bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connecting dementia risk loci to the CSF proteome identifies pathophysiological leads for dementia
Authors: Reus Lianne M , Jansen Iris E , Tijms Betty M , Visser Pieter Jelle , Tesi Niccoló , van der Lee Sven J , Vermunt Lisa , Peeters Carel F W , De Groot Lisa A , Hok-A-Hin Yanaika S , Chen-Plotkin Alice , Irwin David J , Hu William T , Meeter Lieke H , van Swieten John C , Holstege Henne , Hulsman Marc , Lemstra Afina W , Pijnenburg Yolande A L , van der Flier Wiesje M , Teunissen Charlotte E , del Campo Milan Marta 
Published: March 2024

Abstract
Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia.
We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins [proximity extension-based (PEA) immunoassays] in a deeply-phenotyped mixed memory clinic cohort [n = 502, mean age (standard deviation, SD) = 64.1 (8.7) years, 181 female (35.4%)], including patients with Alzheimer’s disease (AD, n = 213), dementia with Lewy bodies (DLB, n = 50) and frontotemporal dementia (FTD, n = 93), and controls (n = 146). Validation was assessed in independent cohorts (n = 99 PEA platform, n = 198, mass reaction monitoring-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not.
We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P = 1.65 × 10−8), ZCWPW1-PILRB (rs1476679, P = 2.73 × 10−32), CTSH-CTSH (rs3784539, P = 2.88 × 10−24) and HESX1-RETN (rs186108507, P = 8.39 × 10−8), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90 × 10−7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for FTD loci, either for the total sample as for analyses performed within FTD only.
Protein QTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.
RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity
Authors: Maroofian Reza , Sarraf Payam , O’Brien Thomas J , Kamel Mona , Cakar Arman , Elkhateeb Nour , Lau Tracy , Patil Siddaramappa Jagdish , Record Christopher J , Horga Alejandro , Essid Miriam , Selim Laila , Benrhouma Hanene , Ben Younes Thouraya , Zifarelli Giovanni , Pagnamenta Alistair T , Bauer Peter , Khundadze Mukhran , Mirecki Andrea , Kamel Sara Mahmoud , Elmonem Mohamed A , Ghayoor Karimiani Ehsan , Jamshidi Yalda , Offiah Amaka C , Rossor Alexander M , Youssef-Turki Ilhem Ben , Hübner Christian A , Munot Pinki , Reilly Mary M , Brown André E X , Nagy Sara , Houlden Henry 
Published: March 2024

Abstract
Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence.
In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping.
All affected individuals (seven males and seven females, aged 9–50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress.
Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.
ESKtides: a comprehensive database and mining method for ESKAPE phage-derived antimicrobial peptides
Authors: Wu Hongfang , Chen Rongxian , Li Xuejian , Zhang Yue , Zhang Jianwei , Yang Yanbo , Wan Jun , Zhou Yang , Chen Huanchun , Li Jinquan , Li Runze , Zou Geng 
Published: March 2024

Abstract
‘Superbugs’ have received increasing attention from researchers, such as ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), which directly led to about 1 270 000 death cases in 2019. Recently, phage peptidoglycan hydrolases (PGHs)–derived antimicrobial peptides were proposed as new antibacterial agents against multidrug-resistant bacteria. However, there is still a lack of methods for mining antimicrobial peptides based on phages or phage PGHs. Here, by using a collection of 6809 genomes of ESKAPE isolates and corresponding phages in public databases, based on a unified annotation process of all the genomes, PGHs were systematically identified, from which peptides were mined. As a result, a total of 12 067 248 peptides with high antibacterial activities were respectively determined. A user-friendly tool was developed to predict the phage PGHs–derived antimicrobial peptides from customized genomes, which also allows the calculation of peptide phylogeny, physicochemical properties, and secondary structure. Finally, a user-friendly and intuitive database, ESKtides ( http://www.phageonehealth.cn:9000/ESKtides), was designed for data browsing, searching and downloading, which provides a rich peptide library based on ESKAPE prophages and phages.
Database URL: 10.1093/database/baae022
Pan-enteric Capsule Endoscopy to Characterize Crohn’s Disease Phenotypes and Predict Clinical Outcomes in Children and Adults: The Bomiro Study
Authors: Oliva Salvatore , Veraldi Silvio , Russo Giusy , Aloi Marina , Rizzello Fernando , Gionchetti Paolo , Alvisi Patrizia , Labriola Flavio , Vecchi Maurizio , Eidler Pini , Elli Luca , Dussias Nikolas , Tontini Gian Eugenio , Calabrese Carlo 
Published: March 2024

