bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of human brain cancers using genomic and immune cell characterization of cerebrospinal fluid through CSF-BAM
Authors: Pearlman Alexander H. , Wang Yuxuan , Kalluri Anita , Parker Megan , Cohen Joshua D , Dudley Jonathan , Rincon-Torroella Jordina , Xia Yuanxuan , Gensler Ryan , Alfonzo Horwitz Melanie , Theodore John , Dobbyn Lisa , Popoli Maria , Ptak Janine , Silliman Natalie , Judge Kathy , Groves Mari , Jackson Christopher M. , Jackson Eric M. , Jallo George I. , Lim Michael , Luciano Mark , Mukherjee Debraj , Naidoo Jarushka , Rozati Sima , Sterling Cole H. , Weingart Jon , Koschmann Carl , Mansouri Alireza , Glantz Michael , Kamson David , Schreck Karisa C. , Pardo Carlos A. , Holdhoff Matthias , Paul Suman , Kinzler Kenneth W. , Papadopoulos Nickolas , Vogelstein Bert , Douville Christopher , Bettegowda Chetan 
Published: December 2024

AbstractPatients who have radiographically detectable lesions in their brain or other symptoms compatible with brain tumors pose challenges for diagnosis. The only definitive way to diagnose such patients is through brain biopsy, an obviously invasive and dangerous procedure. Here we present a new workflow termed “CSF-BAM” that simultaneously identifiesBcell or T cell receptor rearrangements,Aneuploidy, andMutationsusing PCR-mediated amplification of both strands of the DNA from CSF samples. We first describe the details of the molecular genetic assessments and then establish thresholds for positivity using training sets of libraries from patients with or without cancer. We then applied CSF-BAM to an independent set of 206 DNA samples from patients with common, aggressive cancer types as well as other forms of brain cancers. Among the 126 samples from patients with the most common aggressive cancer types (high grade gliomas, medulloblastomas, or metastatic cancers to the brain), the sensitivity of detection was >81%. None of 33 CSF-BAM assays (100% specificity, 90% to 100% credible interval) were positive in CSF samples from patients without brain cancers. The sensitivity of CSF-BAM was considerably higher than that achieved with cytology. CSF-BAM provides an integrated multi-analyte approach to identify neoplasia in the central nervous system, provides information about the immune environment in patients with or without cancer, and has the potential to inform the subsequent management of such patients.Statement of significanceThere is a paucity of technologies beyond surgical biopsy that can accurately diagnose central nervous system neoplasms. We developed a novel, sensitive and highly specific assay that can detect brain cancers by comprehensively identifying somatic mutations, chromosomal copy number changes, and adaptive immunoreceptor repertoires from samples of cerebrospinal fluid.
VEXAS anemia is a mosaic erythroblastopenia
Authors: Rodrigues François , Hardouin Giulia , El Hoss Sara , Ghoul Aya , Gautier Emilie-Fleur , Dussiot Michaël , Peltier Sandy , Amireault Pascal , Soldan Vanessa , Miccio Annarita , Debili Mounia , Jachiet Vincent , Trovati Maciel Thiago , Rossignol Julien , Allemand Eric , Mekinian Arsène , Georgin-Lavialle Sophie , Salma Mohammad , Soler Eric , Gleizes Pierre-Emmanuel , O’Donohue Marie-Françoise , Kosmider Olivier , Rodriguez Manuel S. , Hermine Olivier ,   French VEXAS group,   MINHEMON
Published: December 2024

AbstractVEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently discovered autoinflammatory disorder linked to somatic mutations in theUBA1gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combiningin vivoassessments of patients’ mature red cells and marrow erythroblasts, alongsidein vitrobase-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lackUBA1mutations beyond the basophilic stage of erythroid differentiation.In vitrobase editing ofUBA1variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of theUBA1-WT compartment. These insights may aid clinicians in tailoring treatment strategies.
ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression
Authors: Li Ang , Dong Li , Li Xuejun , Yi Jianxun , Ma Jianjie , Zhou Jingsong 
Published: December 2024

AbstractDifferent muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels ofALDH3A1in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1G93A) reaching end-stage,ALDH3A1expression was sustained at high level in EOMs, whereas substantial upregulation ofALDH3A1occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation markerANKRD1expression. Interestingly, sciatic nerve transection in wildtype mice inducedALDH3A1andANKRD1expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression ofALDH3A1protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate thatALDH3A1may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.
KP.2-based monovalent mRNA vaccines robustly boost antibody responses to SARS-CoV-2
Authors: Wang Qian , Mellis Ian A. , Wu Madeline , Bowen Anthony , Gherasim Carmen , Valdez Riccardo , Shah Jayesh G. , Purpura Lawrence J. , Yin Michael T. , Gordon Aubree , Guo Yicheng , Ho David D. 
Published: December 2024

