bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating Geochemistry with Other Reservoir Diagnostic Tools – Implications for Infill Planning and Development in the Midland Basin
Authors: Famubode Oyebode , Acosta Nelson , Bachleda Jana , Silva Cristhian , Gallegos Dana , Gomez Beatriz , Jin Muqing , Ge Shuangyu , Lv Tao
Published: December 2023

This study examined parent-child well interaction in three stacked producing formations in an unconventional field in the Midland Basin. By combining geochemical fingerprinting to determine which formations were being drained along with pressure interference analysis, microseismic data, petrophysical data, and production results, we identified important trends that may affect landing and spacing decisions in future infill drilling and multi-bench development plans.

This paper describes a new workflow for integrating lithology, Oil-in-Place Index (OIPI), Rock Quality Index (RQI), and microseismic data to measure the influence of the parent wells on the child wells and the vertical drainage patterns of all the horizontal wells in the study area. Understanding these interactions and drainage volumes may lead to better field development planning and aid in decision making on the viability of field development projects.
Drilling and Well Construction in Lean Clearances in Northern Region of Pakistan
Authors: Iftikhar Ali , Nasrumminallah Muhammad , Rasheed Hassaan , Sabir Shahid Majeed , Sharif Yasir
Published: December 2023

Subject well is an exploratory well with a target depth of +/- 6000M, in one of the most challenging northern region of Pakistan. Well has multiple challenges with regards to drilling and well construction the least to mention are losses, borehole instability, intercalated formations, with steep dips along with a fault. Lean clearances in a five Casing Strings well construction were a requirement to isolate the problematic zones for safe drilling, this included running of longest 16" Liner for the first time in Pakistan, borehole enlargement of 14 3/4" to 16", later on running of 13 5/8" Flush x 13 3/8" coupled connection casing with narrow annular clearance, with customized Cementing Job to avoid surging.

Running of 16" liner, drilling and construction of next section called for robust technical applications that includes drilling with aerated mud, running of 16" Liner with liner hanger for the first time in Pakistan, borehole enlargement while overcoming the various challenges as various formations (limestone, Sandstones, Clays) were drilled and later enlarged using hydraulic Under Reamer. Fit for purpose mud was used while drilling and further optimized to solid free for the smooth running of 13 5/8" × 13 3/8" Casing through lean clearance of 16" Liner. Casing running strategy has been devised to avoid Surge to formation at the same time ensuring it gets to bottom without any held up. The objectives of the section were met successfully. The paper will serve as a platform for other Operating companies in Pakistan to benefit from the lessons learnt and best drilling practices
Step-Change in Cement Design Assures Well Integrity Under Dynamic Stress
Authors: Mahmood Ahmad A. , Jan Usman A. , Khan Anum Y. , Rasheed Hassaan , Salazar Jose , Shah Khurram A. , Khan Shahjahan
Published: December 2023

The Kohat Plateau in Pakistan features major Gas and Condensate producing fields with majority of the blocks owned and operated by two of the country's biggest E&P Operators. Operators are known to frequently encounter severe drilling challenges, and over time, have devised certain technology solutions that have helped curtail the major drilling challenges to a good extent, helping improve the time and cost expended in reaching the target depths. However, the problems arising after the Drilling cycle – foremost being Sustained Casing Pressure (SCP) – require expensive remedial treatments and loss of production; this paper presents a solution to this particular challenge of SCP including in-depth cause analysis, treatment design and implementation.

In the analysis stage, the drilling data of wells experiencing SCP in one of the Casing annuli was reviewed to pinpoint possible areas of compromised well integrity. It was observed that sections having good Cement bonds and sufficient Top of Cement in the annulus also became compromised over time, indicating operations conducted after the drilling phase could be responsible for the annular fluid migration, and hence SCP. It must be noted that extensive drill-stem tests to assess the reservoir economics as well as production pressures generate significant dynamic stress on the well structure. Through the use of custom stress-analysis software for annular Cement, it was concluded that it is this stress that causes the primary isolation of the constructed well, the annular Cement, to fail allowing annular migration of formation fluids. A new class of stress-resistant, auto-repair Cements was seen to resist any mechanical failure under stress enabling Operators to drill wells with lasting structural integrity. Mechanical properties including Young's Modulus, Poisson Ratio and Annular Expansion co-efficient were analyzed to design a Cement system capable of withstanding the applied stress. The first in-country application was conducted as the Intermediate-section Cementing in a new well. The system exhibited good isolation with average 10mV amplitude (free pipe amplitude 51 mV) in Cased Hole bond logs and no annular pressure is observed till date in the section more than 02 years after the primary cementing operation.

