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• Amorphous alloys were prepared by ball milling method, and the effect of amorphous alloy on mortar performance was studied. • The sterilization mechanism of amorphous alloys was investigated by particle leaching concentration and reactive oxygen species test. • The feasibility of amorphous alloy mortar application in sewage environment was explored. Due to the superior catalytic properties, amorphous alloy (AA) can be used in concrete of sewage system to achieve wastewater treatment and bacteria inactivation, thus mitigating microbial-induced concrete corrosion and promoting the durability of concrete. In this study, three types of Cu/Ti amorphous alloys (AA) prepared by ball milling method according to different copper/titanium atomic ratios (35:65, 50:50, 65:35) were employed as anti-bacteria agent for cement mortars. Detailed investigations were conducted into the physical, mechanical, and anti-bacteria properties of amorphous alloys mortars (AAM) in the range of addition 0.3%-0.9% AA. It was demonstrated that the produced AA had a higher degree of amorphism, smaller particles size, and higher zeta potential with the increase of titanium content, leading to the reduce of total porosity of AAM up to 18.33%, and the enhancement of compressive and flexural strength at 28d up to 13.30% and 25.55%, respectively. In addition, the synthesized AA showed excellent antibacterial performances, in which the bacteriostasis rates on Escherichia coli for three types of AA all reached up to 100% after 24 h immersion. After adding in the cement mortars, the anti-bacterial activity and catalytic degradation capacity of AAM increased as the AA contents increased. AAM with 0.9 % Cu 50 Ti 50 could achieve the best performance of bacteria inactivation and wastewater, in which 95.17% of bacteria was killed after 72 h and the degradation efficiency of Rhodamine B dyes reached up to 100% after 6 h. The findings are expected to facilitate the development of new functional applications of AAM in wastewater treatment. [ABSTRACT FROM AUTHOR]

• Spherical Al-Li alloys were originally prepared via the centrifugal atomization. • Prepared Al-Li alloys consist of evenly-distributed α-Al and Al-Li compounds. • Al-Li alloys show higher heat release and reaction rate than pure Al. • The shorter ignition delay of Al-Li/KP than Al/KP is due to lower E a of Al-Li. • Microexplosion has been observed when Al-Li alloys are used in energetic materials. To improve the heat release and reactivity of Al, Li was incorporated into Al via the centrifugal atomization in this study for obtaining Al-Li alloy powders. The microstructure and composition of the samples were characterized by SEM, XRD, and ICP. The oxidation kinetics were evaluated via TG/DSC, and the energetic performance of the Al-Li/KP composites was tested. The results show that spherical Al-Li alloy powders with the well-distributed dendritic structure are obtained that are mainly composed of αAl and Al-Li compounds. The oxidization rate of Al-Li alloy powders is higher than pure Al, owing to the decreasing activation energy caused by the catalysis of the soluble Li in Al and Al-Li compounds. The shorter ignition delay and higher reaction rate of Al-Li/KP with increasing Li content in Al-Li alloy powders is a result of the microexplosion of Al-Li. Therefore, Al-Li alloy powders with high reactivity are promising fuels for energetic materials. [ABSTRACT FROM AUTHOR]

• Magnesium-Gadolinium alloy is innovatively utilized for the fuel of Mg-base ignition charge. • As the fuel, Mg-Gd alloy powder exhibits its better oxidation resistance than Mg powder. • MGTV can stably combust at 0.03 MPa, while MTV can only combust at 0.05 MPa. • The burning rate and radiation properties of MGTV are enormously higher than MTV. • The improved combustion property is due to the highest melting and boiling points of Gd. The present work aims at improving the combustion properties of Mg-based ignition charge at low ambient pressure. An innovative idea of using the alloy powder of Magnesium-Gadolinium as the fuel in Mg/Teflon/Viton (MTV) has been experimented with. EXPLO5 was initially used to theoretically investigate the combustion properties of MTV under low ambient pressure. The combustion properties of Mg-Gd alloy/Teflon/Viton (MGTV) at pressures of 0.1, 0.07, 0.05, 0.03, and 0.01 MPa were investigated with MTV and Mg-Al alloy/Teflon/Viton (MATV) set as the controls. The radiation properties of MGTV in the open air were studied employing a far-infrared thermal imager, and the heats of combustion and explosion were investigated by a calorimeter. Furthermore, thermogravimetry/differential scanning calorimetry (TG/DSC) was conducted on Mg-Gd alloy and MGTV samples. X-ray diffraction studies were performed on the residue of MGTV after the calcination at 700 and 1000 °C. The results showed that as the fuel, Mg-Gd alloy powder exhibits its best oxidation resistance than Mg and Mg-Al alloy powders. MGTV could stably combust at the pressure of 0.03 MPa, while the controls could only combust stably at 0.05 MPa. The burning rate of MGTV was, respectively, 62 and 25% higher than that of MTV at 0.1 and 0.05 MPa. The flame area, radiation intensity, and radiation energy of MGTV in the open air were, respectively, 68%, 237% and 102% higher than those of MTV and commensurate with MATV. However, the heats of combustion and explosion of MGTV was the least. Further investigation showed that the MGTV could react with O 2 at the temperature of 700 °C. The key to improve the burning characteristics was the melting and boiling points of Gd. The combustion mechanism of MGTV was also proposed. [ABSTRACT FROM AUTHOR]

