bluuebunny/crossref_metadata_2025 huggingface dataset:
Seizures exacerbate excitatory‐inhibitory imbalance and tau seeding effects in 5XFAD mice
Authors: Barbour Aaron J , Gourmaud Sarah , Stewart David A , Li Xiaofan , Zebrowitz Sydney E , Ferrigno Sarah , Lee Virginia M.‐Y. , Talos Delia M , Jensen Frances E
Published: June 2023

Background

Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological proteins, tau, and ß‐amyloid, both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Central to the progression of AD is the spread of tau along neuronal networks likely via neuronal activity. Our previous work suggests a bidirectional relationship between AD and epilepsy with seizures inducing AD pathology and vice versa (Gourmaud et al. Brain, 2021; awab268). Additionally, there is evidence of excitatory‐inhibitory (E:I) imbalance in AD reminiscent of E:I imbalances involved in epileptogenesis. Thus, we hypothesized that seizures can exacerbate E:I imbalance in AD models and that this enhanced hyperexcitability promotes the propagation of pathological tau.

Method

We utilized the Five times familial AD (5XFAD) model and an established pentylenetetrazol (PTZ) kindling method to induce seizures in these and WT littermates. To model pathological tau spread seen in AD, a cohort of animals also underwent intracerebral injection of human AD‐derived tau (AD‐tau) into the hippocampus and overlying cortex prior to seizure induction. Western blots were performed for the Cl− transporters, K+‐ Cl−cotransporter 2 (KCC2) and Na+‐K+‐Cl− cotransporter 1 (NKCC1), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunits, GluA2 and GluA1, and GABAAR subunits α1 and α3, given their roles in E:I balance. AD‐tau injected mice were also examined by western blot for phospho‐tau AT8 [Ser202; Thr205] and phospho‐tau AT180 [Thr231] in sites proximal (hippocampus) and distal (frontal cortex) to injection site to determine the effects of seizures on tau propagation.

Result

PTZ‐kindling enhanced the dysregulation of Cl‐ transporters, NKCC1 and KCC2 (p<0.05, n = 12‐19) and GluA2/GluA1 ratios (p<0.05, n = 12‐19) in 5XFAD mice, while 5XFAD mice showed decreased GABAARα1 (p<0.05, n = 12‐19). No significant changes were seen in the hippocampus for AT8 nor AT180, but seizure induction elevated AT8 levels in the frontal cortex across genotypes (p<0.05, n = 5‐9).

Conclusion

Our data suggest that seizures exacerbate E:I imbalance in 5XFAD mice and tau propagation in both WT and 5XFAD mice. Thus, drugs targeting mechanisms involved in E:I balance or controlling seizures with antiseizure medication shows therapeutic efficacy for AD patients with comorbid seizures.
Lighter sleep and obstructive sleep apnea associate with higher enlarged perivascular spaces 15 years later
Authors: Baril Andree‐Ann , Pinheiro Adlin A , Himali Jayandra Jung , Sanchez Erlan , Pase Matthew P. , Seshadri Sudha , Demissie Serkalem , Romero Jose Rafael
Published: June 2023

Background

Enlarged perivascular spaces (ePVS) and sleep disturbances have been associated with incident dementia. While healthy sleep is suggested to promote glymphatic clearance in the brain, poorer sleep may be associated with higher ePVS burden (representing impaired perivascular drainage), which may contribute to sleep’s role in dementia risk. We assessed the association between sleep characteristics measured with polysomnography and subsequent ePVS burden.

Method

Within the Framingham Heart Study, 522 participants (age: 46.1±9.0 years; 50.4%M) underwent a full‐night in‐home polysomnography. Sleep variables measuring sleep architecture (total sleep time, wake after sleep onset, sleep efficiency), sleep stages (N1, N2, N3 and REM sleep in absolute minutes and percent of total sleep time), and obstructive sleep apnea severity (apnea‐hypopnea index, obstructive sleep apnea categories [mild, moderate, severe], sleep time <90% SaO2) were extracted. On average 16.7 ± 2.6 years later, participants underwent magnetic resonance imaging. ePVS were rated in the basal ganglia and centrum semiovale, and dichotomized for analyses: low burden (<20 counts, grade 1 and 2) or high burden (>20 counts, grade 3 and 4). Logistic regressions analyses relating sleep characteristics to ePVS burden were used, adjusted for age, sex, time interval between polysomnography and magnetic resonance imaging, APOE4 allele carrier status, hypertension, and smoking.

Results

21 participants had high ePVS burden in basal ganglia, and 68 participants in the centrum semiovale. Longer time spent in N1 (minutes and % of total sleep time; OR[95%]: 1.02[1.00‐1.04], p = 0.026; 1.11[1.03‐1.19], p = 0.008 respectively), shorter time spent in N3 (minutes; OR[95%]: 0.99[0.98‐0.99], p = 0.029), and longer time spent <90% SaO2 (OR[95%]: 1.03[1.00‐1.05], p = 0.025) were associated with higher ePVS burden in the centrum semiovale. No other associations between sleep characteristics and ePVS ratings were observed.