This design approach was subsequently extended to other fields, with successful applications that reduced, and in certain cases, eliminated the need for remedial work. By presenting a detailed field application of flexible and self-healing Cement, the paper puts forth a general, stepwise approach for the selection of a Cement design that promises lasting annular isolation and minimizes the risk of communication behind the casing.
Comparative Analysis of Well Deliverabilities Through Different Perforation Strategies in a Mature Field, Deployment of Completion Conveyed Underbalance Perforation – A Case Study
Authors: Ansari Mansoor , Ijaz Muhammad , Ali Anjum Zulfiqar , Inam Sahir , ul Hussnain Muhammad Sana , Ullah Rafi , Shafee Imran , Zia Faisal , Atiq Ibtihaj
Published: December 2023

Wellbore deliverability impairment caused during drilling, testing, and completion operations remains an inevitable operational challenge. The TCP Shoot and Pull perforation method is widely deployed in the country; however, the requirement of kill cycle afterward ultimately hinders the perforation performance. On the other hand, underbalance perforations post well completion presents their challenges with limited IDs, compromised penetration (smaller gun size), and most importantly; maintaining underbalance in subsequent perforation runs. Therefore, the Operational Best Practices developed throughout the years needs to be tailored as per individual well requirement.

The performance of the existing perforation methodology of TCP Shoot & Pull (Overbalanced) and Thru-Tubing (Underbalanced / Balanced) were evaluated for recently completed wells in a mature gas field. The well test interpretation indicated near wellbore damage in wells completed overbalance across the sandstone formation, significantly affecting the deliverability of the wells.

Unlike most carbonates, Acid Stimulation is not readily adopted for clastic formations due to its associated risks, therefore, it becomes quintessential to identify suitable perforation techniques to improve well deliverability. Completion Conveyed Perforation guns were successfully deployed at the newly drilled development well, which showed significant improvement in the well's deliverability compared to the existing methods of perforation.

This paper presents the successful application of Completion Conveyed Underbalance Perforations (CCUP) in development wells along with well performance improvement compared to previous strategies. The CCUP technique was risk assessed and selected for the new development wells in a mature gas field. The 4-1/2" casing guns were conveyed with a drop-sub assembly in the permanent packer tail. Following well completion operation, underbalance was induced in the wellbore. The guns were successfully activated and dropped in rat-hole through Slickline.
Engineered Ultra-Low Invasion Loss Control Solution Allows Circulation, Ensuring Cement Placement and Zonal Isolation in Liner Cementing Jobs and Through Coiled Tubing – Case Studies
Authors: Fazal Muhammad Adnan , Ahmad Syed Hamza , Yousuf Arif , Rehman Aziz ur , Noor Sameer Mustafa , Nazir Irfan
Published: December 2023

The conventional loss cure techniques are largely reactive and include addition of coarse grade particle, fibrous material and other viscous pills that are lost into formation during loss cure attempts. Being highly invasive, these loss cure solutions block pore throats and line producing fractures causing considerable formation damage and loss of net asset value. Moreover, these techniques pose additional challenges while placing thru slim liners and coiled tubing (in rigless applications) due to elevated risk of getting the circulation ports plugged. Moreover, during the era of technological revolution and decarbonization, an effective and efficient solution aids to promote the practices producing low carbon emission. The proactive wellbore shielding loss cure is a particle size distribution-based LCM solution having excellent fluid loss properties and exhibiting low permeability barrier at the fluid-rock interface. The low permeable shielding effect offers less invasion across a broad range of pores (1microns to 4,000microns) and thereby protecting formation from any permanent impairment. The solution covers the wide range applications of loss cure throughout well life ensuring zonal isolation and saving significant rig time. Customized particle size distribution does allow LCM solution to be pumpable thru liner complying the allowable particle sizes (less than 1,000microns) and concentrations (upto 18 lbs/bbl) and for coiled tubing specialized applications with allowable particles size of 100 microns while maintaining rheological properties (Fluid Loss<50 ml/30 min, 5lbs/100ft2>Ty<10lbs/100ft2 & PV<90 cp).