Abstract

Background
Pan-enteric capsule endoscopy (PCE) provides useful information for the management of Crohn’s disease (CD), especially in children. No study has evaluated the ability of PCE to characterize CD phenotypes and outcomes in children and adults.

Methods
In a prospective multicenter observational study, we recruited patients with CD &gt;6 years from 4 centers in Italy. Patients underwent clinical, biomarker assessment and PCE. Lesions were graded using the PCE system. For each segment, the most common lesion (MCL), the most severe lesion (MSL), and the extent of involvement were defined. Disease severity, extent, and clinical outcomes were compared between children and adults. A logistic regression analysis was used to identify predictive factors for negative outcomes in both age groups.

Results
One hundred ninety-four consecutive patients (adults/children: 144/50) were evaluated for a total of 249 procedures. Children were more likely to have extensive disease, particularly in the colon. Higher MCL scores were independently associated with treatment escalation (odds ratio [OR], 4.09; 95% CI, 1.80-9.25; P = .001), while &gt;30% disease extent was more indicative of clinical and endoscopic relapse (OR, 2.98; 1.26-7.08; P = .013). Disease extent was the only factor associated with endoscopic recurrence in children (OR, 4.50; 95% CI, 1.47-13.77; P = .008), while severe lesions in adults provided a better predictor of treatment escalation (OR, 4.31; 95% CI, 1.52-12.1; P = .006). Postexamination, PCE contributed to a change of therapy in 196/249 (79%) of the procedures.

Conclusions
PCE allowed the characterization of CD phenotypes in children and adults by assessing disease severity and extent, which are of different importance in predicting clinical outcomes in these age groups.
Rilpivirine and cabotegravir trough concentrations in people with HIV on long-term treatment with long-acting injectable antiretrovirals
Authors: Cossu Maria Vittoria , Cattaneo Dario , Moschese Davide , Giacomelli Andrea , Soloperto Sara , D’Avolio Antonio , Antinori Spinello , Gori Andrea , Rizzardini Giuliano , Gervasoni Cristina 
Published: March 2024

Abstract

Objective
Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment.

Methods
Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated.

Results
Sixty-seven PWH were identified. LAI treatment duration was 216 ± 80 weeks (range 32–320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; P &lt; 0.05). No differences were found in rilpivirine (160 ± 118 versus 189 ± 81 ng/mL; P = 0.430) and cabotegravir (1758 ± 807 versus 1969 ± 802 ng/mL; P = 0.416) trough concentrations in males (n = 55) versus females (n = 12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index &gt;30 kg/m2 (n = 9) versus non-obese participants (1916 ± 905 versus 1606 ± 576 ng/mL; P = 0.131). Three out of the 67 PWH had at least one drug concentration &lt;4×PA-IC90: 100% of PWH had undetectable HIV viral load.