Conclusion

Lighter sleep, as characterized by longer N1 sleep and shorter N3 sleep, as well as the hypoxemia component of obstructive sleep apnea are associated with higher ePVS burden in subsequent brain magnetic resonance imaging. If replicated, these findings suggest a role for sleep disturbances in glymphatic clearance and cerebral small vessel disease, which may be implicated in the association between sleep and dementia risk.
Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Gibson Erin , Beg Mirza Faisal , Popuri Karteek , Mackenzie Ian R , Rosen Howard J. , Kantarci Kejal , Boeve Brad F. , Boxer Adam L , Tartaglia Carmela , Hsiung Ging‐Yuek Robin ,   the ALLFTD Consortium
Published: June 2023

Background

White matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.

Method

Participants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.

Result

We analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01).

Conclusion

WMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.
Systemic and central nervous system metabolome changes associated with Ginkgo biloba treatment in non‐demented subjects
Authors: Clark Christopher , Popp Julius
Published: June 2023

Background

In order to characterize the biochemical changes associated with Ginkgo biloba treatment, at metabolite and pathway level, we used a state‐of‐the‐art untargeted metabolomics approach in a well characterized cohort of healthy non‐demented subjects, with or without Ginkgo biloba treatment.

Method

We analysed data including cerebrospinal fluid (CSF) and peripheral blood measurements of proteomics, metabolomics, the methionine pathway, lipidomics, minerals, miRNAs, sterols and neuroinflammatory markers in samples obtained from both groups, covering over 2500 analytes and/or molecules.

Result

Data analysis at individual metabolic levels revealed differences in the expression of 15 analytes at CSF level and 25 analytes in peripheral blood, including 13 unidentified miRNAs. Pathway enrichment revealed these changes were associated with an overrepresentation of insulin signalling, platelet degranulation and hemostasis in peripheral blood and with growth factor signalling at CSF levels.

Conclusion

These results demonstrate the ability of this approach to uncover metabolic changes in patients undergoing a Ginkgo treatment. In further steps, we will perform enrichment analysis in CSF samples and build multivariate models accounting for potential confounders and a multi‐omics model, to assess the interactions between different biological pathways and levels; these approaches will require the recruitment of additional participants for the gingko group. This will also allow targeted omics approaches to further explore these alterations and relate them with the clinical evolution of participants over time, including cognitive decline and non‐cognitive symptoms at follow‐up visits.
Random forest selected transcripts from multiple neurodegenerative diseases reveal common affected cellular processes
Authors: Huseby Carol J. , Delvaux Elaine , Brokaw Danielle L. , Coleman Paul D.
Published: June 2023

Background

Neurodegenerative diseases such as Alzheimer’s disease are associated with changes in specific molecular pathways involving metabolomic and biological processes active in both the central nervous system and vascular peripheral system. Each disease results in neurodegeneration in vulnerable regions and cell types specific to that disease and are expressed in whole blood as disease progresses. Machine learning can be applied to the entire blood transcriptome of neurodegenerative diseases providing information for a pathophysiological relationship and gives us the advantage of using the vast knowledge of gene expression to analyze pathways affected thereby guiding insight into possible treatment strategies. We applied our unique machine learning algorithm to public data sets for selection of transcripts that guide our discovery of affected pathways.

Methods

We used large public blood microarray mRNA expression datasets, with platforms of more than 30,000 probes covering 10,000 genes, to discover disease transcripts using a novel Random Forest algorithm which selected supervised predictors for six different neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), behavioral variant frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and Friedreich’s ataxia (FRDA).

Results

Our machine learning selection of transcript disease classifiers reveals that neurodegenerative diseases have common themes as well as unique individual differences. Molecular components which overlap across diseases might be considered neurodegeneration generalities or a result of mixed pathology, while differential components identified by selected feature transcripts may represent unique dysfunctions.

Conclusion

Our Random Forest algorithm selected important features hidden in mRNA expression values from blood of affected individuals of six neurodegenerative diseases compared to healthy controls. For each of the six diseases studied here, the selected features were categorized by pathway analysis into eight main functional groups. The dysfunction of any or multiple functional groups combined can lead to synapse and cell loss in these neurodegenerative diseases each with specific vulnerabilities in particular tissue and cell types. Vulnerability is usually associated with those cells vulnerable to the disease pathology and are often first to exhibit cell death from cytotoxic events such as neuroinflammation, mitochondrial dysfunction, transcription alterations, apoptosis, protein synthesis dysfunction, cytoskeletal changes, and ubiquitylation/proteasome stalls.
Hypogyrification in midlife women with surgical menopause, a population at risk for late life Alzheimer’s
Authors: Gravelsins Laura , Brown Alana , Almey Anne , Gervais Nicole J , Duchesne Annie , Rieck Jenny , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Witt Suzanne Tyson , Classon Elisabeth , Lykke Nina , Theodorsson Elvar , Ernerudh Jan , Lundqvist Elisabeth Åvall , Kjølhede Preben , Morrison India , Novembre Giovanni , Engström Maria , Bernardini Marcus , Foulkes William , Rajah Natasha , Grady Cheryl , Einstein Gillian
Published: June 2023

Background

Women with early ovarian hormone deprivation due to bilateral salpingo‐oophorectomy (BSO; ovarian and fallopian tube removal) are at risk for later life Alzheimer’s disease (AD), but estradiol therapy (ET) may be protective (Rocca et al., 2007). Working memory (WM), temporarily maintaining and manipulating information in mind, depends on structural integrity of fronto‐parietal brain regions (Burzynska et al., 2012). WM declines have been observed in midlife women with BSO not taking ET (Gervais et al., 2020), however, structural brain–WM relationships in this midlife population remain unexplored. This study aimed to: 1) Investigate fronto‐parietal cortical thickness and gyrification (folding) changes in younger women after early BSO and their relationship to WM, and 2) Explore whether ET ameliorates these changes.