This paper demonstrates the working principle and practical applications of engineered solution for loss cure and successfully achieving zonal isolation in 7" liner being placed as pre-cement spacer in naturally fractured formation. The wellbore shielding pre-cement spacer ensured the cement rise above loss point thus achieving zonal isolation in partial to complete losses environment and helps in minimizing formation's impairment. The same approach was adopted to cure losses in rigless with coiled tubing in both carbonate and sandstone reservoirs for well killing and zonal isolation without plugging the CT BHA and circulation ports while complying design requirements.
5-Aza-4’-thio-2’-deoxycytidine induces C>G transversions in a specific trinucleotide context and leads to acute lymphoid leukemia
Authors: Aplan Peter , Bertoli Ryan , Chung Yang Jo , Difilippantonio Michael , Wokasch Anthony , Marasco Madison , Klimaszewski Haley , Garber Susannah , Zhu Yuelin , Walker Robert , Cao Dengchao , Doroshow James , Meltzer Paul
Published: December 2023

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that are used clinically to decrease 5’-cytosine methylation, with the aim of re-expression of tumor suppressor genes. We used a murine pre-clinical model of myelodysplastic syndrome based on transplantation of cells expressing a NUP98::HOXD13 transgene to investigate 5-Aza-4’-thio-2’-deoxycytidine (Aza TdCyd or ATC), a thiol substituted DNMTi, as a potential therapy. We found that ATC treatment led to lymphoid leukemia in wild-type recipient cells; further study revealed that healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C > G transversions in a previously unrecognized, specific 5’-NCG-3’ context. These mutations involved dozens of genes well-known to be involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Treatment of human cells in vitro showed thousands of acquired C > G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C > G transversions. Taken together, these findings demonstrate that DNMTi can be potent mutagens in human and mouse cells, both in vitro and in vivo.
Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket
Authors: García-Nafría Javier , Arroyo-Urea Sandra , Nazarova Antonina , Carrión-Antolí Ángela , Bonifazi Alessandro , Battiti Francisco , Lam Jordy , Newman Amy , Katritch Vsevolod
Published: December 2023

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R coupled to a Go heterotrimer and bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide new insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
Shea tree agroforestry systems in Northern Ghana: Population structure, management of trees and impact of canopy microclimate
Authors: Jepsen Thea , Stopponi Gaia , Jørgensen Niels O. G.
Published: December 2023

The shea tree (Vitellaria paradoxa) is an important tree species in agroforestry systems and bushlands in West Africa and shea nuts are a fundamental resource for rural livelihoods. In this study, sustainability and interactions in agroforestry systems of shea trees were investigated around the Nakpalli village in Northern Ghana. Focus of the study was structure and density of shea tree populations, below-canopy microclimate and co-cultivation of yams (Dioscorea rotundata) under shea tree canopies, and water stress of the trees in the driest season. Shea tree populations are well conserved in this area, but Weibull-distributions of the tree populations and quantification of seedlings showed a lower tree density, especially of seedlings and small trees, in agroforestry fields and fallows, as compared to uncultivated bushlands. This indicates that intensified agroforestry practices might negatively affect the regeneration of shea populations and their long-term regeneration in these agroforestry systems. Co-cultivation of yams in shea canopies allowed production of 11.5 t/ha as compared to 20.8 kg/ha at open field conditions. The lower production may have been caused by an almost 74% reduction of photosynthetically active radiation below canopies, relative to outside the canopies. Shea trees in fields, fallows and bushlands had high predawn leaf water potentials, indicating a low water stress, even in the middle of the dry season. The thriving of shea in the area underlines the importance of conserving this well-adapted indigenous tree in the agroforestry systems and avoiding removal, e.g., by mechanical soil preparation and negative impacts from future climate extremes.
Apoplastic pH determines the hypocotyl response to auxin dosage and light
Authors: Wei Ning , Wang Jiajun , Jin Dan , Deng Zhaoguo , Song Zihao , Zheng Lidan , Zeng Haiyue , Kinoshita Toshinori , Liao Zhihua , Chen Haodong , Deng Xingwang
Published: December 2023