Conclusions
At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.
Age-Related Differences in Neutralizing Antibody Responses against SARS-CoV-2 Delta and Omicron Variants in 151 SARS-CoV-2-Naïve Metropolitan Residents Boosted with BNT162b2
Authors: Lee Beomki , Bae Go Eun , Jeong In Hwa , Kim Jong-Hun , Kwon Min-Jung , Kim Jayoung , Kim Byoungguk , Lee June-Woo , Nam Jeong-Hyun , Huh Hee Jin , Kang Eun-Suk 
Published: March 2024

Abstract

Background
Although age negatively correlates with vaccine-induced immune responses, whether the vaccine-induced neutralizing effect against variants of concern (VOCs) substantially differs across age remains relatively poorly explored. In addition, the utility of commercial binding assays developed with the wild-type SARS-CoV-2 for predicting the neutralizing effect against VOCs should be revalidated.

Methods
We analyzed 151 triple-vaccinated SARS-CoV-2-naïve individuals boosted with BNT162b2 (Pfizer-BioNTech). The study population was divided into young adults (age &lt; 30), middle-aged adults (30 ≤ age &lt; 60), and older adults (age ≥ 60). The plaque reduction neutralization test (PRNT) titers against Delta (B.1.617.2) and Omicron (B.1.1.529) variants were compared across age. Antibody titers measured with commercial binding assays were compared with PRNT titers.

Results
Age-related decline in neutralizing titers was observed for both Delta and Omicron variants. Neutralizing titers for Omicron were lower than those against Delta in all ages. The multiple linear regression model demonstrated that duration from third dose to sample collection and vaccine types were also significant factors affecting vaccine-induced immunity along with age. The correlation between commercial binding assays and PRNT was acceptable for all age groups with the Delta variant, but relatively poor for middle-aged and older adults with the Omicron variant due to low titers.

Conclusions
This study provides insights into the age-related dynamics of vaccine-induced immunity against SARS-CoV-2 VOCs, corroborating the need for age-specific vaccination strategies in the endemic era where new variants continue to evolve. Moreover, commercial binding assays should be used cautiously when estimating neutralizing titers against VOCs, particularly Omicron.
A Stochastic Production Frontier Analysis of Factors That Affect Productivity and Efficiency of Logging Businesses in Virginia
Authors: Sartori Pedro J , Schons Stella Z , Barrett Scott 
Published: March 2024

Abstract
Understanding the effect of the relationship between timber harvesting attributes on loggers’ productivity and efficiency is crucial for the feasibility and expansion of sustainable forest management and logging. We applied a stochastic production frontier model to firm-level operational data collected from 202 loggers in Virginia, United States, in 2019. Logging equipment value, physiographic region, tract area, number of workers and crews in the woods, college education level, and harvest type statistically increase harvesting productivity. Harvesting productivity in the Coastal Plain was the greatest of all physiographic regions, and pine clearcut productivity was statistically greater than that of hardwood thinning. On the other hand, manual felling reduces harvesting productivity. We found an average efficiency rate of 67% among firms in our sample, which is similar to that found in the literature. The estimated values can show factors that improve forest harvest productivity through better planning and investments while improving the sustainable use of inputs and resources.
Study Implications: We empirically analyzed factors affecting logging productivity and efficiency in the southern US state of Virginia. Increased productivity was associated with working in the Coastal Plain physiographic region, investing in logging equipment, increasing the number of workers and crews in the woods, increasing pine clearcut as opposed to hardwood thinning, choosing optimal harvesting tract size, and having a college education as opposed to no high school degree. Manual felling reduces harvesting productivity, and average BMP implementation time does not affect harvesting productivity. Our results can be used as a guide in planning future decisions to increase logging productivity.
Effects and driving factors of domestic sewage from different sources on nitrous oxide emissions in a bog
Authors: Li Yue , Chen Zhongbing , Wang Xue , Jiang Haibo , He Chunguang , Shi Yao , Sheng Lianxi 
Published: March 2024

