rapid SARS‐CoV‐2 Detection at the Point‐of‐care
Authors: Tortolini Cristina , Angeloni Antonio , Antiochia Riccarda
Published: September 2022

Here, a novel biosensing platform for the detection of SARS‐CoV‐2 usable both at voltammetric and impedimetric mode is reported. The platform was constructed on a multi‐walled carbon nanotubes (MWCNTs) screen‐printed electrode (SPE) functionalized by methylene blue (MB), antibodies against SARS‐CoV‐2 spike protein (SP), a bioactive layer of chitosan (CS) and protein A (PrA). The voltammetric sensor showed superior performances both in phosphate buffer solution (PBS) and spiked‐saliva samples, with LOD values of 5.0±0.1 and 30±2.1 ng/mL, compared to 20±1.8 and 50±2.5 ng/mL for the impedimetric sensor. Moreover, the voltammetric immunosensor was tested in real saliva, showing promising results.
UV-dependent freshwater effect factor of nanoscale titanium dioxide for future life cycle assessment application
Authors: Zhang Shaoqiong , Ke Mingyan , Li Liang , Chen Keyan , Hicks Andrea , Wu Fan , You Jing
Published: September 2022

Environmental impacts of nanoscale titanium dioxide (TiO2) should be assessed throughout the lifetime of nanoparticles (NPs) to improve the state of knowledge of the overall sustainability. Life cycle assessment (LCA) has been previously recognized as a promising approach to systematically evaluating environmental impacts of NPs. As a result of their unique nanospecific properties, characterization factors (CF) were previously used for compensating the release and potential impacts of TiO2 NPs. However, because TiO2 NPs are known to generate reactive oxygen species and elicit toxicity to freshwater organisms, the lack of adequate UV-dependent effect factors (EFs) remains a major shortcoming when addressing their life cycle impacts. To complement the LCA of TiO2-NPs-enabled products under their specific applications, we recapitulated the freshwater toxicity of TiO2 NPs and then modeled in USEtox to determine trophic level EF ranges under UV and non-UV exposure conditions. Results indicate that EFs derived for non-UV exposure were 52 (42.9‒65) potentially affected fraction (PAF) m3/kg, and combined toxicity data derived EFs were 70.1 (55.6‒90.5) PAF m3/kg. When considering only the UV-induced exposure condition, the modeled EF increased to 500 (333‒712) PAF m3/kg. Our work highlights that case-dependent EFs should be considered and applied to reflect more realistic ecological impacts and illustrate comprehensive life cycle environmental impacts for nanoenabled products. Integr Environ Assess Manag 2023;19:578–585. © 2022 SETAC
Social environment risk factors for violence, family context, and trajectories of social‐emotional functioning among Latinx adolescents
Authors: Stoner Marie C. D. , Browne Erica N. , Raymond‐Flesch Marissa , McGlone Linda , Morgan‐Lopez Antonio , Minnis Alexandra M.
Published: September 2022

Introduction

High social‐emotional functioning, including emotion regulation and nonviolent conflict resolution, constitute developmental competencies of adolescence that promote health and well‐being. We used prospective longitudinal data from a predominantly Latinx population to understand how family context and social environment risk factors for violence related to patterns of social‐emotional functioning during the transition between middle school and high school.

Methods

We prospectively interviewed 599 8th graders every 6 months for 2 years. We used trajectory models to explore longitudinal patterns of emotion regulation and nonviolent problem solving and multinomial regression to distinguish how these groups were associated with family context, partner and peer gang involvement, and neighborhood social disorder.

Results

Youth reporting lower neighborhood disorder in 8th grade were more likely to be in the high emotion regulation trajectory group. Youth without exposure to gangs through peers and partners in 8th grade were more likely to be in the high nonviolent problem‐solving skills trajectory group. Family cohesion was associated with being in the high trajectory groups for both emotional regulation and problem‐solving skills.