Linear energy density is often used as a design parameter to select laser power and scanning speed for the laser powder bed fusion (LPBF) of alloys. In the present study, the effects of laser power and scanning speed on the depth and width of remelted track and porosity of the as-built Mg-15Gd-1Zn-0.4Zr (GZ151K, wt%) alloy were systematically studied. The experimental results present that the depth and width of remelted track and porosity vary significantly despite using the same linear energy density value but different combinations of laser power and scanning speed values, indicating the limitations of linear energy density when changing laser power and scanning speed simultaneously. Furthermore, sensitivity level analysis was conducted to assess the relative importance of laser power and scanning speed to the depth and width of remelted track and porosity. It was found that scanning speed is more important to the depth and width of remelted track than laser power, while laser power is more important to the porosity than scanning speed. Therefore, using the linear energy density as a design parameter for LPBF is not always reliable, and the present study can provide some guidance for selecting process parameters for the LPBF of alloys. [Display omitted] • The depth and width of remelted track and porosity vary significantly despite using the same linear energy density. • Linear energy density is not always reliable especially when changing laser power and scanning speed simultaneously. • Scanning speed is more important to the depth and width of remelted track than laser power. • Laser power is more important to the porosity than scanning speed. [ABSTRACT FROM AUTHOR]

Zn has been incorporated into Mg via centrifugal atomization in this work. The prepared Mg-Zn alloys have been characterized via SEM/EDS and XRD. The thermal behavior and combustion of Mg-Zn alloys have been tested by TG/DSC and laser ignition. Then, Mg-Zn alloys have been applied in pyrotechnics with PTFE as the oxidizer, followed by measuring the reactivity and ignition delay. Mg-5%Zn and Mg-10%Zn alloys consisting of α-Mg and eutectic phase (α-Mg and MgZn 2) in a high degree of sphericity with evenly distributed Zn were obtained. Thermal behavior characterization indicates that the oxidation of Mg-Zn alloys initiates ∼50 °C earlier than Mg along with a higher oxidation rate, which could be attributed to the lower melting point of MgZn 2 and Zn. In addition, the oxidation rate of Mg-Zn alloys is also higher than Mg that is the result of significantly lower apparent activation energy of Mg-Zn alloys than Mg. Due to the great discrepancy of melting and evaporation point between Mg, MgZn 2 , and Zn, a visible microexplosion phenomenon has been observed during the combustion process of Mg-Zn alloys. Then, Mg-Zn alloys have been applied as the fuel to replace Mg in Mg/PTFE pyrotechnics. The ignition delay of Mg-Zn/PTEE composites is shorter than that of Mg/PTFE, which is due to the easier oxidization initiation of Mg-Zn alloys compared to Mg. Besides, the lower melting and evaporation points of MgZn 2 and Zn than Mg can accelerate the combustion of Mg-Zn alloys, leading to the improved peak pressure and reaction rate of Mg-Zn/PTEE. Thus, the lower apparent activation energy of Mg-Zn alloys and the lower melting point of MgZn 2 and Zn could promote the energetic kinetics of Mg-Zn alloys synergistically. Above all, the prepared Mg-Zn alloys in this study are ambitious candidates in pyrotechnics for controllable ignition and reactivity kinetics. [ABSTRACT FROM AUTHOR]

• Spherical Al-Zr alloy powders were originally prepared via centrifugal atomization. • The prepared Al-Zr alloys consists of Al and Al 3 Zr. • Al-Zr alloy powders show advanced peak temperature and higher reaction rate than Al. • The activation energy of Al-Zr is significantly lower than that of pure Al. • Al-Zr alloys are used in energetic materials for greatly improved combustion behavior. To improve the energetic behavior of Al, heterogeneous Al-Zr alloy powders were prepared by high-speed centrifugal atomization in this paper, the phase composition of which is Al and Al 3 Zr. The thermal analysis results show that the main oxidation process of Al-Zr occurs at 800 °C–1200 °C. The oxidation peak temperature of the alloy is 25 °C lower than that of Al, accompanied with a higher weight gain and faster oxidation rate. Besides, the activation energy (E k) is significantly reduced by 74 kJ/mol. Compared with Al/CuO, the ignition delay of Al-Zr/CuO is shortened by 0.6 ms, and the reaction temperature is advanced by 29 °C. This is due to the earlier concentrated heat release of Al 3 Zr and the grain refinement of Al-Zr that aggravates the shell fracture and result in more intense oxidation of the alloy powders. Therefore, Al-Zr alloy powders possess a significantly enhanced combustion performance than Al. [ABSTRACT FROM AUTHOR]