Abstract
Direct sewage discharge may enhance soil nitrous oxide (N2O) emissions, worsening the greenhouse effect. However, the effects of sewage discharge into bogs on N2O flux, drivers and influencing mechanisms remain unclear. Additionally, investigating the impact of reclaimed water on N2O flux is important for bog replenishment and water shortage alleviation. This study simulated sewage from different sources into a bog and analyzed N2O fluxes, soil (organic carbon, total nitrogen, ammonium nitrogen, nitrate nitrogen, total phosphorus, available phosphorus, pH and electrical conductivity), plant (species richness and biomass) and microorganisms (ammonia-oxidizing archaea, napA, nirS, nirK and nosZ genes). Results showed that the reclaimed water did not significantly change N2O flux, while 50% tap water mixed with 50% domestic sewage and domestic sewage significantly increased the N2O flux. Among soil factors, available nitrogen and pH were key in influencing N2O flux. Among plant parameters, species richness was the primary factor affecting N2O flux. Nitrogen transformation functional genes contributed the most to the increase in the N2O fluxes, with an increase in domestic sewage input leading to a higher abundance of these genes and subsequent N2O emissions. Therefore, domestic sewage should be considered, as it significantly increases N2O emissions by affecting the soil, plants and microorganisms, thereby increasing the global warming potential. This study’s findings suggest that using treated reclaimed water for bog replenishment could be an environmentally friendly approach to wetland management.
Effects of the conversion of natural tropical rainforest to monoculture rubber plantations on soil hydrological processes
Authors: Chen Qiaoyan , Fu Ruiyu , Cheng Siyuan , Qiao Dong , Hu Zhongmin , Zhang Zijia , Dai Licong 
Published: March 2024

AbstractRubber plantations have increased significantly under unprecedented economic growth in tropical areas, which leads to soil degradation and thereby alters soil hydrological processes. However, our understanding of how forest conversion affects soil hydrological processes remains unclear. Here, we collected soil samples from secondary forests (SF) and rubber plantations (RP) to determine the soil hydrological characteristics. We found the topsoil (0–20 cm) water retention in SF was higher than that of RP but displayed the contrast pattern in a deeper soil layer (20–60 cm). Meanwhile, the soil infiltration rates among the two vegetation types decreased significantly with infiltration time, with higher stable soil infiltration rates in SF than those in RP. Moreover, soil properties were also impacted by the forest conversion, such as the topsoil capillary porosity (CP) and total porosity (TP) in SF were higher than those of RP but contrasted in a deep soil layer. In comparison, the topsoil bulk density (BD) in SF was lower than that of RP, but contrasted in the deep soil layer and reached a significant level in the 0–10 and 40–50 cm (P &lt; 0.05). Overall, the soil water retention was mainly determined by the CP, which could explain 31.56% of the total variance in soil water retention, followed by TP (26.57%) and soil BD (26.47%), whereas soil texture exerts a weak effect on soil water retention. Therefore, we can conclude that the conversion of tropical rainforest into rubber plantations may accelerate soil erosion owing to its lower topsoil water retention and soil infiltration rates.
Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer
Authors: Xu Yingqi , Ji Hao , Zhang Yidan , Xiong Liwen , Han Baohui , Zhong Hua , Xu Jianlin , Zhong Runbo 
Published: March 2024

Abstract

Background
The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC).

Patients and Methods
The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety.

Results
A total of 74 631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments.

Conclusion
Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.
Architected materials for artificial reefs to increase storm energy dissipation
Authors: Ronglan Edvard , Rubio Alfonso Parra , da Silva Alexis Oliveira , Fan Dixia , Gair Jeffrey L , Stathatou Patritsia Maria , Bastidas Carolina , Strand Erik , Ferrandis Jose del Aguila , Gershenfeld Neil , Triantafyllou Michael S 
Published: March 2024

Abstract
Increasing extreme weather events require a corresponding increase in coastal protection. We show that architected materials, which have macroscopic properties that differ from those of their constituent components, can increase wave energy dissipation by more than an order of magnitude over both natural and existing artificial reefs, while providing a biocompatible environment. We present a search that optimized their design through proper hydrodynamic modeling and experimental testing, validated their performance, and characterized sustainable materials for their construction.