Conclusion

Emotion regulation and nonviolent problem‐solving skills had different associations with the social environment risk factors for violence examined, indicating that mechanisms of influence and strategies for intervention may vary. The association between problem‐solving skills and exposure to gangs through peers and partners shows that social norms may be important targets of change. Additionally, interventions with parents that build family cohesion during adolescence may buffer environmental exposures that shape adolescents' ability to practice protective social‐emotional behaviors.
Bradykinin/bradykinin 1 receptor promotes brain microvascular endothelial cell permeability and proinflammatory cytokine release by downregulating Wnt3a
Authors: Huang Linqiang , Liu Mengting , Jiang Wenqiang , Ding Hongguang , Han Yongli , Wen Miaoyun , Li Ya , Liu Xiaoyu , Zeng Hongke
Published: September 2022

Stroke is a life‐threatening disease with limited therapeutic options. Damage to the blood–brain barrier (BBB) is the key pathological feature of ischemic stroke. This study explored the role of the bradykinin (BK)/bradykinin 1 receptor (B1R) and its mechanism of action in the BBB. Human brain microvascular endothelial cells (BMECs) were used to test for cellular responses to BK by using the Cell Counting Kit‐8 assay, 5‐ethynyl‐2′‐deoxyuridine staining, enzyme‐linked immunosorbent assay, flow cytometry, immunofluorescence, cellular permeability assays, and western blotting to evaluate cell viability, cytokine production, and reactive oxygen species (ROS) levels in vitro. A BBB induced by middle cerebral artery occlusion was used to evaluate BBB injuries, and the role played by BK/B1R in ischemic/reperfusion (I/R) was explored in a rat model. Results showed that BK reduced the viability of BMECs and increased the levels of proinflammatory cytokines (interleukin 6 [IL‐6], IL‐18, and monocyte chemoattractant protein‐1) and ROS. Additionally, cellular permeability was increased by BK treatment, and the expression of tight junction proteins (claudin‐5 and occludin) was decreased. Interestingly, Wnt3a expression was inhibited by BK and exogenous Wnt3a restored the effects of BK on BMECs. In an in vivo I/R rat model, knockdown of B1R significantly decreased infarct volume and inflammation in I/R rats. Our results suggest that BK might be a key inducer of BBB injury and B1R knockdown might provide a beneficial effect by upregulating Wnt3a.
Exploration of the underlying mechanisms of isoniazid/rifampicin‐induced liver injury in mice using an integrated proteomics and metabolomics approach
Authors: Song Yanqing , Qu Xiaoyu , Tao Lina , Gao Huan , Zhang Yueming , Zhai Jinghui , Gong Jiawei , Hu Tingting
Published: September 2022

The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass‐based untargeted metabolomics and label‐free quantitative proteomics approach was used to clarify the mechanism of INH/RIF‐induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7 or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for mass spectrum‐based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.
The increasing proportion of adult discharges at children's hospitals, 2004–2019
Authors: Allen Anna Q. , Hall Matt , Goodman Denise M. , McCoy Elisha , Winer Jeffrey C. , Kleinman Michael S.
Published: September 2022

Significant medical advances now enable individuals with pediatric illnesses to survive into adulthood. Finding medical homes for these individuals often remains challenging. We utilized the Pediatric Health Information System to measure the variation in and growth of admissions to children's hospitals, stratified by age and payor from 2004 to 2019. We identified 8,097,081 patient encounters from 30 hospitals. Compared to children, adults discharged at children's hospitals are more likely to have a complex chronic condition, have a higher median cost, and have a longer median length of stay. Hospital‐level adult discharges ranged from 1.9% to 10.1% (median 4.1%; interquartile range: 2.8%–5.4%). Significantly higher increases were seen in each adult age subgroup (18–20, 21–25, and >25 years old) compared to the pediatric age group (p < .001). The number of adults discharged from children's hospitals is increasing faster than children, impacting children's hospitals and the populations they serve.
The bystander effect: Impact of rural hospital closures on the operations and financial well‐being of surrounding healthcare institutions
Authors: Ramedani Shayann , George Daniel R. , Leslie Douglas L. , Kraschnewski Jennifer
Published: September 2022