[Display omitted] • Increased pressure reduced molecular weight and enhanced esterification degree of WSP. • Increased inlet temperature enhanced molecular weight and esterification degree of WSP. • Higher pressure and elevated temperature enhanced total carotenoid bioaccessibility. • Higher esterification degree of WSP induced to higher carotenoid bioaccessibility. The effect of high pressure homogenization (HPH) compared with simple blending and milling on mixed juice properties, including water-soluble pectin (WSP) characteristics and total carotenoid bioaccessibility (TCB) was investigated. Overall, HPH treatments, which comprised of varied pressures, passes and inlet temperature (IT) affected WSP characteristics. Increased pressure showed decreased molecular weight (M w), galacturonic acid (GalA) content and branching, and enhanced degree of methylesterification (DM) and chain linearity, suggesting degradation of RG-I fragments. Two passes at 140 MPa enhanced GalA content, nevertheless it reduced DM, implying rearrangement of depolymerized fractions. Besides, elevated IT combined with high pressure increased GalA content and DM signifying thermo-solubilization of certain HG-rich pectin. Notably, the TCB was enhanced by higher pressure and elevated temperature, which had positive relationship with DM and chain linearity of WSP and negative correlations with GalA content and M w. Results highlighted the potential of HPH to improve WSP characteristics to enhance TCB. [ABSTRACT FROM AUTHOR]

Abstract: Tourette syndrome (TS) is a complex childhood neurodevelopmental disorder characterized by motor and vocal tics. Recently, altered numbers of GABAergic-parvalbumin (PV) and cholinergic interneurons were observed in the basal ganglia of individuals with TS. Thus, we postulated that gamma-amino butyric acid (GABA)- and acetylcholine (ACh)-related genes might be associated with the pathophysiology of TS. Total RNA isolated from whole blood of 26 un-medicated TS subjects and 23 healthy controls (HC) was processed on Affymetrix Human Exon 1.0 ST arrays. Data were analyzed to identify genes whose expression correlated with tic severity in TS, and to identify genes differentially spliced in TS compared to HC subjects. Many genes (3627) correlated with tic severity in TS (p <0.05) among which GABA- (p= 2.1×10−3) and ACh- (p= 4.25×10−8) related genes were significantly over-represented. Moreover, several GABA and ACh-related genes were predicted to be alternatively spliced in TS compared to HC including GABA receptors GABRA4 and GABRG1, the nicotinic ACh receptor CHRNA4 and cholinergic differentiation factor (CDF). This pilot study suggests that at least some of these GABA- and ACh-related genes observed in blood that correlate with tics or are alternatively spliced are involved in the pathophysiology of TS and tics. [Copyright &y& Elsevier]

Abstract: Using whole genome exon microarrays 120 exons were differentially expressed between medication-free multiple sclerosis (MS) subjects in remission and healthy control subjects (HS) (p<0.001, fold change>|1.2|). These exons differentiated MS from HS using cluster analyses, principal components analyses (PCAs) and cross-validation. In addition, 340 genes (transcripts) were predicted to be alternatively spliced in MS compared to HS. These findings may provide insight into the pathophysiology of MS and potentially provide prognostic and diagnostic biomarkers. However, given that multiple comparisons were performed on a very small sample, these preliminary findings require confirmation using a much larger independent cohort. [ABSTRACT FROM AUTHOR]

• Pressures over 200 MPa retained more amounts of bioactives than non-homogenization. • Juice evaluation model was built by factor analysis and analytic hierarchy process. • Juice at 250 MPa, 1 pass and 25 °C has the best sensory and nutritional qualities. • Artificial neural networks predicted antioxidant activities (≤5%). The present work optimized high-pressure homogenization (HPH) parameters for not-from-concentrate combined peach and carrot juices, based on a two-step comprehensive model using factor analysis and analytic hierarchy process methods. Treating combined juice with pressures over 200 MPa retained more amounts of the bioactive compounds (carotenoids and polyphenols) than non-homogenization. Nutrition-oriented optimization, with higher judgement weight on nutritional properties, and sense-oriented optimization, with higher weight on sensory properties, were set up. Combined juice (250 MPa, 1 pass and 25 °C) had the best quality, based on the nutrition- and sense-oriented models. Back propagation neural network (BPNN) models could predict antioxidant capacities of the combined juice with greater accuracy compared with stepwise linear regression. The relative errors of BPNN prediction model were ≤ 5%. [ABSTRACT FROM AUTHOR]