AbstractIn response to the ongoing evolution of SARS-CoV-2, COVID-19 mRNA vaccines were recently updated to encode the spike protein of the KP.2 subvariant of the JN.1 sublineage. However, the immunogenicity of KP.2-based monovalent mRNA vaccines (KP.2 MV) has yet to be fully evaluated and reported, particularly against dominant and growing viral variants KP.3.1.1 and XEC, which bear some distinct mutations from KP.2. Here we report that KP.2 MV boosters elicit robust neutralizing antibody titers in a cohort of 16 healthy adult participants against all tested variants in pseudovirus neutralization assays. The highest post-boost geometric mean titers were against older variants D614G (17,293) and BA.5 (14,358), suggestive of immune imprinting, but the post-boost titers against currently dominant or growing viruses KP.3.1.1 (1,698) and XEC (1,721) were still robust. Fold-changes in titers were highest against recent JN.1 subvariants, including JN.1, KP.2, KP.3, KP.3.1.1, and XEC, (5.8-to-7.8-fold), compared to older variants D614G and BA.5 (1.6- and 2.5-fold), which suggests that KP.2 MV boosters have at least partially mitigated immune imprinting. Overall, these results show that KP.2 MV boosters elicit robust neutralizing antibodies against dominant SARS-CoV-2 viruses.
The sparse driver system forin vivosingle-cell labeling and manipulation inDrosophila
Authors: Xu Chuanyun , Luo Liqun 
Published: December 2024

SUMMARYIn this protocol, we introduce a sparse driver system for cell-type specific single-cell labeling and manipulation inDrosophila, enabling complete and simultaneous expression of multiple transgenes in the same cells. The system precisely controls expression probability and sparsity via mutantFRTsites with reduced recombination efficiency and tunable FLP levels adjusted by heat-shock durations. We demonstrate that this generalizable toolkit enables tunable sparsity, multi-color staining, single-cell trans-synaptic tracing, single-cell manipulation, andin vivoanalysis of cell-autonomous gene function.For details on the use and execution of this protocol, please refer to Xu et al. 2024.GRAPHICAL ABSTRACT
Extracellular microbes are required for mosquito development even in the presence ofWolbachia
Authors: Serrato-Salas Javier , Bemplidaki Danai , Roger Ivan , Epelboin Yanouk , Gendrin Mathilde 
Published: December 2024

AbstractWolbachiais an endosymbiotic bacterium infecting a wide array of invertebrates that gained attention for its potential to curb the transmission of vector-borne diseases. Its capacity to colonize arthropod populations is generally driven by vertical transmission and reproductive manipulation. In some insect species,Wolbachiaadditionally became an essential nutritional symbiont, providing vitamins to its host. As mosquito larvae require microbe-derived vitamins for development, we studied whether such a support ofWolbachiawould exist in mosquitoes but be masked by the presence of other microbes. We choseCulex quinquefasciatusspecies to address this question, as it is highly colonized withWolbachia. We developed a method to produceCulex quinquefasciatusdevoid of extracellular microbiota and demonstrated thatWolbachiaalone is insufficient to support larval development. Using transient colonization withEscherichia coli, we managed to produce adultCulex quinquefasciatusharboringWolbachiaonly. When curbingWolbachiainfection of theseE. coli-colonized larvae via tetracycline treatment, we obtained a higher larval development. Together, our data indicate thatWolbachiadoes not support development but rather acts here as a metabolic burden, and thatE. coliis sufficient for development success even in a species that grows in “dirty” water. This opens the way towards gnotobiology studies inCulex quinquefasciatusand highlights the complex relationships betweenWolbachiaand its mosquito host.Author summaryWolbachiais a bacterium infecting many invertebrates that gained attention for its potential to curb the transmission of vector-borne diseases, such as dengue. In some insect species,Wolbachiaprovides vitamins to its host. As mosquito larvae require microbe-derived vitamins for development, we studied whether such a support ofWolbachiawould exist in mosquitoes but be masked by the presence of other microbes. We choseCulex quinquefasciatusspecies to address this question, as it is highly colonized withWolbachia. We developed a method to produceCulex quinquefasciatusdevoid of extracellular microbiota and demonstrated thatWolbachiaalone is insufficient to support larval development. We transiently colonized these larvae withEscherichia colito rescue larval development and to produce adults harboringWolbachiaonly. When curbingWolbachiainfection of theseE. coli-colonized larvae via tetracycline treatment, we obtained a higher larval development. Together, our data indicate thatWolbachiadoes not support development but rather acts here as a metabolic burden, and thatE. coliis sufficient for development success even in a mosquito species that grows in “dirty” water.
Lysosomal function, resistance to stress and repair are compromised by expression of the Alexander disease GFAP R239C mutant
Authors: Hernández-Gerez Elena , Goya-Iglesias Nuria , Viedma-Poyatos Álvaro , Pajares María A. , Pérez-Sala Dolores 
Published: December 2024