The phytohormone auxin and light both regulate plant elongation growth. Light suppresses hypocotyl elongation, whereas auxin promotes it. However, auxin can reverse its effect and inhibit elongation when applied to etiolated seedlings or in high dosages. How dosages or light conditions change the effect of auxin on hypocotyl growth has long been mysterious. We found that, regardless of the dosage, more auxin induces more transcription of SAURs (Small Auxin-Up RNAs), leading to a stronger activation of plasma membrane proton pump H+-ATPases (AHAs), and consequently, progressive acidification of the apoplast in hypocotyls. Apoplastic acidification promotes growth, but when the pH drops below a threshold, further acidification inhibits elongation. The short hypocotyl phenotype caused by auxin overdosage can be alleviated by inactivating the AHA activity. Light irradiation downregulates SAUR levels and decreases AHA activity in the hypocotyl. Light-grown hypocotyls exhibit a higher apoplastic pH, which impedes cell elongation and counteracts auxin induced over-acidification. Our findings indicate that the biphasic effect of auxin results from the biphasic response of cell elongation to decreasing apoplastic pH. Auxin and light antagonistically regulate the SAUR-PP2C.D-AHA pathway, eventually achieving the apoplastic pH appropriate for the hypocotyl growth of the given environment.
The peculiar precursor of a gamma-ray burst from a binary merger involving a magnetar
Authors: Xiong Shaolin , Xiao Shuo , Zhang Yan-Qiu , Zhu Zi-Pei , Gao He , Xu Dong , Zhang Shuang-Nan , Peng Wenxi , Li X.B. , Zhang Peng , Lu Fangjun , Lin Lin , Liu Liang-Duan , Zhang Zhen , Ge Mingyu , Tuo Y.L. , Xue Wang-Chen , Fu Shao-Yu , Liu Xing , Liu Jin-Zhong , Li An , Wang Tian-Cong , Zheng Chao , Wang Yue , Jiang Shuai-Qing , Li Jin-Da , Liu Jia-Cong , Cao Zhou-Jian , Luo Xi-Hong , Yang Jiao-Jiao , Yi Shu-Xu , Wang Xi-Lu , Cai C. , Yi Q.B. , Zhao Yi , Xie Sheng-Lun , Li C.K. , Luo Qi , Liao Jin-Yuan , Song Liming , Zhang Shu , Qu J.L. , Liu C.Z. , Li Xu-Fang , Xu Y.P. , Li Tipei
Published: December 2023

The milestone discovery of GW 170817-GRB 170817A-AT 2017gfo1 has shown that gravitational wave (GW) could be produced during the merger of neutron star-neutron star/black hole and that in electromagnetic (EM) wave a gamma-ray burst (GRB) and a kilonova (KN) are generated in sequence after the merger. Observationally, however, EM property before the merger phase is still unclear. Here we report a peculiar precursor in a KN-associated long-duration GRB 211211A, providing evidence of the EM before the merger. This precursor lasts ∼ 0.2 s, and the waiting time between the precursor and the main burst is ∼ 1 s, comparable to that between GW 170817 and GRB 170817A. The spectrum of the precursor could be well fit with a non-thermal cutoff power-law (CPL) model instead of a blackbody. Especially, an Quasi-Periodic Oscillation (QPO) with frequency of ∼22 Hz is most likely detected in the precursor. These temporal and spectral properties indicate that this precursor is probably produced by a catastrophic flare accompanying with magnetoelastic or crustal oscillations of a magnetar in binary compact merger2. The strong magnetic field of the magnetar can also account for the prolonged duration of GRB 211211A. However, it poses a challenge to reconcile the rather short lifetime of a magnetar3 with the rather long spiraling time of a binary neutron star system only by the GW radiation before merger.
The potential of hydrolates for use in the production of alfalfa micro sprouts: sanitizers and flavour enhancers
Authors: Acimovic Milica , Samardžić Nataša , Šovljanski Olja , Lončar Biljana , Jeremić Jovana Stanković , Pezo Lato , Konstantinović Bojan , Vasiljević Sanja
Published: December 2023

Sprouted seeds and microgreens are emerging as innovative specialty raw salad crops, valued for their health-promoting properties. However, the risk of foodborne illnesses associated with microbial contamination in microgreens underscores the need for effective sanitization in their production. This study explores using hydrolates, by-products of essential oil distillation from six plants, as natural sanitizers in alfalfa microgreen production. The research investigates their impact on seed germination, antimicrobial activity, and sensory attributes. Results revealed that oregano, fennel, lavender, and lemon catmint hydrolates decrease alfalfa seed germination, while peppermint and hop hydrolates have no significant impact. Peppermint and fennel hydrolates demonstrate notable efficacy in antimicrobial testing. Sensory analysis indicates differences in odour and flavour, with peppermint, oregano, and lavender receiving high scores. According to the results, peppermint hydrolate can be considered a favourable option for alfalfa micro sprout production, contributing to sustainable and organic approaches in urban agriculture and underlining the importance of natural sanitizers for food safety.
Assembly and comparative analysis of the complete mitochondrial genome of Saussurea inversa (Asteraceae)
Authors: Dai Wubin , Ju Xiuting , Shi Guomin , He Tao
Published: December 2023