Method

Women with early BSO taking ET (BSO+ET: M±SDage = 45±5.1; n = 26), or not taking ET (BSO: M±SDage = 46±5.0y; n = 26) were compared to premenopausal, age‐matched controls (AMC: M±SDage = 44±2.9y; n = 42) from Toronto and Montreal, Canada, and Linköping, Sweden. T1‐weighted scans were acquired on Siemens Prisma/Philips 3T scanners. WM was measured using Digit Span Backwards (Wechsler, 1945) maximum span and Digit Ordering Task (Petrides et al., 1993) errors. Average cortical thickness and gyrification of fronto‐parietal regions were calculated from CIVET (Ad‐Dab’bagh et al. 2005), adjusting for scanner and past cancer treatment.

Result

Linear models showed no group differences in cortical thickness or WM. However, they showed BSO had significant hypogyrification (reduced cortical folding) in the supplementary motor area (SMA), part of the posterior prefrontal cortex, compared to AMC (adjusted for brain volume; FDR‐corrected p = 0.028). BSO+ET had intermediate SMA gyrification, and did not differ from either group. SMA gyrification was unrelated to WM, and gyrification–WM relationships did not differ by group.

Conclusion

We found SMA hypogyrification in younger women with BSO compared to AMC and BSO+ET. The SMA supports WM manipulation and is an early area affected by age‐related gyrification declines (Madan, 2021). Moreover, hypogyrification may reflect reduced brain connectivity, and gyrification globally declines with AD severity (Liu et al., 2012). Although SMA hypogyrification in women with BSO was unrelated to WM, it may serve as an early sign of later life cognitive decline.
Imipramine treatment reduces Alzheimer’s disease neuropathologies in cerebral organoid models of Alzheimer’s disease and Down syndrome
Authors: Johnson Noah R , Dooling Breanna , Aghili Leila , Chial Heidi J , Potter Huntington
Published: June 2023

Background

Familial Alzheimer’s disease (fAD) is a autosomal dominant, early‐onset form of AD caused by genetic mutations such as duplication of the amyloid precursor protein gene (APP) on one chromosome (APPdup) or point mutations in APP such as the London mutation (APPV717I), both of which cause overproduction of the amyloid‐beta peptide (Aβ). People with Down syndrome (DS) also have a form of fAD due to triplication of APP which resides on chromosome 21. By age 40, all people with DS develop AD brain pathology, including Aβ plaques and neurofibrillary tangles of phosphorylated tau (pTau), and most go on to develop early‐onset dementia. We previously identified imipramine by high‐throughput screening for novel inhibitors of apolipoprotein E (apoE), which is the strongest risk factor for AD other than age itself. Here, we developed and characterized new cerebral organoid (CO) models of fAD and DS and used them to study common pathological mechanisms and to evaluate imipramine as a novel AD treatment.

Method

We obtained human induced pluripotent stem cells (hiPSCs) from multiple donors with fAD (APPdup or APPV717I), DS, or healthy controls (HC), all with the APOE3/3 genotype, and generated COs using validated techniques. We treated COs beginning at 45 days in vitro with 1 or 10 μM imipramine in the culture medium, and we collected treated and untreated organoids after 120 days for analysis by immunoblotting, immunohistochemistry, and ELISA.

Result

COs from fAD or DS donors were significantly reduced in size compared to those from HC donors. Increased expression of APP, Aβ, pTau, and apoE were observed in fAD and DS COs relative to HC COs. Levels of Aβ and apoE were positively correlated in all COs. Imipramine treatment significantly reduced the levels of some neuropathologies in AD COs, but did not affect the size or cellular composition of HC COs.

Conclusion

We characterized several new CO models of fAD and DS, which will be useful for identifying commonalities in disease mechanisms as well as for dissecting the roles of chromosome 21 genes other than APP. Our results indicate that imipramine and other therapeutics targeting the role of apoE are promising approaches to treating AD.
Synergic Electron and Defect Compensation Minimizes Voltage Loss in Lead‐Free Perovskite Solar Cells
Authors: Liu Gengling , Jiang Xianyuan , Feng Wenhuai , Yang Guo , Chen Xi , Ning Zhijun , Wu Wu‐Qiang
Published: June 2023

