bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-18 primes T cells with an antigen-inexperienced memory phenotype for proliferation and differentiation into effector cells through Notch signaling
Authors: Li Wen , Jin Denan , Takai Shinji , Inoue Natsuko , Yamanishi Kyosuke , Tanaka Yoshimasa , Okamura Haruki 
Published: August 2024

Abstract
Recent studies have revealed that a subset of CD8+ T cells exhibit innate features and can be activated by cytokines. However, the precise mechanisms underlying the proliferation and differentiation of these cells remain unclear. Here, we demonstrated that CD44highCD8+ T cells in the mouse spleen express functional interleukin-18 (IL-18) receptors, whereas CD44lowCD8+ T cells do not. In response to IL-18 stimulation, these cells activated various metabolic pathways, upregulated the expression of surface molecules, such as c-Kit (CD117), CD25, and PD-1, and induced progression through the G1/S phase in the cell cycle. IL-18-primed cells, expressing a high-affinity receptor for IL-2, exhibited robust proliferation in response to IL-2 and underwent differentiation into effector cells. The splenic CD44highCD8+ T cells exhibited high expression levels of CD122, CD62L, CCR7, and CXCR3, along with CD5, indicating their potential for migration to the lymph nodes, where they could undergo expansion and terminal differentiation into effector cells. Additionally, in a tumor model, administration of IL-18 increased the accumulation of CD8+ T cells in both the lymph nodes and tumors. It is noteworthy that stimulation of CD44highCD8+ T cells with IL-18 upregulated the Notch-1 receptor and c-Myc. Moreover, inclusion of γ-secretase inhibitors attenuated the effect of IL-18 on both proliferation and interferon-γ production in the cells. These results demonstrate that IL-18 primes CD44highCD122highCXCR3highCD62LhighCD8+ T cells for expansion and differentiation into effector cells in a Notch signaling-dependent manner.
PHO1: linking phosphate nutrition translocation and floral signalling in plants
Authors: He Cunman , Shou Huixia 
Published: August 2024

This article comments on:
Dai S, Chen H, Shi Y, Xiao X, Xu L, Qin C, Zhu Y, Yi K, Lei M, Zeng H. 2024. PHOSPHATE1-mediated phosphate translocation from roots to shoots regulates floral transition in plants. Journal of Experimental Botany 75, 5054–5075. https://doi.org/10.1093/jxb/erae222
ENPP1 induces blood–brain barrier dysfunction and promotes brain metastasis formation in human epidermal growth factor receptor 2-positive breast cancer
Authors: Santos Liliana , Tomatis Francesca , Ferreira Hugo R S , Almeida Sara F F , Ciputra Edward , Sereno José , Almeida Rui , Teixeira Paulo , Ribeiro Ana Sofia , Moreira João N , Silva Ana P , Ferreira Lino , Abrunhosa Antero J , Gomes Célia M 
Published: August 2024

Abstract

Background
Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients. Understanding how disseminating tumor cells manage to cross the blood–brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation.

Methods
We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model.

Results
Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival.

Conclusions
We demonstrated that metastatic BC cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ BC.
Whey Protein Intervention and Inflammatory Factors and Oxidative Stress: Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Farahmandpour Fatemeh , Haidari Fatemeh , Heidari Zeinab , Hajarzadeh Samaneh , Ahangarpour Akram 
Published: August 2024

Abstract

Context
Whey protein (WP), a high-biological-value protein contained in milk, may have anti-inflammatory properties and can reduce proinflammatory cytokines; however, the current evidence is inconclusive.

Objective
The aim of this study was to further investigate the effects of whey protein supplementation on inflammatory factors and oxidative stress in adults.

Data Sources
We conducted a comprehensive search up to March 2022 using relevant key words in databases such as PubMed, Scopus, Embase, and the Cochrane Central Register of Controlled Trials, focusing on randomized controlled trials (RCTs).

Data Extraction
RCTs that examined the impact of WP on C-reactive protein, tumor necrosis factor alpha, interleukin-6, glutathione, malondialdehyde, and total antioxidant capacity were selected independently by 2 authors. Results were pooled using a random-effects model as weighted mean differences and 95% CIs.

Data Analysis
The results of the present study demonstrated that WP supplementation had no significant effect on the modulation of inflammation and oxidative stress compared with the control. None of the predefined subgroup analyses explained the differences in the effects of WP supplementation on inflammatory factors and oxidative stress.