Saussurea inversa is a perennial herb used in traditional Chinese medicine and is effective against rheumatoid arthritis. In this study, we sequenced the complete mitochondrial(mt) genome of S. inversa (GenBank accession number: ON584565.1). The circular mt genome of S. inversa was 335,372 bp in length, containing 62 genes, including 33 mRNAs, 22 tRNAs, six rRNAs, and one pseudo-gene, with 1,626 open reading frames. The GC content was 45.14%. Predictive analysis of substantial RNA-editing of its presence found that the most abundant RNA editing is ccmFn, with 36. Gene migration was observed to occur between the mt and chloroplast(cp) genomes of S. inversa via the detection of homologous gene fragments. Phylogenetic analysis revealed that S. inversa was clustered with Arctium tomentosum (Asteraceae). Our findings provide extensive information regarding the mt genome of S. inversa and help lay the foundation for future studies on the genetic variations, phylogeny, and breeding of S. inversa via an analysis of the mt genome.
Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration
Authors: Weiner Louis , Fitzgerald Allison , Maynard Rachael , Marcisak Emily , Nasir Apsra , Glasgow Eric , Jablonski Sandra , Veken Pieter Van Der , Pearson Gray , Eisman Shira , Mace Emily , Fertig Elana
Published: December 2023

Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novel in vivo zebrafish and in vitro 3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors.
An archaeal chromatin protein condenses DNA through bridging-induced phase separation
Authors: Zhang Zhenfeng , Ding Niannian , Wang Mengxue , Li Haodun , Sun Fei , Chen Yuanyuan , Yang Yunfeng , Zhang Yi , Huang Junkai , Dai Xin , Shen Yulong , Fu Yu , Huang Li
Published: December 2023

Phase separation serves an important role in the three-dimensional chromosome organization and remodeling in eukaryotes. Whether this process is involved in archaeal chromosome organization is unknown. Here we demonstrate that archaeal DNA condensing protein1 (aDCP1) from the hyperthermophilic crenarchaeon Sulfolobus islandicus is able to bridge DNA efficiently and form large protein-DNA condensates with a droplet- or gel-like morphology in vitro. Within the condensates, aDCP1 exhibits a fast dynamic while the DNA appears in a solid-like state. At the single-molecule level, aDCP1 efficiently compacts DNA through a three-step mechanism, which presumably entails the clustering of aDCP1 on the DNA and the subsequent fusion of the clusters. Deletion of the aDCP1 gene results in noticeable changes in chromosome conformation in S. islandicus, which are characterized by enhanced interactions between the A and B compartments and reduced interactions within the self-interacting domains as well as between domains in the same compartment. Taken together, our results indicate that aDCP1 is capable of inducing DNA bridging-induced phase separation and serves a role in chromosome organization in the organism.
Sex differences in mitochondrial gene expression during viral myocarditis
Authors: Florio Damian Di , Gorelov David , McCabe Elizabeth , Beetler Danielle , Shapiro Katie , Bruno Katelyn , Chekuri Isha , Jain Angita , Whelan Emily , Salomon Gary , Khatib Sami , Bonvie-Hill Natalie , Giresi Presley , Balamurugan Varsini , Weigel Gabriel , Fliess Jessica , Darakjian Ashley , Edenfield Brandy , Kocsis Christian , McLeod Christopher , Cooper Leslie , Audet-Walsh Etienne , Coronado Michael , Sin Jon , Fairweather DeLisa
Published: December 2023

Background
Myocarditis is an inflammation of the heart muscle most often caused by an immune response to viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood.
Methods
Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis to understand sex differences in the transcriptional landscape of myocarditis and identify candidate transcription factors that might drive sex differences in myocarditis.
Results
The hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. When comparing females to males with myocarditis, males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial transcriptional support (e.g., mitochondrial electron transport genes). In contrast, females were enriched for pathways related to mitochondrial respiration and bioenergetics, which were confirmed by higher transcript levels of master regulators of mitochondrial function including peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), nuclear respiratory factor 1 (NRF1) and estrogen-related receptor alpha (ERRα). TRANSFAC analysis identified ERRa as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis.
Conclusions
Master regulators of mitochondrial function were elevated in females with myocarditis compared to males and may promote sex differences in mitochondrial respiratory transcript expression during viral myocarditis resulting in less severe myocarditis in females following viral infection.
Increase of prostate specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing [223Ra]RaCl2 therapy
Authors: Lu Hsi-Huei , Chiu Nan-Tsing , Tsai Mu-Hung
Published: December 2023

Background
[223Ra]RaCl2 is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during the course of treatment. We retrospectively collected data from mCRPC patients who underwent [223Ra]RaCl2 treatment at our institution between August 2020 and June 2023. Prostate specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to [223Ra]RaCl2 treatment; interim PSADT was calculated from PSA measurements before [223Ra]RaCl2 treatment and prior to the 4th course injection. Overall survival was calculated from start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival.
Results
We included 35 patients from our institution, with a median overall survival of 13.3 months. Eighteen (51.4%) completed all six courses of treatment. PSADT response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSADT response (HR = 0.318, 95% CI 0.133–0.762, p = 0.010) when compared to patients without a PSADT response.
Conclusions
Dynamic changes in PSADT were associated with survival in mCRPC patients receiving [223Ra]RaCl2 therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefit.
Tracing the Invisible Mutant ADNP protein in Helsmoortel- Van der Aa Syndrome patients
Authors: D'Incal Claudio Peter , Cappuyns Elisa , Choukri Kaoutar , De Man Kevin , Szrama Kristy , Konings Anthony , Bastini Lina , Gabriele Michele , Rizzuti Ludovico , Vitriolo Alessandro , Testa Giuseppe , Mohn Fabio , Bühler Marc , Aa Nathalie Van der , Dijck Anke Van , Kooy R. Frank , Berghe Wim Vanden
Published: December 2023

Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines, showing disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detectnative mutant ADNP protein,whereas alternative experimental protein enrichment strategies such as co-immunoprecipitation and mass spectrometry also depend on appropriately characterized antibodies that are not currently available. This study aims to shape awareness for critical assessment of ADNP mutant protein analysis in Helsmoortel-Van der Aa syndrome.
VEXAS Syndrome: Complete molecular remission after hypomethylating therapy
Authors: Sockel Katja , Goetze Katharina , Ganster Christina , Bill Marius , Georgi Julia-Annabell , Balaian Ekaterina , Aringer Martin , Trautmann Karolin , Uhlig Maria , Bornhäuser Martin , Haase Detlef , Thiede Christian
Published: December 2023

The Vexas syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While various therapeutic strategies have been explored in case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation is considered the only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of the underlying UBA1 mutant clone outside the context of allogeneic HCT. Both patients received treatment with the hypomethylating agent Azacitidine, and deep molecular remission triggered treatment de-escalation and even cessation with sustained molecular remission in one of them. Prospective studies are necessary to clarify which VEXAS patients will benefit most from hypomethylating therapy and to understand the variability in the response to different treatment strategies.
The effect of lining hydraulic properties on the efficiency and cost of irrigation canal reconstruction
Authors: Zelenakova Martina , Zeleňáková Martina , Arifjanov Aybek , Abd-Elhamid Hany F. , Gergeľová Marcela Bindzárová , Fatxulloyev Alisher , Allayorov Davronjon
Published: December 2023

Irrigation canals play an important role in the economic development of Uzbekistan which is located in arid zone and shared user of transboundary water resources. Almost three fourth of the irrigation network in Uzbekistan is unlined that subject to some natural processes such as vegetation, erosion, sedimentation, and seepage. The efficiency of the irrigation networks in Uzbekistan is about 63%. Lining of canals is the major protection measure against water scarcity for Uzbekistan. This study aims to investigate how the hydraulic properties of different lining materials such as geomembrane, concrete, asphalt, sand mixed bentonite and stone pitching affect the rehabilitation cost of canals. In this study, field data and hydrodynamic model HEC-RAC are used for analysis of using different lining materials on the efficiency of the canal and then the costs of rehabilitation were compared. To apply the hydrodynamic model HEC-RAS, flow and bathymetric parameters were measured by employing the acoustic Doppler current profiler system for a reach of length 1.0 km in Tashkent magistral canal. The obtained R2 between modeled and measured data equals to 0.86. The use of different lining materials such as geomembrane, concrete, asphalt, sand mixed bentonite and stone pitching affect the channel geometry with different ranges from 21.69 to 34.41 per running meter (RMT). With different cross-sectional values, rehabilitation of the first reach of Toshkent magistral canal costs about $ 260, 688, 536, 286, 210 thousand respectively. In the point of lifetime, geomembrane then concrete, and stone pitching showed the minimum annual coverage value containing $32, 46, 10 thousand per year respectively. Stone pitching with the longest durability is the most efficient technique to improve water-use efficiency of Toshkent magistral canal. This study could help the policy makers to select the best material for lining based on the lifetime, cost and durability.
Selection of Track Form in Railway Tunnel from a Life Cycle Analysis Perspective
Authors: Prokopov Andrej , Aava Birgitta Olsson , Famurewa Stephen Mayowa , Rantatalo Matti
Published: December 2023