Sn perovskite solar cells have been regarded as one of the most promising alternatives to the Pb‐based counterparts due to their low toxicity and excellent optoelectronic properties. However, the Sn perovskites are notorious to feature heavy p‐doping characteristics and possess abundant vacancy defects, which result in under‐optimized interfacial energy level alignment and severe nonradiative recombination. Here, we reported a synergic “electron and defect compensation” strategy to simultaneously modulate the electronic structures and defect profiles of Sn perovskites via incorporating a traced amount (0.1 mol %) of heterovalent metal halide salts. Consequently, the doping level of modified Sn perovskites was altered from heavy p‐type to weak p‐type (i.e. up‐shifting the Fermi level by ~0.12 eV) that determinately reducing the barrier of interfacial charge extraction and effectively suppressing the charge recombination loss throughout the bulk perovskite film and at relevant interfaces. Pioneeringly, the resultant device modified with electron and defect compensation realized a champion efficiency of 14.02 %, which is ~46 % higher than that of control device (9.56 %). Notably, a record‐high photovoltage of 1.013 V was attained, corresponding to the lowest voltage deficit of 0.38 eV reported to date, and narrowing the gap with Pb‐based analogues (~0.30 V).
Atomic‐Scale Insights into the Interlayer Characteristics and Oxygen Reactivity of Bilayer Borophene
Authors: Li Linfei , Schultz Jeremy F. , Mahapatra Sayantan , Liu Xiaolong , Zhang Xu , Hersam Mark C. , Jiang Nan
Published: June 2023

Bilayer (BL) two‐dimensional boron (i.e., borophene) has recently been synthesized and computationally predicted to have promising physical properties for a variety of electronic and energy technologies. However, the fundamental chemical properties of BL borophene that form the foundation of practical applications remain unexplored. Here, we present atomic‐level chemical characterization of BL borophene using ultrahigh vacuum tip‐enhanced Raman spectroscopy (UHV‐TERS). UHV‐TERS identifies the vibrational fingerprint of BL borophene with angstrom‐scale spatial resolution. The observed Raman spectra are directly correlated with the vibrations of interlayer boron–boron bonds, validating the three‐dimensional lattice geometry of BL borophene. By virtue of the single‐bond sensitivity of UHV‐TERS to oxygen adatoms, we demonstrate the enhanced chemical stability of BL borophene compared to its monolayer counterpart by exposure to controlled oxidizing atmospheres in UHV. In addition to providing fundamental chemical insight into BL borophene, this work establishes UHV‐TERS as a powerful tool to probe interlayer bonding and surface reactivity of low‐dimensional materials at the atomic scale.
Cooperative Bimetallic Catalysis via One‐Metal/Two‐Ligands: Mechanistic Insights of Polyfluoroarylation‐Allylation of Diazo Compounds
Authors: Wang Gao‐Yin , Ge Zhaoliang , Ding Kuiling , Wang Xiaoming
Published: June 2023

Metal/ligand in situ assembly is crucial for tailoring the reactivity & selectivity in transition metal catalysis. Cooperative catalysis via a single metal/two ligands is still underdeveloped, since it is rather challenging to harness the distinct reactivity profiles of the species generated by self‐assembly of a single metal precursor with a mixture of different ligands. Herein, we report a catalytic system composed of a single metal/two ligands for a three‐component reaction of polyfluoroarene, α‐diazo ester, and allylic electrophile, leading to highly efficient construction of densely functionalized quaternary carbon centers, that are otherwise hardly accessible. Mechanistic studies suggest this reaction follows a cooperative bimetallic pathway via two catalysts with distinct reactivity profiles, which are assembled in situ from a single metal precursor and two ligands and work in concert to escort the transformation.
Copper‐Catalyzed Regiodivergent Internal Allylic Alkylations
Authors: Manna Madhu Sudan , Yoo Seok Yeol , Sharique Mohammed , Choi Hyoju , Pudasaini Bimal , Baik Mu‐Hyun , Tambar Uttam K.
Published: June 2023

We report a copper‐catalyzed, regioselective, and stereospecific alkylation of unbiased internal allylic carbonates with functionalized alkyl and aryl Grignard reagents. The reactions exhibit high stereospecificity and regioselectivity for either SN2 or SN2′ products under two sets of copper‐catalyzed conditions, which enables the preparation of a broad range of products with E‐alkene selectivity. Density functional theory calculations reveal the origins of the regioselectivity based on the different behaviors of homo‐ and heterocuprates.
Mechanistic Understanding of Efficient Polyethylene Hydrocracking over Two‐Dimensional Platinum‐Anchored Tungsten Trioxide
Authors: Zhou Qimin , Wang Deliang , Wang Qingyue , He Kailin , Lim Khak Ho , Yang Xuan , Wang Wen‐Jun , Li Bo‐Geng , Liu Pingwei
Published: June 2023