The Mg-11Gd-2Zn-0.4Zr (GZ112K, wt.%) alloys fabricated by selective laser melting (SLM) still contain some hard and brittle β-(Mg,Zn) 3 Gd eutectic phase with an area fraction of 4.86% despite the ultra-fast cooling rate of SLM process, so post heat treatment is necessary. The effects of different solution conditions and aging heat treatment on microstructure and mechanical properties of the SLMed GZ112K alloys were systematically analyzed. The results show that the optimized solution condition (400 °C × 12 h) for the SLMed GZ112K alloys can not only transform hard and brittle β-(Mg,Zn) 3 Gd eutectic phase into relatively softer lamellar 14H type long period stacking order (LPSO) structure leading to the improved elongation (EL) of the SLM-T4 alloys, but also retain the fine grains of the SLMed GZ112K alloys to a large extent with a small average grain size of 3.1 μm in the SLM-T4 state contributing to the high yield strength (YS) of the SLM-T4 and SLM-T6 GZ112K alloys. After peak aging heat treatment, basal γ′ precipitates or lamellar 14H-LPSO structure and dense prismatic elliptical β′ precipitates coexist in the SLM-T6 GZ112K alloys. As a result, the SLM-T6 GZ112K alloys exhibit YS of 343 ± 9 MPa, ultimate tensile strength (UTS) of 371 ± 4 MPa and EL of 4.0 ± 0.05%, while those of the SLMed GZ112K alloys are 332 ± 3 MPa, 351 ± 5 MPa and 8.6 ± 1.0%. The ultra-high YS of SLM-T6 GZ112K alloys results from the fine grain strengthening, the precipitation strengthening from β′ aging precipitates, the secondary phase strengthening from LPSO structure and X phase and the extra composite strengthening from the coexistence of basal and prismatic precipitates. The findings indicate that appropriate post heat treatment is an effective scheme for modifying microstructure and mechanical properties of the SLMed alloys. • The SLMed GZ112K alloys achieve excellent strength-ductility synergy: YS of 332 MPa, UTS of 351 MPa and EL of 8.6%. • The optimized solution condition transformed eutectic phase into 14H-LPSO structure and retained fine grains. • The SLM-T4 GZ112K alloys exhibit highest ductility: YS of 281 MPa, UTS of 311 MPa and EL of 14.4%. • Peak aging heat treatment results in an ultra-high YS of 343 MPa in the SLM-T6 GZ112K alloys. [ABSTRACT FROM AUTHOR]

We report on the direct electrodeposition of nickel and cobalt nanowire arrays within the nanopores of ordered porous alumina films prepared by a two-step anodization. SEM and TEM images reveal that the pore arrays are regularly arranged throughout the alumina film. X-ray diffraction and TEM analysis show that the nickel and cobalt nanowires are single crystalline with highly preferential orientation. The aspect ratio of nanowires is over 300. M–H hysteresis loops determined by VSM indicate that the nanowire arrays obtained possess obvious magnetic anisotropy. Because of proper square ratio and coercivity the nanowire arrays of nickel seem to be more suitable candidates for perpendicular magnetic recording medium than those of cobalt. [Copyright &y& Elsevier]

• The molecular structure of pectin is often altered during food processing. • Effects of processing on pectin structure are highly dependent on the plant origin. • Targeted control of pectin structure enhances texture, rheology, and nutrition. • Finding balance among quality indicators of processed product is major challenge. Pectin, a major polysaccharide found in the cell walls of higher plants, plays major roles in determining the physical and nutritional properties of fruit- and vegetable-based products. An in-depth understanding of the effects of processing operations on pectin structure and functionality is critical for designing better products. This review, therefore, focuses on the progress made in understanding the effects of processing on pectin structure, further on pectin functionality, consequently on product properties. The effects of processing on pectin structure are highly dependent on the processing conditions. Targeted control of pectin structure by applying various processing operations could enhance textural, rheological, nutritional properties and cloud stability of products. While it seems that optimizing product quality in terms of physical properties is counteracted by optimizing the nutritional properties. Therefore, understanding plant component biosynthesis mechanisms and processing mechanisms could be a major challenge to balance among the quality indicators of processed products. [ABSTRACT FROM AUTHOR]