The use of greenhouse gas emissions as a criterion for decision-making within the rail industry is increasing. The demand for the consideration of this criterion affects the type of decision models acceptable by railway infrastructure managers in the planning, construction, and maintenance of railway assets. The total amount of greenhouse gas emitted from a track solution in tunnels during its service life depends on the track form (i.e., ballasted track or the ballastless track), the type of construction, maintenance machines used, the current traffic profile, and the length of the tunnel. However, the development in the design of ballastless track systems during recent decades to make them environmentally friendly is a motivation for infrastructure managers to rethink and consider the use of the system. This paper addresses the effect of applying the optimized ballastless track system Rheda 2000® in a railway tunnel (the Hallsberg-Stenkumla tunnel) as part of a new line project in Sweden. The greenhouse gas emissions, represented by life cycle CO2 equivalent emission is calculated using the climate impact software developed by the Swedish Transport Administration Trafikverket. The result is compared with the estimated emission from the conventional ballasted tracks. The study shows that CO2 equivalent emissions by a ballastless track during its life cycle is 10% lower than that of the ballasted track. The primary total emission driver for both track form solutions is the emissions generated at the manufacturing of rails. The second important emission factor for the ballasted track solution is the emission from the renewal of the track form during its life cycle. The second important emission factor for the ballastless track solution is concrete manufacturing. The model applied in the study is an integral part of an integrated decision support system for effectively selecting track solutions from a lifecycle perspective.
Factors Associated With the Dietary Patterns of Brazilian Adolescents: Analysis of the 2019 National School Health Survey
Authors: Silva Alanna Gomes da , Silva Thales Philipe Rodrigues da , Malta Deborah Carvalho
Published: December 2023

Background
during adolescence there are physical, psychic, and social changes that influence feeding behaviors and lifestyle, which can contribute to the development of several diseases, including obesity. This study aimed to identify the food consumption patterns of Brazilian adolescents and to verify their associated factors.
Methods
Cross-sectional study with data from the 2019 National School Health Survey (PeNSE). Students aged 13 to 17 participated in the survey, totaling a sample of 125,123 adolescents. Principal component analysis was used to identify the feeding behavior patterns. To evaluate the association, logistic regression was used, estimated by the Odds Ratio, with the respective 95% confidence intervals.
Results
Two main components were identified, the first related to a healthy food consumption pattern (regular consumption of fruits, vegetables, and beans) and the second to a mixed pattern (non-regular consumption of sweets, soft drinks, and food from snack bars). As for the associated factors, the adolescents most likely to belong to component 1 lived in the Midwest and Southeast regions, their mothers had higher education, and they had healthier lifestyle habits. Adolescents who belonged to component 2, on the other hand, were positively associated with being male, aged 16 and 17, studying in public schools, not consuming alcoholic beverages, and not being sedentary.
Conclusions
This study evidenced the formation of two food consumption patterns and both were associated with socioeconomic variables and healthy lifestyle habits. The identification of food consumption patterns among adolescents enables health surveillance and the strengthening of policies aimed at the school environment, with a view to reducing diseases and health problems.
Lentiviral mediated delivery of CRISPR/Cas9 reduces intraocular pressure in a mouse model of myocilin glaucoma
Authors: Patil Shruti V. , Kaipa Balasankara Reddy , Ranshing Sujata , Sundaresan Yogapriya , Millar J. Cameron , Nagarajan Bhavani , Kiehlbauch Charles , Zhang Qihong , Jain Ankur , Searby Charles C. , Scheetz Todd E. , Clark Abbot F. , Sheffield Val C. , Zode Gulab S.
Published: December 2023

Mutations in myocilin (MYOC) are the leading known genetic cause of primary open-angle glaucoma, responsible for about 4% of all cases. Mutations in MYOC cause a gain-of-function phenotype in which mutant myocilin accumulates in the endoplasmic reticulum (ER) leading to ER stress and trabecular meshwork (TM) cell death. Therefore, knocking out myocilin at the genome level is an ideal strategy to permanently cure the disease. We have previously utilized CRISPR/Cas9 genome editing successfully to target MYOC using adenovirus 5 (Ad5). However, Ad5 is not a suitable vector for clinical use. Here, we sought to determine the efficacy of adeno-associated viruses (AAVs) and lentiviruses (LVs) to target the TM. First, we examined the TM tropism of single-stranded (ss) and self-complimentary (sc) AAV serotypes as well as LV expressing GFP via intravitreal (IVT) and intracameral (IC) injections. We observed that LV_GFP expression was more specific to the TM injected via the IVT route. IC injections of Trp-mutant scAAV2 showed a prominent expression of GFP in the TM. However, robust GFP expression was also observed in the ciliary body and retina. We next constructed lentiviral particles expressing Cas9 and guide RNA (gRNA) targeting MYOC (crMYOC) and transduction of TM cells stably expressing mutant myocilin with LV_crMYOC significantly reduced myocilin accumulation and its associated chronic ER stress. A single IVT injection of LV_crMYOC in Tg-MYOCY437H mice decreased myocilin accumulation in TM and reduced elevated IOP significantly. Together, our data indicates, LV_crMYOC targets MYOC gene editing in TM and rescues a mouse model of myocilin-associated glaucoma.
AhR ligands from LGG metabolites promote piglet intestinal ILC3 activation and IL-22 secretion to inhibit PEDV infection
Authors: Wang Junhong , Zhao Yibo , Cui Tong , Bao Hongyu , Gao Ming , Cheng Mingyang , Sun Yu , Lu Yiyuan , Guan Jiayao , Zhang Di , Jiang Yanlong , Huang Haibin , Shi Chunwei , Wang Jianzhong , Wang Nan , Hu Jingtao , Yang Wentao , Yang Guilian , Zeng Yan , Wang Chunfeng , Cao Xin
Published: December 2023