Chemical upcycling of polyethylene (PE) can convert plastic waste into valuable resources. However, engineering a catalyst that allows PE decomposition at low temperatures with high activity remains a significant challenge. Herein, we anchored 0.2 wt.% platinum (Pt) on defective two‐dimensional tungsten trioxide (2D WO3) nanosheets and achieved hydrocracking of high‐density polyethylene (HDPE) waste at 200–250 °C with a liquid fuel (C5–18) formation rate up to 1456 gproducts ⋅ gmetal species−1 ⋅ h−1. The reaction pathway over the bifunctional 2D Pt/WO3 is elucidated by quasi‐operando transmission infrared spectroscopy, where (I) well‐dispersed Pt immobilized on 2D WO3 nanosheets trigger the dissociation of hydrogen; (II) adsorption of PE and activation of C−C cleavage on WO3 are through the formation of C=O/C=C intermediates; (III) intermediates are converted to alkane products by the dissociated H. Our study directly illustrates the synergistic role of bifunctional Pt/WO3 catalyst in the hydrocracking of HDPE, paving the way for the development of high‐performance catalysts with optimized chemical and morphological properties.
Functional Characterization and Cyclization Mechanism of a Diterpene Synthase Catalyzing the Skeleton Formation of Cephalotane‐Type Diterpenoids
Authors: Li Changkang , Wang Shuai , Yin Xinxin , Guo Aobo , Xie Kebo , Chen Dawei , Sui Songyang , Han Yaotian , Liu Jimei , Chen Ridao , Dai Jungui
Published: June 2023

CsCTS, a new diterpene synthase from Cephalotaxus sinensis responsible for forming cephalotene, the core skeleton of cephalotane‐type diterpenoids with a highly rigid 6/6/5/7 tetracyclic ring system, was functionally characterized. The stepwise cyclization mechanism is proposed mainly based on structural investigation of its derailment products, and further demonstrated through isotopic labeling experiments and density functional theory calculations. Homology modeling and molecular dynamics simulation combined with site‐directed mutagenesis revealed the critical amino acid residues for the unique carbocation‐driven cascade cyclization mechanism of CsCTS. Altogether, this study reports the discovery of the diterpene synthase that catalyzes the first committed step of cephalotane‐type diterpenoid biosynthesis and delineates its cyclization mechanism, laying the foundation to decipher and artificially construct the complete biosynthetic pathway of this type diterpenoids.
Divergent Stabilities of Tetravalent Cerium, Uranium, and Neptunium Imidophosphorane Complexes**
Authors: Otte Kaitlyn S. , Niklas Julie E. , Studvick Chad M. , Boggiano Andrew C. , Bacsa John , Popov Ivan A. , La Pierre Henry S.
Published: June 2023

The study of the redox chemistry of mid‐actinides (U−Pu) has historically relied on cerium as a model, due to the accessibility of trivalent and tetravalent oxidation states for these ions. Recently, dramatic shifts of lanthanide 4+/3+ non‐aqueous redox couples have been established within a homoleptic imidophosphorane ligand framework. Herein we extend the chemistry of the imidophosphorane ligand (NPC=[N=PtBu(pyrr)2]−; pyrr=pyrrolidinyl) to tetrahomoleptic NPC complexes of neptunium and cerium (1‐M, 2‐M, M=Np, Ce) and present comparative structural, electrochemical, and theoretical studies of these complexes. Large cathodic shifts in the M4+/3+ (M=Ce, U, Np) couples underpin the stabilization of higher metal oxidation states owing to the strongly donating nature of the NPC ligands, providing access to the U5+/4+, U6+/5+, and to an unprecedented, well‐behaved Np5+/4+ redox couple. The differences in the chemical redox properties of the U vs. Ce and Np complexes are rationalized based on their redox potentials, degree of structural rearrangement upon reduction/oxidation, relative molecular orbital energies, and orbital composition analyses employing density functional theory.
Stereoselective Synthesis of the O‐antigen of A. baumannii ATCC 17961 Using Long‐Range Levulinoyl Group Participation
Authors: Duan Liangshen , Nie Qin , Hu Yongxin , Wang Liming , Guo Kaiyan , Zhou Zhuoyi , Song Xu , Tu Yuanhong , Liu Hui , Hansen Thomas , Sun Jian‐song , Zhang Qingju
Published: June 2023

Herein, we described the first synthesis of the pentasaccharide and decasaccharide of the A. baumannii ATCC 17961 O‐antigen for developing a synthetic carbohydrate‐based vaccine against A. baumannii infection. The efficient synthesis of the rare sugar 2,3‐diacetamido‐glucuronate was achieved using our recently introduced organocatalytic glycosylation method. We found, for the first time, that long‐range levulinoyl group participation via a hydrogen bond can result in a significantly improved β‐selectivity in glycosylations. This solves the stereoselectivity problem of highly branched galactose acceptors. The proposed mechanism was supported by control experiments and DFT computations. Benefiting from the long‐range levulinoyl group participation strategy, the pentasaccharide donor and acceptor were obtained via an efficient [2+1+2] one‐pot glycosylation method and were used for the target decasaccharide synthesis.
Synthesis and properties of a new polycarboxylic acid multi‐polymer scale inhibitor suitable for industrial circulating water
Authors: Xiao Yulun , Ren Dajun , Zhai Junlin , Wang Zhaobo , Zhang Le , Xie Junfeng , Li Yajing , Zhang Shuqin , Zhang Xiaoqing , Gong Xiangyi , Chen Wangsheng
Published: June 2023