• Lower pectin concentration caused higher β-carotene bioaccessibility. • Medium methoxyl pectin resulted in higher β-carotene bioaccessibility. • Sucrose could achieve the highest β-carotene bioaccessibility than other sugars. • Viscosity showed no marked difference in all the systems during digestion. There is lack of information about the effects of pectin and sugars on carotenoid delivery in a simple juice model system. Therefore, the effect of pectin and sugars on β-carotene bioaccessibility (CBA) and the characteristics of digestive fluids in juice model systems were studied. Carotenoid retention ratio (CRR) in the small intestine and the characteristics of digestive fluids, including color parameters and rheological properties, were investigated to gain insight into the mechanism that can alter carotenoid bioaccessibility. Results illustrated that higher pectin concentration, medium methoxyl pectin (MMP), and low methoxyl pectin (LMP) increased the initial apparent viscosity. However, there was no marked difference for the apparent viscosity of all systems in the stomach and small intestine phases. Generally, systems with sugars had higher CRR than those with pectin. Lower pectin concentration increased CBA. Systems with MMP had higher CBA than those containing high methoxyl pectin (HMP) and LMP; therefore, the effects of degree of methoxylation (DM) were not proportional to CBA. Among systems with different sugars, sucrose could achieve the highest CBA (4.59%). A comprehensive investigation of the effects of pectin and sugars on carotenoid delivery during digestion will be a theoretical guidance to improve nutritional qualities of juice products. [ABSTRACT FROM AUTHOR]

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8-16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure., (© 2024. The Author(s).)

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo. Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR., Competing Interests: Declaration of interests F.M. is employed by AstraZeneca and reports stock and other ownership interests from AstraZeneca. J.Z.D. reports research funding from AstraZeneca and consulting fees from AstraZeneca, Genagon, AmMax Bio, NuProbe, and Launchpad Therapeutics. S.T. and N.G. are employed by mProbe and report research funding, stock, and other ownership interests from mProbe. S.M. reports grants from Boehringer Ingelheim and Daiichi Sankyo and serves on the scientific advisory board of Bionseek. Y.Y.J. acknowledges research funding from the National Cancer Institute, Department of Defense, Cycle for Survival, Fred’s Team, Inspirna, AstraZeneca, Arcus Biosciences, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck, and Transcenta. She has served on advisory boards and/or done consulting for AbbVie, AmerisourceBergen, AskGene Pharma, Inc., Arcus Biosciences, Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi Sanyko, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Guardant Health, Inc., Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Pfizer, Seagen, Silverback Therapeutics, and Zymeworks, Inc., as well as Clinical Care Options, HMP Education, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, and Research to Practice. She also holds stock options in Inspirna. W.P. acknowledges research funding from the National Cancer Institute, Break Through Cancer, Parker Institute for Cancer Immunotherapy (PICI), Society for Immunotherapy of Cancer, The Society of MSK, Merck, Astellas, Miracogen, Amgen, and Revolution Medicines. He has served on advisory boards and/or done consulting for Astellas, EXACT Therapeutics, and Innovent Biologics. He has received honoraria for continuing medical education for American Physician Institute and Integrity. R.Y. has served as an advisor for Array BioPharma/Pfizer, Mirati Therapeutics, and Amgen; received a speaker’s honorarium from Zai Lab; and has received research support to her institution from Array BioPharma/Pfizer, Boehringer Ingelheim, Boundless Bio, Mirati Therapeutics, and Daiichi Sankyo. B.T.L. reports grants and other support from Amgen and grants from the NIH during the conduct of the study; grants and personal fees from Hengrui USA; grants and other support from Genentech Roche, Lilly, AstraZeneca, and Daiichi Sankyo; nonfinancial support and other support from Resolution Bioscience; grants and nonfinancial support from MORE Health; nonfinancial support from Jiangsu Hengrui Medicine; personal fees from Boehringer Ingelheim; grants from the NIH outside the submitted work; and a patent for US62/685,057 issued, a patent for US62/514,661 issued, royalties from Karger Publishers, and licensing with Shanghai Jiao Tong University Press. S.C. has received personal consulting fees from Novartis, AstraZeneca, Nuvalent, Genesis Therapeutics, eFFECTOR Therapeutics, SAGA Diagnostics, Prelude Therapeutics, and Casdin Capital. S.C. has research funding from AstraZeneca and Daiichi Sankyo., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glycyl radical enzymes (GREs) catalyze mechanistically diverse radical-mediated reactions, playing important roles in the metabolism of anaerobic bacteria. The model bacterium Escherichia coli MG1655 contains two GREs of unknown function, YbiW and PflD, which are widespread among human intestinal bacteria. Here, we report that YbiW and PflD catalyze ring-opening C-O cleavage of 1,5-anhydroglucitol-6-phosphate (AG6P) and 1,5-anhydromannitol-6-phosphate (AM6P), respectively. The product of both enzymes, 1-deoxy-fructose-6-phosphate (DF6P), is then cleaved by the aldolases FsaA or FsaB to form glyceraldehyde-3-phosphate (G3P) and hydroxyacetone (HA), which are then reduced by the NADH-dependent dehydrogenase GldA to form 1,2-propanediol (1,2-PDO). Crystal structures of YbiW and PflD in complex with their substrates provided insights into the mechanism of radical-mediated C-O cleavage. This "anhydroglycolysis" pathway enables anaerobic growth of E. coli on 1,5-anhydroglucitol (AG) and 1,5-anhydromannitol (AM), and we probe the feasibility of harnessing this pathway for the production of 1,2-PDO, a highly demanded chiral chemical feedstock, from inexpensive starch. Discovery of the anhydroglycolysis pathway expands the known catalytic repertoire of GREs, clarifies the hitherto unknown physiological functions of the well-studied enzymes FsaA, FsaB, and GldA, and demonstrates how enzyme discovery efforts can cast light on prevalent yet overlooked metabolites in the microbiome.

