bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease
Authors: Jiang Lulu , Roberts Rebecca , Wong Melissa , Zhang Lushuang , Webber Chelsea Joy , Kilci Alper , Jenkins Matthew , Sun Jingjing , Sun Guangxin , Rashad Sherif , Dedon Peter C , Daley Sarah Anne , Xia Weiming , Ortiz Alejandro Rondón , Dorrian Luke , Saito Takashi , Saido Takaomi C , Wolozin Benjamin 
Published: May 2023

Abstract
The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL−G−F MAPTP301S mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APPNL−G−F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL−G−F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.
Highly accurate enzyme turnover number prediction and enzyme engineering with PreKcat
Authors: Yu Han , Deng Huaxiang , He Jiahui , Keasling Jay , Luo Xiaozhou 
Published: May 2023

Abstract
Prediction of enzyme turnover number (kcat) is essential for designing and optimizing enzymes for various biotechnological and industrial applications, but the limited performance of current prediction tools on diverse tasks hinders their practical applications. Here, we introduce PreKcat, a method based on pretrained language models for highly accurate kcat prediction from protein sequences and substrate structures. A two-layer framework derived from PreKcat was proposed to allow robust kcat prediction in considering environmental factors, including pH and temperature. In addition, four representative re-weighting methods were systematically explored to successfully reduce the prediction error in high kcat values prediction tasks. Furthermore, PreKcat showed strong generalizability in two extended tasks, Km and kcat / Km prediction. Using PreKcat, we achieve significant increases kcat and kcat / Km (approximately 7-fold and 3.5-fold, respectively) on one enzyme, the highest reported values to date. PreKcat is a valuable tool for deciphering the mechanisms of enzyme kinetics and enables novel insights into enzyme engineering and their industrial applications.
Ex-vivo Expansion of Bone Marrow-derived Mesenchymal Stromal Cells for Clinical Use: the Starting Platelet Concentration of Human Platelet Lysate Affects Cell Proliferation, Senescence and Phenotype
Authors: Becherucci Valentina , Nisticò Francesco , Piccini Luisa , Ceccantini Riccardo , Brugnolo Francesca , Ermini Stefano , Allegro Elisa , Bisin Silvia , Pavan Paola , De Rienzo Elena , Bindi Brbara , Cunial Vanessa , Astori Giuseppe , Bambi Franco 
Published: May 2023

Abstract
Background: In the last decades the replacement of fetal bovine serum (FBS) with human Platelet Lysate (hPL) for ATMPs expansion has been for a long time investigated to overcome FBS-related issues. Despite several studies confirming hPL safety and efficacy in Mesenchymal Stromal Cell (MSC) expansion, there are still gaps in the knowledge of hPL as a supplement, like the composition and release criteria. As growth factors are released after thrombocytes lysis during hPL production, starting platelet concentration may affect hPL quality. This study aimed to investigate hPL starting platelet concentration effects on bone marrow-derived MSC (BM-MSC) ex-vivo expansion.
Methods: MSC were isolated from the bone marrow (BM) of 7 donors and cultured from passage 1 to 5 in 4 different conditions: DMEM 10% FBS and DMEM 5% hPL varying starting platelet concentration. Particularly hPL was produced by in-hospital Transfusion Service, in three different starting platelet concentrations (sPLTC): high (4x109 PLTS/ml), medium (2x109 PLTS/ml) and low (1x109 PLTS/ml). The study focused on the analysis of parameters that are mostly affected by hPL such as cell proliferation, immunophenotype, telomeric length, differentiation and senescence.
Results: Evaluation of proliferation indexes (PDT and PD) underlined dose-dependent effects of sPLTC, also confirmed by flow cytometry cell cycle analysis. Immunophenotype seems not to be affected by sPLTC. Differences were instead detected by adhesion molecules markers CD10, CD106, CD166, and CD146 expression, as their expression showed a dose-dependent downregulation, based on the sPLTC. Differentiation potential seems to be unaffected by different sPLTC as all cell batches differentiated into osteoblasts, adipocytes and chondrocytes. On the contrary senescence and relative telomeric length RTL (detected by SA-β-GAL activity and PNA-FITC flow cytometry) are strongly affected by sPLTC, in a dose-dependent manner. Particularly high sPLTC results in cell senescence associated with decreased RTL.
Conclusions: our data showed that sPLTC affects some BM MSCs properties, underlying its importance during hPL preparation. According to this study, we suggest a medium sPLTC for hPL preparation, as the best compromise between the increase in proliferation index and effects on senescence.
SARS-CoV-2 antibodies recognize 23 distinct epitopic sites
on the receptor binding domain
Authors: Jiang Jiansheng , Boughter Christopher , Ahmad javeed , Natarajan Kannan , Boyd Lisa , Meier-Schellersheim Martin , Margulies David 
Published: May 2023