Multipolymer TPEG‐IA‐AMPS was synthesized by free‐radical polymerization using isopentenol polyoxyethylene ether (TPEG), itaconic acid (IA) and 2‐acrylamide‐2‐methylpropanesulfonic acid (AMPS) as monomers. In addition, the monomers and the synthesized multipolymer were characterized and analyzed by infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance (1H‐NMR) and gel permeation chromatography (GPC). And then, the control variable method and static scale inhibition method were used to measure the influence of different synthesis conditions on the calcium carbonate scale inhibition performance of multipolymer, and the optimum synthesis conditions of terpolymer were determined. Meanwhile, the influence of different factors on the scale inhibition performance of calcium carbonate scale and calcium sulfate scale under the optimum synthesis conditions was also explored. Moreover, scanning electron microscope (SEM) and x‐ray diffraction (XRD) were used to analyze the scale inhibition mechanism. The results show that the synthesized multipolymer TPEG‐IA‐AMPS is suitable for industrial recycling wastewater in harsh environment such as high alkalinity, high hardness and high PH.
Sustainable self‐curing epoxy adhesives from Chios natural Mastic (Pistacia lentiscus L.)
Authors: Anastasiou Dimitrios E. , Patsidis Anastasios C. , Andreopoulou Aikaterini K.
Published: June 2023

This study outlines a method for the epoxidation of poly‐beta‐myrcene, a biopolymer that can be easily extracted from the natural resin of the Chios Mastic tree (Pistacia lentiscus L.). The resulting epoxidation products are self‐curing, and have a nearly 100% green carbon content. These Mastic Epoxide products (MASTEP) have the potential to be useful thermosetting resins. One specific product (MASTEP A), was used as an adhesive to create Single Lap Joints, which were then subjected to tensile shear stress tests. MASTEP A was found to be 25%–83% stronger than three commonly used conventional or “semi‐green” epoxy adhesives. Another specific product (MASTEP B), was found able to be thermally converted into a semi‐crystalline form. In order to clarify the 3D chemical structure of MASTEP, IR, and DSC investigations were conducted. The entire production process was designed to be environmentally friendly. The results of this research represent a significant advancement in the development of environmentally friendly epoxies and pave the way to a wide range of potential further research.
Adipose tissue‐derived mesenchymal stem cells ameliorate cognitive impairment in Alzheimer's disease rat model: Emerging role ofSIRT1
Authors: Nabil Mohamed , Kassem Dina H. , Ali Azza A. , El‐Mesallamy Hala O.
Published: June 2023

Alzheimer's disease (AD) is a complex form of neurodegenerative dementia. Growing body of evidence supports the cardinal role of sirtuin1 (SIRT1) in neurodegeneration and AD development. Recently, adipose tissue‐derived mesenchymal stem cells (Ad‐MSCs) have made their mark for a wide array of regenerative medicine applications, including neurodegenerative disorders. Therefore, the present study aimed to investigate the therapeutic potential of Ad‐MSCs in AD rat model, and to explore the possible implication of SIRT1. Ad‐MSCs were isolated from rat epididymal fat pads and properly characterized. Aluminum chloride was used to induce AD in rats, and afterward, a group of AD‐induced rats received a single dose of Ad‐MSCs (2 × 106cell, I.V per rat). One month after Ad‐MSCs transplantation, behavioral tests were done, brain tissues were collected, then histopathological and biochemical assessments were performed. Amyloid beta and SIRT1 levels were determined by enzyme‐linked immunosorbent assay. Whereas expression levels of neprilysin, BCL2 associated X protein,B‐cell lymphoma‐2,interleukin‐1β,interleukin‐6,and nerve growth factor in hippocampus and frontal cortex brain tissues were assessed using reverse transcriptase quantitative polymerase chain reaction. Our data demonstrated that transplantation of Ad‐MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti‐amyloidogenic, antiapoptotic, anti‐inflammatory, as well as neurogenic effects. Furthermore, Ad‐MSCs were found to possibly mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad‐MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD.
A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma
Authors: Sun Weijing , Veeramachaneni Nirmal , Al‐Rajabi Raed , Madan Rashna , Kasi Anup , Al‐Kasspooles Mazin , Baranda Joaquina , Saeed Anwaar , Phadnis Milind A. , Godwin Andrew K. , Olyaee Mojtaba , Streeter Natalie , Nagji Alykhan , Dai Junqiang , Williamson Stephen
Published: June 2023

Background

Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively.

Methods

Patients with locally advanced (T1N1‐3M0 or T2‐3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging‐laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m2/Leucovorin 400 mg/m2/5‐FU bolus 400 mg/m2 then infusion 2400 mg/m2 for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post‐neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4–8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI‐related markers PD‐L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy.

Results

Thirty‐seven patients completed the preoperative treatment. Twenty‐nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08–0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73–0.98) had ypRR with TRS ≤2. Twenty‐six patients finished adjuvant therapy with a median 36.3‐month follow‐up. Three patients had recurrence/metastatic disease (at 9‐, 10‐, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD‐L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059).