Intestinal metaplasia (IM) is a premalignant condition that increases the risk for subsequent gastric cancer (GC). Traditional Chinese medicine generally plays a role in the treatment of IM, and the phytochemical naringenin used in Chinese herbal medicine has shown therapeutic potential for the treatment of gastric diseases. However, naringenin's specific effect on IM is not yet clearly understood. Therefore, this study identified potential gene targets for the treatment of IM through bioinformatics analysis and experiment validation. Two genes (MTTP and APOB) were selected as potential targets after a comparison of RNA-seq results of clinical samples, the GEO dataset (GSE78523), and naringenin-related genes from the GeneCards database. The results of both cell and animal experiments suggested that naringenin can improve the changes in the intestinal epithelial metaplasia model via MTTP/APOB expression. In summary, naringenin likely inhibits the MTTP/APOB axis and therefore inhibits IM progression. These results support the development of naringenin as an anti-IM agent and may contribute to the discovery of novel IM therapeutic targets., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Alternative splicing (AS) plays an important role in various physiological processes in eukaryotes, such as the stress response. However, patterns of AS events remain largely unexplored during salinity acclimation in fishes. In this study, we conducted AS analysis using RNA-seq datasets to explore splicing patterns in the gill tissues of rainbow trout exposed to altered salinity environments, ranging from 0 ‰ (T0) to 30 ‰ (T30). The results revealed 1441, 351, 483, 1051 and 1049 differentially alternatively spliced (DAS) events in 5 pairwise comparisons, including T6 vs. T0, T12 vs. T0, T18 vs. T0, T24 vs. T0, and T30 vs. T0, respectively. These DAS events were derived from 1290, 328, 444, 963 and 948 genes. Enrichment analysis indicated that these DAS genes were related to RNA splicing and processing. Among these, 14 DAS genes were identified as members of the large heterogeneous nuclear RNP (hnRNP) gene family. Alternative 3' splice site (A3SS), exon skipping (SE) and intron retention (RI) events resulted in the fragmentation or even loss of the functional RNA recognition motif (RRM) domains in hnrnpa0, hnrnp1a, hnrnp1b and hnrnpc genes. The incomplete RRM domains would hinder the interactions between hnRNP genes and pre-mRNAs. It would in turn influence the splicing patterns and mRNA stability of downstream target genes in response to salinity changes. The study provides insights into salinity acclimation in gill tissues of rainbow trout and serves as a significant reference on the osmoregulation mechanisms at post-transcription regulation levels in fish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

[Formula: see text] state estimation is addressed for continuous-time neural networks in the paper. The norm-bounded uncertainties are considered in communication neural networks. For the considered neural networks with uncertainties, a reduced-order [Formula: see text] state estimator is designed, which makes that the error dynamics is exponentially stable and has weighted [Formula: see text] performance index by Lyapunov function method. Moreover, it is also given the devised method of the reduced-order [Formula: see text] state estimator. Then, considering that sampling the output y(t) of the neural network at every moment will result in waste of excess resources, the event-triggered sampling strategy is used to solve the oversampling problem. In addition, a devised method is also given for the event-triggered reduced-order [Formula: see text] state estimator. Finally, by the well-known Tunnel Diode Circuit example, it shows that a lower order state estimator can be designed under the premise of maintaining the same weighted [Formula: see text] performance index, and using the event-triggered sampling method can reduce the computational and time costs and save communication resources., (© 2024. The Author(s).)