Abstract
The COVID-19 pandemic and SARS-CoV-2 variants have dramatically illustrated the need for a better understanding of antigen (epitope)-antibody (paratope) interactions. To gain insight into the immunogenic characteristics of epitopic sites (ES), we systematically investigated the structures of 340 Abs and 83 nanobodies (Nbs) complexed with the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein. We identified 23 distinct ES on the RBD surface and determined the frequencies of amino acid usage in the corresponding CDR paratopes. We describe a clustering method for analysis of ES similarities that reveals binding motifs of the paratopes and that provides insights for vaccine design and therapies for SARS-CoV-2, as well as a broader understanding of the structural basis of Ab-protein antigen (Ag) interactions.
Electrocardiographic Changes During Sustained Normobaric Hypoxia in Patients After Myocardial Infarction
Authors: Kramer Tilmann , Hoenemann Jan-Niklas , Weis Henning , Hoffmann Fabian , Rosenkranz Stephan , Baldus Stephan , Hellmich Martin , Levine Benjamin , Jordan Jens , Tank Jens , Limper Ulrich 
Published: May 2023

Abstract
Background
Whether physically fit patients who have recovered from myocardial infarction can safely stay and exercise at high altitude is unclear. Myocardial tissue hypoxia and pulmonary hypertension could affect cardiac function, electrophysiology and predispose to arrythmias.
Methods
We included four non-professional male athletes (57.8 ± 3.3 years). All were clinically stable 37 to 104 months after left ventricular ST-elevation myocardial infarction and subsequent drug-eluting stenting of single-vessel coronary artery disease. Oxygen was gradually decreased to a minimum of 11.8% followed by oxygen increase back to 20.9%. ECG, ergometry, and echocardiography were performed in normoxia and hypoxia.
Results
In hypoxia, ECG showed significant QTc interval prolongations using Bazett’s (402 ± 13 to 417 ± 25ms), Fridericia's (409 ± 12 to 419 ± 19ms), and Holzmann’s (103 ± 4 to 107 ± 6%) formula compared to normoxia. The response was partly reversed during recovery. Echocardiographic signs of pulmonary hypertension during normobaric hypoxia correlated significantly with altered QTc intervals (p < 0.001).
Conclusions
Even exceptionally healthy and fully revascularized patients post myocardial infarction may be susceptible to hypoxia-induced QTc prolongation and VES, particularly during physical exertion. Patients after myocardial infarction should be advised to seek consultation and examination by a cardiovascular specialist with expertise in high-altitude medicine prior to physical activities at high altitude.
Simultaneous Fractionation of Low-gluten Flour and Gum from Durian Seed: Process-Properties Relationship
Authors: Chew Zhi Ling , Kua Yin Leng , Gan Suyin , Tan Khang Wei , Lee Terri Zhuan Ean , Cheng Wai Kit , Lau Harrison Lik Nang 
Published: May 2023