Conclusions

The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long‐time survival benefits.
Genomic characterization between HER2‐positive and negative gastric cancer patients in a prospective trial
Authors: Hu Qingjiang , Oki Eiji , Yamada Teppei , Kashiwada Tomomi , Sonoda Hideto , Kataoka Masato , Kawanaka Hirofumi , Tsuji Yasushi , Makiyama Akitaka , Nakashima Yuichiro , Ota Mitsuhiko , Kimura Yasue , Yoshizumi Tomoharu
Published: June 2023

Background

We aimed to clarify the genomic characteristics of HER2‐positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial.

Methods

We collected 80 formalin‐fixed paraffin‐embedded (FFPE) samples (49 HER2+ and 31 HER2‐) from gastric cancer patients who participated in the TROX‐A1 trial (UMIN000036865). We queried a 435‐gene panel (CANCERPLEX‐JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2‐ gastric cancer patients were analyzed.

Results

Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2‐negative patients. The number of total mutations in HER2‐negative patients with ARID1A mutation was remarkably higher than that in HER2‐positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2‐positive cases was significantly higher than that in HER2‐negative cases. Moreover, PTEN deletion was more common in HER2‐positive cases. Finally, we found that, compared with HER2‐positive patients, HER2‐negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune‐related pathways in HER2‐negative patients.

Conclusions

According to the genomic profiling of HER2‐positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2‐positive gastric cancer, HER2‐negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.
A Meta‐Analysis of Catalytic Hydrogenation of Levulinic Acid to γ‐Valerolactone
Authors: Niaze Ambereen Aziz , Dhaker Deepa , Upadhyayula Sreedevi
Published: June 2023

Selective hydrogenation of biomass‐derived levulinic acid (LA) to γ‐valerolactone (GVL) is an important reaction in biomass upgradation to produce valuable fuels and chemicals. Increasing demand for renewable energy sources has stipulated growth in catalytic research and has generated a massive amount of experimental data over the years. Inside this numerous data, fresh insights into property‐performance associations can be found. However, the incomplete existence and unclear structure of these data records have hampered systematic information extraction thus far. This research proposes a meta‐analysis approach for identifying associations between the physico‐chemical properties of a catalyst and its reaction performance. The approach combines data from literature with insights from textbooks and statistical methods. A hypothesis is formulated based on a researcher's intuition and statistical significance is checked against the data. Repetitive hypothesis refining gives robust, clear, and analyzable chemical models. The results can be used to guide future research and catalyst production. The method for catalytic hydrogenation of LA to GVL is shown and validated here.
Nucleobase and Linker Modification for Triple‐Helical Recognition of Pyrimidines in RNA Using Peptide Nucleic Acids
Authors: Kumpina Ilze , Baskevics Vladislavs , Nguyen Khoi D. , Katkevics Martins , Rozners Eriks
Published: June 2023

Triple‐helical recognition of any sequence of double‐stranded RNA requires high affinity Hoogsteen hydrogen binding to pyrimidine interruptions of polypurine tracts. Because pyrimidines have only one hydrogen bond donor/acceptor on Hoogsteen face, their triple‐helical recognition is a formidable problem. The present study explored various five‐membered heterocycles and linkers that connect nucleobases to backbone of peptide nucleic acid (PNA) to optimize formation of X•C‐G and Y•U‐A triplets. Molecular modeling and biophysical (UV melting and isothermal titration calorimetry) results revealed a complex interplay between the heterocyclic nucleobase and linker to PNA backbone. While the five‐membered heterocycles did not improve pyrimidine recognition, increasing the linker length by four atoms provided promising gains in binding affinity and selectivity. The results suggest that further optimization of heterocyclic bases with extended linkers to PNA backbone may be a promising approach to triple‐helical recognition of RNA.
Astragaloside II enhanced sensitivity of ovarian cancer cells to cisplatin via triggering apoptosis and autophagy
Authors: Zhang Lijia , Liu Ye , Lei Xue , Liu Xiaowai , Sun Heng , Liu Songjiang
Published: June 2023

Cisplatin (DDP) based chemotherapy occurs a reduced therapeutic effect on the later treatment of ovarian cancer (OC) due to DDP resistance. Astragaloside II (ASII), a natural product extracted from Radix Astragali, has shown promising anticancer effects. However, the effects of ASII on OC have not been clarified. In this study, we found that ASII inhibited cell growth and promoted cell apoptosis of DDP‐resistant OC cells in vitro and in vivo. Further study showed that ASII downregulated multidrug resistance‐related protein MDR1 and cell cycle‐related protein Cyclin D1 and PCNA, and also upregulated apoptosis‐related protein leaved PRAP and cleaved caspase‐3. In addition, ASII induced autophagy, characterized by upregulation of LC3II expression, downregulation of p62 expression, and elevation of LC3 punctuation, may be associated with inhibition of the AKT/mTOR signaling pathway. Moreover, the messenger RNA‐sequencing was used to identify potential molecules regulated by ASII. In conclusion, these findings indicated that ASII increased sensitivity of DDP in the treatment of OC.
A Doubly Dissipative System Driven by Chemical and Radiative Stimuli
Authors: Valentini Matteo , Frateloreto Federico , Conti Matteo , Cacciapaglia Roberta , Del Giudice Daniele , Di Stefano Stefano
Published: June 2023