Purpose: Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition., Methods: We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes., Results: We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI - 77 to - 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22)., Conclusions: SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon., Methods: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR)., Results: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations., Conclusions: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Zero-valent iron (ZVI) has been extensively studied for its efficacy in removing heavy metals, nitrate, and chlorinated organic compounds from contaminated water. However, its limited effectiveness due to rapid passivation and poor selectivity is prompting for alternative solutions, such as the use of aluminium alloys. In this study, the efficacy of five distinct aluminium alloys, namely Al-Mg, Al-Fe, Al-Cu, and Al-Ni, each comprising 50 % Al by mass at a concentration of 10 g/L, was assessed using copper, nitrate and trichloromethane (TCM) as model contaminants. Results show that chemical pollutants reacted immediately with Al-Mg. On the contrary, the remaining three alloys exhibited a delay of 24 h before demonstrating significant reactivity. Remarkably, Al-Mg alloy reduced nitrate exclusively to ammonium, indicating minimal preference for nitrate reduction to N 2 . In contrast, the Al-Cu, Al-Ni, and Al-Fe alloys exhibited N 2 selectivity of 3 %, 5 %, and 19 %, respectively. The removal efficiency of copper, nitrate and TCM reached 99 % within 24 h, 95 % within 48h and 48 % within 48h, respectively. Noteworthy findings included the correlation between Fe concentration within the Al-Fe alloy and an increased N 2 selectivity from 9.3 % to 24.1 %. This resulted in an increase of Fe concentration from 10 % to 58 % albeit with a concurrent reduction in reactivity. Cu 2+ removal by Al-Fe alloy occurred via direct electron transfer, while the removal of nitrate and TCM was facilitated by atomic hydrogen generated by the alloy's hydrolysis. Intriguingly, nitrate and TCM suppressed Cu 2+ reduction, whereas Cu 2+ improved nitrate reduction and TCM degradation. These findings demonstrate the great potential of Al-Mg and Al-Fe alloys as highly efficient agents for water remediation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Frederic Coulon reports a relationship with Heliyon that includes: employment., (© 2023 The Authors. Published by Elsevier Ltd.)

This retrospective study aims to assess the diagnostic utility of peripheral blood eosinophil counts in distinguishing between benign and malignant pulmonary nodules (PNs) prior to surgical intervention. We involved patients presenting with PNs measuring ≤30 mm as the primary CT imaging finding prior to surgical procedures at the General Hospital of Northern Theater Command in Shenyang, China, during the period spanning 2021 to 2022. Multivariable logistic regression analysis and receiver operator characteristic curve analysis, along with area under the curve (AUC) calculations, were used to determine the diagnostic value of eosinophil. A total of 361 patients with PN were included, consisting of 135 with benign PN and 226 with malignant PN. Multivariable logistic regression analysis showed that eosinophil percentage (OR = 1.909, 95% CI: 1.323-2.844, P < .001), absolute eosinophil value (OR = 0.001, 95% CI: 0.000-0.452, P = .033), tumor diameter (OR = 0.918, 95% CI: 0.877-0.959, P < .001), nodule type (OR = 0.227, 95% CI: 0.125-0.400, P < .001), sex (OR = 2.577, 95% CI: 1.554-4.329, P < .001), and age (OR = 0.967, 95% CI: 0.945-0.989, P = .004) were independently associated with malignant PN. The diagnostic value of regression model (AUC [95% CI]: 0.775 [0.725-0.825]; sensitivity: 74.3%; specificity: 71.1%) was superior to eosinophil percentage (AUC [95% CI]: 0.616 [0.556-0.677]; specificity: 66.8%; specificity: 51.1%) (Delong test: P < .001). Peripheral blood eosinophil percentage might be useful for early malignant PN diagnosis, and combining that with other characteristics might improve the diagnostic performance., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

To emphasize that differences in pectin structure among cultivars play a crucial role in the texture and quality of fruits and vegetables, the sugar content and methyl-esterification of pectin fractions from 13 apple cultivars was studied. Cell wall polysaccharides were isolated as alcohol-insoluble solids (AIS) and subsequently extracted to yield water-soluble solids (WSS) and chelating-soluble solids (ChSS). All fractions contained significant amounts of galacturonic acid, while sugar compositions varied between cultivars. AIS and WSS pectins showed a degree of methyl-esterification (DM) > 50 %, while ChSS pectins had either a medium (∼50 %) or low (<30 %) DM. Homogalacturonan as major structure was studied using enzymatic fingerprinting. Methyl-ester distribution of pectin was described by degrees of blockiness and -hydrolysis. Novel descriptive parameters were obtained by measuring the levels of methyl-esterified oligomers released by endo-PG (DB PGme ) and PL (DB PLme ). Pectin fractions differed in relative amounts of non-, moderately-, and highly methyl-esterified segments. WSS pectins were mostly lacking non-esterified GalA sequences, while ChSS pectins had medium DM and many non-methyl-esterified blocks or a low DM with many intermediate methyl-esterified GalA blocks. These findings will be of help to better understand physicochemical properties of apple and its products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases., Methods: A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest; systemic progression of disease and death were considered competing risks., Results: The median age was 65 years, and the most common 5' fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval [CI]: 0%-10%), 10% (95% CI: 0%-22%), 17% (3%-30%), 17% (3%-30%), and 20% (5%-35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI: 0%-0%)., Conclusions: CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None