Abstract
In this study, valuable low-gluten flour and gum were fractionated simultaneously from durian seed via a green and safe aqueous extraction method at maximum atom economy. As the extraction process significantly affected the properties and hence, the application of the flour and gum, the process-properties relationship of extraction temperature and W/S ratio were investigated and presented in this paper. The demucilaged durian seed flour (DDSF) and durian seed gum (DSG) solubilities and water absorption capacity (WAC) were found improved at higher extraction temperature (85 °C) due to bond cleavage and retention of amylose and hydrophilic amino acids. Furthermore, DSG with a solubility of 46.67% was the highest that can be achieved by current aqueous extraction method as further increase of W/S ratio and DSG yield exerted no effect on the solubility. Besides, the oil absorption capacity (OAC) of DSG was found higher than the DDSF due to the presence of nonpolar amino acids and fatty acids that tended to bind with the hydrophobic oil. OAC was mainly determined by the extraction yield and distribution of these hydrophobic fraction, instead of the degree of degradation. Higher overall yield was found at higher extraction temperature of 85 °C for simultaneous extraction of DDSF and DSG. While lower W/S ratio at 1:1 was preferable to obtain higher yield of DDSF, a higher W/S ratio at 5:1 was required for higher yield of DSG. Other than the extraction temperature, drying temperature and duration were key factors determining the colour of the extracted DDSF and DSG.
Risk of control failure to insecticides malathion, profenophos+cypermethrin mixture, and fipronil in boll weevil (Coleoptera: Curculionidae) populations from Bahia, Brazil
Authors: Coelho Beatriz Sousa , Leite Suzany Aguiar , Santos Mateus Pereira dos , Guedes Raul Narciso Carvalho , Bastos Cristina Schetino , Moreira Aldenise Alves , Bonfim João Evilásio Vasconcelos , Castellani Maria Aparecida 
Published: May 2023

Abstract
Background: To control the boll weevil Anthonomus grandis grandis (Coleoptera: Curculionidae), a key pest of cotton in the Americas, insecticides have been intensively used to manage their populations, increasing selection pressure for resistant populations. Thus, this study aimed detect insecticide resistance and assess insecticide control failure likelihhod of boll weevil populations exposed to malathion, profenophos+cypermethrin, and fipronil insecticides.
Results: Twelve populations of the boll weevil were collected from commercial cotton fileds of the state of Bahia, northeastern Brazil. These populations were exposed to malathion, profenophos+cypermethrin mixture and fipronil, at their respective maximum label dose for field applications. Three replicates of ten adult beetles were exposed to the insecticides and mortality was recorded 24 hours after exposure to the insecticides. The control failure likelihood was determined after 48 hours. The highest median lethal times (LT50) were observed for malathion and the profenophos+cypermethrin mixture. Resistance to at least one insecticide was detected in 11 populations; three populations were resistant to malathion and profenophos+cypermethrin; seven were resistant to all insecticides used. The resistance levels were low (<10-fold) for the three insecticides. Among 12 populations tested, 58% exhibited significant risk of control failure for the insecticide’s malathion and to profenophos+cypermethrin. The insecticide fipronil was efficient for the control of the boll weevil in 83% of the populations.
Conclusion: The results confirm the significant risk of insecticide control failure in the boll weevil populations to the main compounds used in the region. Thus, proper insecticide resistance management plans are necessary for the boll weevil in the region, particularly for malathion and fipronil insecticides.
Differential target multiplexed spinal cord stimulationusing a paddle-type lead placed at the appropriate site for neuropathic pain after spinal cord injury in patients with past spinal surgical histories: Study protocol for an exploratory clinical trial
Authors: Tanei Takafumi , Maesawa Satoshi , Nishimura Yusuke , Nagashima Yoshitaka , Ishizaki Tomotaka , Ando Masahiko , Kuwatsuka Yachiyo , Hashizume Atsushi , Kurasawa Shimon , Saito Ryuta 
Published: May 2023

Abstract
Background: Neuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation.
Methods: A single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: 1) effectiveness of DTM and tonic stimulations during the SCS trial; 2) changes of assessment items from 1 to 24 months; 3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; 4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and 5) whether gait function improves from 1 to 24 months.
Discussion: A paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories.
Trial registration: Japan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP.
Mixed-method study on the effects of conditional cash transfer program on the under- and overnutrition in children and adolescents: a school-based evidence from Caraga Region, the Philippines
Authors: Herrera Deborah Jael , Herrera Miraluna , Amora Donnacham , Bas Sherlyn , Miranda Caryl Aya , Hal Guido Van 
Published: May 2023