AbstractIntermediate filaments are critical regulators of cell responses and organizers of cellular structures. GFAP (glial fibrillary acidic protein) is an intermediate filament protein mainly expressed in astrocytes. GFAP mutations are associated with Alexander disease (AxD), a type of leukodystrophy that causes degeneration of astrocytes and ultimately neurodegeneration. AxD astrocytes display protein aggregation, proteostasis defects and altered organelle homeostasis. We previously showed that expression of GFAP AxD mutants in astrocytes provoked mitochondrial alterations and oxidative stress. Here we have used an astrocytoma cell model to explore the impact of GFAP AxD mutants on the lysosomal degradation pathway. Expression of GFAP AxD mutants in this model elicits marked alterations in lysosomal distribution. Cells expressing the GFAP R239C mutant display defective lysosomal activity and intraluminal acidification. Lysosomes are primary sites of oxidative damage. Moreover, expression of GFAP R239C increases susceptibility of lysosomes to oxidative stress, resulting in a greater loss of lysosomal “mass” and compromised membrane integrity, as revealed by increased intraluminal recruitment of galectins, with respect to cells expressing GFAP wt. Notably, lysosomes in GFAP R239C expressing cells are also more vulnerable to chemically-induced rupture. Interestingly, lysosomes of cells expressing GFAP wt are able to rapidly recover after removal of the damaging agent. In sharp contrast, recovery of acidic vesicles is severely impaired in cells expressing GFAP R239C, suggesting a defect in lysosomal repair. Taken together, our results show that expression of the GFAP AxD mutant is sufficient to deeply perturb lysosomal distribution, function and repair. These alterations could contribute to proteostasis defects and cellular toxicity in AxD.
Distribution of contezolid in different tissues of mice and human patients infected withMycobacterium abscessus
Authors: Li Qi , Wang Yujin , Zhu Qingdong , Lin Yanrong , Chu Naihui , Lu Yu , Nie Wenjuan 
Published: December 2024

AbstractBackgroundLinezolid (LZD), while effective againstMycobacterium abscessus(MAB), can cause myelosuppression and peripheral neuropathy. Contezolid (CZD) shares a similar antimicrobial profile with improved safety, but biodistribution data remain limited. This study evaluated CZD’s biodistribution in MAB-infected mice and humans and its therapeutic potential across infection sites.MethodsMICs of CZD and LZD against 32 clinical MAB isolates and three reference strains were determined. In MAB-infected mice, drug concentrations were quantified in plasma and pulmonary and cerebral tissues at 2, 4, and 8 hours post-administration. In MAB-infected patients, CZD concentrations in bone, plasma, and cerebrospinal fluid were measured at multiple time points and MAB counts in sputum cultures were assessed daily over 14 days.ResultsRespective MIC50and MIC90values were 8 and 32 µg/mL (LZD) and 16 and 32 µg/mL (CZD). Pharmacokinetic CZD and LZD level comparisons revealed peak CZD plasma levels within 2 hours, higher systemic CZD levels, comparable pulmonary tissue concentrations, and slightly lower CZD cerebral tissue penetration. In patients, CZD levels in ankle joint effusion samples reached 2.0885 µg/mL at 6 hours, peaking in the posterior malleolus. Plasma CZD concentrations peaked at 8.2349 µg/mL at 3 hours and dropped to 6.1065 µg/mL by 6 hours, while CSF levels were 0.9295 and 0.792 µg/mL at 3 and 6 hours, respectively. Sputum bacterial burden decreased rapidly within 24 hours of CZD treatment, with near-complete clearance by day 4.ConclusionCZD and LZD exhibit comparable tissue distribution but different site-specific penetration, supporting their potential for treating diverse MAB infections.
Multinucleated giant cells are hallmarks of ovarian aging with unique immune and degradation-associated molecular signatures
Authors: Converse Aubrey , Perry Madeline J. , Dipali Shweta S. , Isola Jose V. V. , Kelly Emmett B. , Varberg Joseph M. , Zelinski Mary B. , Gerton Jennifer L. , Stout Michael B. , Pritchard Michele T. , Duncan Francesca E. 
Published: December 2024