Introduction

There is presently a rural hospital shortage in the United States with 180 closures since 2005 and hundreds of institutions in financial peril. Although the hospital closure phenomenon is well‐established, less is known about the spillover impact on the operations and financial wellbeing of surrounding hospitals. This preliminary study quantified how discrete rural hospital closures impact institutions in their regional proximity, finding a significant increase in inpatient admissions and emergency department visits for these “bystander hospitals”.

Methods

Using a repository of rural hospital closures collected by the UNC Sheps Center for Health Services Research, we identified closures over the past 15 years. Criteria for inclusion were hospitals that had been fully closed between 2005–2016 and with >25‐bed capacity. We then designated surrounding hospitals within a 30‐mile radius of each closed hospital as “bystander hospitals.” We examined the average rate‐of‐change for inpatient admissions and emergency department visits in surrounding hospitals both two years before and after relevant hospital closures.

Results

We identified 53 hospital closures and 93 bystander hospitals meeting our criteria during the study period. With respect to geographic distribution, 66% of closures were in the Southern US, including 21% in Appalachia. Average emergency department visits increased by 3.59% two years prior to a hospital's closure; however, at two years post‐closure the average rate of increase rose to 10.22% (F (4,47) = 2.77, p = 0.0375). Average bystander hospital admissions fell by 5.73% in the two years preceding the hospital closure but increased 1.17% in the two years after (F (4,46) = 3.05, p = 0.0259).

Conclusion

These findings predict a daunting future for rural healthcare. While previous literature has described the acute effects hospital closures have on communities, this study suggests a significant spillover effect on hospitals within the geographic region and a cyclical process at play in the rural healthcare sector. In the absence of significant public health assistance in regions affected by closures, poor health outcomes, including “diseases of despair,” are likely to continue proliferating, disproportionately affecting the most vulnerable. In the COVID‐19 era, it will be especially necessary to focus on hospital closures given increased risk of maintaining solvency due to delayed and deferred care atop already tight margins.
Clinical outcomes and economic burden of seasonal influenza and other respiratory virus infections in hospitalized adults
Authors: Bolek Hatice , Ozisik Lale , Caliskan Zafer , Tanriover Mine Durusu
Published: September 2022

The cost of influenza and other respiratory virus infections should be determined to analyze the real burden of these diseases. We aimed to investigate the clinical outcomes and cost of illness due to respiratory virus infections in hospitalized adult patients. Hospitalized patients who had nasal swab sampling for a suspected viral infection between August 1, 2018 to March 31, 2019 were included. Outcome variables were oxygen requirement, mechanical ventilation need, intensive care unit admission, and cost. At least one viral pathogen was detected in 125 (47.7%) of 262 patients who were included in the study. Fifty‐five (20.9%) of the patients were infected with influenza. Influenza‐positive patients had higher rates for respiratory support, intensive care unit admission, and mortality compared to all other patients. The average cost of hospitalization per person was 2879.76 USD in the influenza‐negative group, while the same cost was 3274.03 USD in the influenza‐positive group. Although all of the vaccinated influenza‐positive patients needed oxygen support, neither of them required invasive mechanical ventilation or intensive care unit admission. The average hospitalization cost per person was 779.70 USD in the vaccinated group compared to 3762.01 USD in the unvaccinated group. Disease‐related direct cost of influenza in the community was estimated as 22 776 075.61 USD in the 18−65 years of age group and 15 756 120.02 USD in the 65 years of age and over group per year. Influenza, compared to other respiratory virus infections, can lead to untoward clinical outcomes and mortality as well as higher direct medical costs in adults.