Abstract
Background This study aimed to determine the effects of Pantawid Pamilyang Pilipino Program (4Ps), a CCT program in the Philippines, on the multiple faces of malnutrition in children and adolescents and examine the perceptions and experiences of parents and other stakeholders on how 4Ps influenced child nutrition.Methods A concurrent mixed-method study was conducted in Caraga Region, the Philippines. Quantitative study utilized 5541 school-based data on child nutrition, socio-demographic and -cultural profiles, and inclusion to 4Ps from 10 representative schools in 4 school divisions. Associations between child nutritional status and inclusion to 4Ps, socio-demographic and -cultural factors, and their interactions were tested using the multilevel mixed-effect logistic models with school and year random effects. The qualitative study, on the other hand, was concurrently conducted through eight (8) focused group discussions (FGDs) cumulating 33 participants to enable triangulation and an in-depth description of the findings. A constructivist grounded theory analytical approach with four-level analysis was performed including identifying text, coding, and developing themes and theoretical framework.Results The likelihood of stunting was lower among 4Ps children (AOR: 0.70, 95%CI: 0.52–0.93) compared with non-4Ps children. Ethnicity was associated with higher odds of stunting among indigenous children from major tribes (AOR: 1.67, 95%CI: 1.08–2.47) compared with non-indigenous children. However, inclusion in the 4Ps has no significant effect on children's concurrent undernutrition and overnutrition. Interactions were found between inclusion to 4Ps and locality, with higher odds of stunting among 4Ps children in Agusan del Sur (AOR = 2.45, 95%CI:1.40–4.30) compared with 4Ps children in Agusan del Norte. Finally, qualitative findings revealed the positive and negative effects of 4Ps on malnutrition which were strongly influenced by parenting styles, parents’ attitudes towards cash grants and cash card management, provisions of child nutrition interventions, and delivery conditions of 4Ps.Conclusions Improving children's nutrition is bolstered in the 4Ps implementation strategies. Targeted strategies to prevent the negative implications of a cash grant and card mismanagement should be considered by policymakers and implementers for a scaled-up impact in decreasing malnutrition in children.
Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data.
Authors: Pondrelli Federica , Minardi Raffaella , Muccioli Lorenzo , Zenesini Corrado , Vignatelli Luca , Licchetta Laura , Mostacci Barbara , Tinuper Paolo , Kooi Craig W. Vander , Gentry Matthew S. , Bisulli Francesca 
Published: May 2023

Abstract
Background: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype-phenotype correlations.
Methods: We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy.
Results: 250 cases described in 70 articles were included. The mutated gene was NHLRC1in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95%CI 1.23-6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95%CI 0.75-5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1genotype wasconfirmed to have a more favourable prognosis in terms of disease duration.
Conclusions: This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.
Participatory Logic Modeling in a Multi-Site Initiative to Advance Implementation Science
Authors: Easterling Douglas , Jacob Rebekah R. , Brownson Ross C. , Haire-Joshu Debra , Gundersen Daniel A. , Angier Heather , DeVoe Jennifer E. , Likumahuwa-Ackman Sonja , Vu Thuy , Glasgow Russell E. , Schnoll Robert 
Published: May 2023

Abstract
Background: It is increasingly being recognized that logic models should be developed through a participatory approach which allows input from those who carry out the program being evaluated. While there are many positive examples of participatory logic modeling, funders have generally not used this approach in the context of multi-site initiatives. This article describes an instance where the funder and evaluator of a multi-site initiative fully engaged the funded organizations in developing the initiative logic model. The focus of the case study is Implementation Science Centers in Cancer Control (ISC3), a multi-year initiative funded by the National Cancer Institute (NCI).
Methods: The case study was collectively constructed by representatives of the seven centers funded under ISC3. Members of the Cross-Center Evaluation (CCE) Work Group jointly articulated the process through which the logic model was developed and refined. Individual Work Group members contributed descriptions of how their respective centers reviewed and used the logic model. Cross-cutting themes and lessons emerged through CCE Work Group meetings and the writing process.
Results: The initial logic model for ISC3 changed in significant ways as a result of the input of the funded groups. Authentic participation in the development of the logic model led to strong buy-in among the centers, as evidenced by their utilization. The centers shifted both their evaluation design and their programmatic strategy to better accommodate the expectations reflected in the initiative logic model.
Conclusions: The ISC3 case study provides a positive example of how participatory logic modeling can be mutually beneficial to funders, grantees and evaluators of multi-site initiatives. Funded groups have important insights about what is feasible and what will be required to achieve the initiative’s stated objectives. They can also help identify the contextual factors that either inhibit or facilitate success, which can then be incorporated into both the logic model and the evaluation design. In addition, when grantees co-develop the logic model, they have a better understanding and appreciation of the funder’s expectations, and thus are better positioned to meet those expectations.