In maintaining organismal homeostasis, gut immunity plays a crucial role. The coordination between the microbiota and the immune system through bidirectional interactions regulates the impact of microorganisms on the host. Our research focused on understanding the relationship between substantial changes in jejunal intestinal flora and metabolites and intestinal immunity during porcine epidemic diarrhea virus (PEDV) infection in piglets. We discovered that Lactobacillus rhamnosus GG (LGG) could effectively prevent PEDV infection in piglets. Further investigation revealed that LGG metabolites interact with type 3 innate lymphoid cells (ILC3) in the jejunum of piglets through the aryl hydrocarbon receptor (AhR). This interaction promotes the activation of ILC3 cells and the production of interleukin-22 (IL-22). Subsequently, IL-22 facilitates the proliferation of IPEC-J2 cells and activates the STAT3 signaling pathway, thereby preventing PEDV infection. Moreover, the AhR receptor exerts its influence on various cell types within organoids, including intestinal stem cells (ISCs), Paneth cells, and enterocytes, fostering their growth and development, suggesting a broad impact of AhR on intestinal health. In conclusion, our study demonstrates the ability of LGG to modulate intestinal immunity and effectively prevent PEDV infection in piglets. These findings highlight the potential application of LGG as a preventive measure against viral infections in livestock.
Reidentification of the causal agent and addition of new symptoms of black leaf blight in fig tree in Japan
Authors: Kikuhara Kenji , Inoue Kouji , Motohashi Kenichi
Published: December 2023

In August 2007, twig blight, branch canker, dieback, and fruit rot were observed in fig trees (cv. Toyomitsuhime) with black leaf blight in Japan. All isolates from each symptomatic part were identified as the fungi causing this disease. These symptoms were reproduced after inoculating their isolates; isolates were then reisolated. We demonstrated this fungus caused new symptoms. The isolates were re-evaluated based on morphological characteristics and phylogenetic analysis of concatenated rDNA-ITS, EF1-α, TUB2, and RPB2 partial sequences. They were phylogenetically classified as a new independent clade. We propose a new species of the fungus as Neofusicoccum ficicola.
Development of a nomogram to predict hemorrhage transformation after mechanical thrombectomy in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation
Authors: Li Yuanhao , Yang Dongliang , Li Jianhua , Xia Rui , Wen Chao , Yang Suosuo , Kang Jian , Li Yuling
Published: December 2023

Background: Hemorrhage transformation (HT) is one of the serious complications after mechanical thrombectomy (MT) in patients with acute ischemic stroke (AIS) and is associated with poor prognosis. The aim of this study was to develop a nomogram to predict the risk of post-MT HT in AIS patients.
Methods: AIS patients treated with MT between January 2020 and June 2022 were enrolled in this study. The enrolled patients were randomly divided into training and validation cohorts, in a 2:1 ratio. Lasso regression and machine learning algorithms were used for feature selection. Multivariate logistic analysis was applied to identify the optimal predictors. A nomogram was developed to predict the risk of post-MT HT. Performance of the nomogram was determined by its discrimination, calibration, and clinical usefulness.
Results:A total of 205 patients were enrolled in the study, with 145 in the training cohort and 60 in the validation cohort. The common risk factors revealed by Lasso regression and random forest algorithm were blood glucose on admission, CRP, NIHSS score, ASPECTS and CRP-to-albumin ratio. Multivariate logistic analysis showed that blood glucose on admission (Odds Ratio (OR)=5.61, 95%CI:1.86-20.83, P=0.004) and CRP (OR=73.52, 95%CI: 25.06-276.77, P<0.001) were independent predictors of post-MT HT. The nomogram was developed based on blood glucose on admission and CRP. Moreover, the proposed nomogram showed good discriminative ability with an area under the curve of 0.924 and 0.846 in the training and validation cohort, respectively. The calibration plot showed good concordance between nomogram prediction and actual observation. Decision curve analysis indicated that the nomogram had favorable clinical application benefits.
Conclusion: This study proposed a nomogram based on CRP and blood glucose on admission to predict the risk of post-MT HT in anterior AIS patients. The nomogram showed reliable predictive performance and can help clinicians identify patients at high risk of HT.