The operation of a dissipative network composed of two or three different crown‐ether receptors and an alkali metal cation can be temporally driven by the use (combined or not) of two orthogonal stimuli of a different nature. More specifically, irradiation with light at a proper wavelength and/or addition of an activated carboxylic acid, are used to modulate the binding capability of the above crown‐ethers towards the metal ion, allowing to control over time the occupancy of the metal cation in the crown‐ether moiety of a given ligand. Thus, application of either or both of the stimuli to an initially equilibrated system, where the metal cation is distributed among the crown‐ether receptors depending on the different affinities, causes a programmable change in the receptor occupancies. Consequently, the system is induced to evolve to one or more out‐of‐equilibrium states with different distributions of the metal cation among the different receptors. When the fuel is exhausted or/and the irradiation interrupted, the system reversibly and autonomously goes back to the initial equilibrium state. Such results may contribute to the achievement of new dissipative systems that, taking advantage of multiple and orthogonal stimuli, are featured with more sophisticated operating mechanisms and time programmability.
Schärfe in der Biosynthese
Authors: Feil Sylvia
Published: June 2023

Wenn mit Chili gewürzte Speisen im Mund brennen, ist das Warum klar: Capsaicin fand den Weg zu seinen Rezeptoren. Doch in der pflanzlichen Biosynthese war noch unklar, wie spezifisch eines der Schlüsselenzyme ist und ob es mit oder ohne Cofaktoren arbeitet. Nun konnte die Capsaicinsynthase rekombinant hergestellt und auf enzymatischer Ebene näher untersucht werden.
Photoelectron Photoion Coincidence Spectroscopy of Biradicals
Authors: Fischer Ingo , Hemberger Patrick
Published: June 2023

The electronic structure of biradicals is characterized by the presence of two unpaired electrons in degenerate or near‐degenerate molecular orbitals. In particular, some of the most relevant species are highly reactive, difficult to generate cleanly and can only be studied in the gas phase or in matrices. Unveiling their electronic structure is, however, of paramount interest to understand their chemistry. Photoelectron photoion coincidence (PEPICO) spectroscopy is an excellent approach to explore the electronic states of biradicals, because it enables a direct correlation between the detected ions and electrons. This permits to extract unique vibrationally resolved photoion mass‐selected threshold photoelectron spectra (ms‐TPES) to obtain insight in the electronic structure of both the neutral and the cation. In this review we highlight most recent advances on the spectroscopy of biradicals and biradicaloids, utilizing PEPICO spectroscopy and vacuum ultraviolet (VUV) synchrotron radiation.
The CSR committee as moderator for the ESG score and market value
Authors: Bifulco Giuseppe Maria , Savio Riccardo , Paolone Francesco , Tiscini Riccardo
Published: June 2023

This paper investigates the relationship between the ESG score and market values. Specifically, we test the moderating role of CSR committee defined as organizational subcommittees of boards of directors that make social and environmental recommendations to the boards of directors and support members in their CSR‐related tasks. We built a panel data set with all the listed companies in STOXX Europe 600, covering the period 2014–2020. Firms' data come from Refinitiv Eikon database which contains financial and ESG scores data of all EU listed companies. Our sample of firm‐level data contains a dataset of 600 European listed companies which are part of the STOXX Europe 600 Index. We included ESG data of STOXX Europe 600 Index components in the period 2014–2020. Our dataset contains a total of 4800 firm‐year observations. We found a negative relationship between ESG score and stock prices while the presence of CSR committee as moderating variable generates no significant evidence of ESG score. The presence of CSR committee is not considerably supporting ESG in achieving higher market performance. The CSR committee plays an essential role in monitoring management activities. This may support management practitioners in better understanding and reacting to stakeholder expectations.
Layered Low‐Dimensional Ruddlesden‐Popper and Dion‐Jacobson Perovskites: From Material Properties to Photovoltaic Device Performance
Authors: Liu Rui , Hu Xin , Xu Maoxia , Ren Haorong , Yu Hua
Published: June 2023

Layered low‐dimensional halide perovskites (LDPs) with multiple quantum well structure have shown increasing research interest in photovoltaic solar cell applications owing to their intrinsic moisture stability and favorable photophysical properties in comparison with their three‐dimensional (3D) counterparts. The most common LDPs are Ruddlesden‐Popper (RP) phases and Dion‐Jacobson (DJ) phases, both of which have made significant research advances in efficiency and stability. However, distinct interlayer cations between RP and DJ phase lead to disparate chemical bonds and different perovskite structures, which endow RP and DJ perovskite with distinctive chemical and physical properties. Plenty of reviews have reported the research progress of LDPs but no summary has elaborated from the perspective of the merits and drawbacks of the RP and DJ phases. Herein, in this review, we offer a comprehensive expound on the merits and promises of RP and DJ LDPs from their chemical structure, physicochemical properties, and photovoltaic performance research progress aiming to provide a new insight into the dominance of RP and DJ phases. Then, we reviewed the recent progress on the synthesis and implementation of RP and DJ LDPs thin films and devices, as well as their optoelectronic properties. Finally, we discussed the possible strategies to resolve existing toughs to realize the desired high‐performance LDPs solar cells.