Introduction: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs)., Methods: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated., Results: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9)., Conclusions: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours., Methods: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020., Results: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS)., Conclusions: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The histone deacetylase 9 (HDAC9) polymorphism rs2107595 is associated with an increased risk for large vessel atherosclerotic stroke (LVAS). In humans, there remains a need to better understand this HDAC9 polymorphism's contribution to large vessel stroke. In this pilot study, we evaluated whether the HDAC9 polymorphism rs2107595 is associated with differences in leukocyte gene expression in patients with LVAS. HDAC9 SNP rs2107595 was genotyped in 155 patients (43 LVAS and 112 vascular risk factor controls). RNA isolated from blood was processed on whole genome microarrays. Gene expression was compared between HDAC9 risk allele-positive and risk allele-negative LVAS patients and controls. Functional analysis identified canonical pathways and molecular functions associated with rs2107595 in LVAS. In HDAC9 SNP rs2107595 risk allele-positive LVAS patients, there were 155 genes differentially expressed compared to risk allele-negative patients (fold change > |1.2|, p < 0.05). The 155 genes separated the risk allele-positive and risk allele-negative LVAS patients on a principal component analysis. Pathways associated with HDAC9 risk allele-positive status involved IL-6 signaling, cholesterol efflux, and platelet aggregation. These preliminary data suggest an association with the HDAC9 rs2107595 risk allele and peripheral immune, lipid, and clotting systems in LVAS. Further study is required to evaluate whether these differences are related to large vessel atherosclerosis and stroke risk.

Background and Purpose: Although peripheral blood mRNA and micro-RNA change after ischemic stroke, any role for long noncoding RNA (lncRNA), which comprise most of the genome and have been implicated in various diseases, is unknown. Thus, we hypothesized that lncRNA expression also changes after stroke., Methods: lncRNA expression was assessed in 266 whole-blood RNA samples drawn once per individual from patients with ischemic stroke and matched with vascular risk factor controls. Differential lncRNA expression was assessed by ANCOVA (P<0.005; fold change>|1.2|), principal components analysis, and hierarchical clustering on a derivation set (n=176) and confirmed on a validation set (n=90). Poststroke temporal lncRNA expression changes were assessed using ANCOVA with confounding factor correction (P<0.005; partial correlation with time since event >|0.4|). Because sexual dimorphism exists in stroke, analyses were performed for each sex separately., Results: A total of 299 lncRNAs were differentially expressed between stroke and control males, whereas 97 lncRNAs were differentially expressed between stroke and control females. Significant changes of lncRNA expression with time after stroke were detected for 49 lncRNAs in men and 31 lncRNAs in women. Some differentially expressed lncRNAs mapped close to genomic locations of previously identified putative stroke-risk genes, including lipoprotein, lipoprotein(a)-like 2, ABO (transferase A, α1-3-N-acetylgalactosaminyltransferase; transferase B, α1-3-galactosyltransferase) blood group, prostaglandin 12 synthase, and α-adducins., Conclusions: This study provides evidence of altered and sexually dimorphic lncRNA expression in peripheral blood of patients with stroke compared with that of controls and suggests that lncRNAs have potential for stroke biomarker development. Some regulated lncRNA could regulate some previously identified putative stroke-risk genes., (© 2016 American Heart Association, Inc.)

Brain edema, the first stage of intracranial hypertension, has been associated with poor prognosis and increased mortality after acute brain injury such as ischemic stroke, intracranial hemorrhage (ICH), and traumatic brain injury (TBI). Acute brain injury often initiates release of many molecules, including glutamate, adenosine, thrombin, oxyhemoglobin, cytokines, reactive oxygen species (ROS), damage-associated molecular pattern molecules (DAMPs), and others. Most of these molecules activate Src family kinases (SFKs), a family of proto-oncogenic non-receptor tyrosine kinases, resulting in blood-brain barrier (BBB) disruption and brain edema at the acute stage after brain injury. However, SFKs also contribute to BBB self-repair and brain edema resolution in the chronic stage that follows brain injury. In this review, we summarize possible pathways through which SFKs are implicated in both brain edema formation and its eventual resolution.

Background: Defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH., Methods: RNA from whole blood was processed on whole-genome microarrays., Results: A total of 293 probe sets were differentially expressed in AD versus controls, 5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies. Regulated blood genes included MMP9, MME (Neprilysin), TGFβ1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2., Conclusions: RNA expression is altered in AD blood irrespective of WMH status. Some genes are shared with AD brain.