SUMMARYThe ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response1, but are also observed in the aging ovary2–4. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by highGpnmbexpression, a putative marker of ovarian and non-ovarian MNGCs5,6. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.
All the lonely people, where do they all come from: age moderating the mediation effect of loneliness among Portuguese students
Authors: Kulari Genta 
Published: December 2024

PurposeThe present study aimed to examine the mediation role of loneliness in the relationship between perceived social support and depressive symptoms among university students in Portugal. The study also investigated the moderation role of age on the mediation model.Design/methodology/approachSurvey data sample consisted of 755 participants (aged 18–55 years) attending university in Lisbon, Portugal, from February through May 2023. Participants completed the UCLA Loneliness Scale, Multidimensional Scale of Perceived Social Support (MSPSS), Depression, Anxiety, Stress Scale. The SPSS Program with PROCESS macro (Model 4 and Model 8) was used to test the hypotheses regarding the mediation and the moderated mediation effects.FindingsThe bootstrap result for indirect effect loneliness (β = −0.083, p < 0.0001) was significant, indicating that loneliness mediated the relationship between perceived social support and depressive symptoms. Moreover, the interaction term (perceived social support x age) had a significant positive effect on the direct negative association between perceived social support and depressive symptoms (B = 0.0312; p < 0.05), showing that age moderated the direct relationship between the aforementioned variables. Importantly, the results showed that age moderated the indirect association (via loneliness) between perceived social support and depressive symptoms.Originality/valueThis research advances our understanding of loneliness among university students of different age ranges while providing empirical data on the effect of loneliness in the relation of social support and depressive symptoms. Moreover, the study delves on possible strategies to combat the expression of loneliness and further depressive symptoms.
Study on the dynamic characteristics of double row self-aligning roller bearings with surface faults
Authors: Yang Huiming , Yang Xia , Huang Yuqi 
Published: December 2024

Purpose
The aim of this study is to establish the nonlinear dynamics equations of roller bearings with surface faults on outer raceway, inner raceway and rolling elements to analyze the dynamic characteristics of the double row self-aligning roller bearings, and provided theoretical basis for bearing fault diagnosis and life prediction.

Design/methodology/approach
First, based on the momentum theorem, the formulas for quantitative calculation of impact load were established, when roller was in contact with the fault of the inner or outer raceway. Then, the fault position piecewise functions and the load-carrying zone piecewise functions were established. Based on these, the nonlinear dynamic equations of double row self-aligning roller bearings are established, and Matlab is used to simulate the faulty bearings at different positions, sizes and rotational speeds. Finally, the vibration test of the fault bearings are completed, and the correctness of the nonlinear dynamic equations of the rolling bearing are verified.

Findings
The simulation and test results show that: the impact load increased with the increasing rotate speed and fault size, and the larger the fault size, the longer the impact load existed and the shorter vice versa.

Originality/value
The nonlinear dynamic equation of double row self-aligning roller bearings is established, which provides a theoretical basis for bearing faults diagnosis and fatigue life prediction.
Cancellation of the ZEDE law in Honduras and international investment law issues
Authors: Sharmin Tanjina 
Published: December 2024

Purpose
In 2013, Honduras Congress passed the Zones for Employment and Economic Development (ZEDE) Organic Law, along with some constitutional changes, to create ZEDEs, which are essentially special economic zones with some unique features. Prospera Honduras Inc., a company with substantial United States investment, invested in Honduras relying on the ZEDE Organic Law and the Free Trade Agreement between Central America, the Dominican Republic and the United States of America (CAFTA-DR). In 2022, Honduras cancelled the ZEDE Organic Law, allegedly harming Prospera Honduras Inc.’s investments. Prospera and some other foreign investors have initiated an investor-state arbitration against Honduras for several alleged breaches of CAFTA-DR provisions. Honduras has remained silent and decided not to participate in the arbitration. This paper aims to examine whether the cancellation of the ZEDE Organic Law gives rise to international investment law obligations under the CAFTA-DR.

Design/methodology/approach
This is a doctrinal research and contains qualitative analysis.

Findings
The article concludes that CAFTA-DR preserves some regulatory space for host states; therefore, it would be wrong to assume that the arbitral decision in Prospera Inc. and others v. Honduras will favour only the foreign investors. This article also argues that, drawing insights from this dispute, future International Investment Agreements should better preserve Indigenous people’s rights. Moreover, the host states should reconsider whether they intend International Investment Agreements (IIAs) to apply to special economic zones in future.

Originality/value
There is no existing scholarly work examining the international investment law issues relating to the cancellation of ZEDEs in Honduras. Therefore, the findings of this article will be novel.