Conclusion
This research suggests that WP supplementation had no significant effect on inflammatory factors and oxidative stress.

Systematic Review Registration
PROSPERO registration no. CRD42022325855.
Correlates of Nucleocapsid Antibodies and a Combination of Spike and Nucleocapsid Antibodies Against Protection of SARS-CoV-2 Infection During the Omicron XBB.1.16/EG.5–Predominant Wave
Authors: Yamamoto Shohei , Oshiro Yusuke , Inamura Natsumi , Nemoto Takashi , Tan Tomofumi , Horii Kumi , Okudera Kaori , Konishi Maki , Mizoue Tetsuya , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Sugiura Wataru , Ohmagari Norio 
Published: August 2024

Abstract

Background
We aimed to examine the association among nucleocapsid (N) antibodies, a combination of N and spike (S) antibodies, and protection against SARS-CoV-2 reinfection.

Methods
We conducted a prospective cohort study among staff at a national medical research center in Tokyo and followed them for the incidence of SARS-CoV-2 infection between June and September 2023 (Omicron XBB.1.16/EG.5 wave). At baseline, participants donated blood samples to measure N- and S-specific antibodies. Cox regression was used to estimate the hazard ratio and protection ([1 – hazard ratio] × 100) against subsequent SARS-CoV-2 infection across these antibody levels.

Results
Among participants with previous infection, higher pre-reinfection N antibodies were associated with a lower risk of reinfection, even after adjusting S antibody levels (P &lt; .01 for trend). Estimation of the protection matrix for N and S antibodies revealed that high levels in N and S antibodies conferred robust protection (&gt;90%) against subsequent infection. In addition, a pattern of low pre-reinfection N antibodies but high vaccine-enhanced S antibodies showed high protection (&gt;80%).

Conclusions
Pre-reinfection N antibody levels correlated with protection against reinfection, independent of S antibodies. If the N antibodies were low, vaccine-boosted S antibodies might enhance the reinfection protection.
Effectiveness of the Original Monovalent and Bivalent COVID-19 Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters in Pregnant Persons Who Were Not Immunocompromised: VISION Network, June 2022–August 2023
Authors: Avrich Ciesla Allison , Lazariu Victoria , Dascomb Kristin , Irving Stephanie A , Dixon Brian E , Gaglani Manjusha , Naleway Allison L , Grannis Shaun J , Ball Sarah , Kharbanda Anupam B , Vazquez-Benitez Gabriela , Klein Nicola P , Natarajan Karthik , Ong Toan C , Embi Peter J , Fleming-Dutra Katherine E , Link-Gelles Ruth , Zerbo Ousseny 
Published: August 2024

Abstract
Pregnant people face increased risk of severe COVID-19. Current guidelines recommend updated COVID-19 vaccination (2023–2024) for those aged ≥6 months, irrespective of pregnancy status. To refine recommendations for pregnant people, further data are needed. Using a test-negative design, we evaluated COVID-19 vaccine effectiveness against medically attended COVID-19 with COVID-19–like illness among pregnant people aged 18 to 45 years during June 2022 to August 2023. When doses were received during pregnancy, vaccine effectiveness was 52% (95% CI, 29%–67%); when received &lt;6 months prior to pregnancy, 28% (95% CI, 11%–42%); and when received ≥6 months prior to pregnancy, 6% (95% CI, −11% to 21%). Pregnant people should stay up-to-date with recommended COVID-19 vaccination.
The Impact of GeneXpert Cerebrospinal Fluid Testing on Tuberculous Meningitis Diagnosis in Routine Care in Botswana
Authors: Milburn James , Ntwayagae Ookeditse , Ngoni Kebatshabile , Suresh Rachita , Lemme Neo , Northcott Cassie , Penney James , Kinsella Matthew , Mechie Imogen , Ensor Samuel , Chebani Tony , Grint Daniel , Tenforde Mark W , Avalos Ava , Ramaabya Dinah , Doyle Ronan , Mokomane Margaret , Mine Madisa , Kranzer Katharina , Jarvis Joseph N 
Published: August 2024

Abstract

Background
Tuberculous meningitis (TBM) disproportionately impacts high–HIV prevalence, resource-limited settings where diagnosis is challenging. The GeneXpert platform has utility in TBM diagnosis, but uptake remains limited. In Botswana, before the introduction of GeneXpert, tuberculosis (TB) testing was only available through mycobacterial culture at the National TB Reference Laboratory. Data describing routine use of Xpert MTB/RIF for cerebrospinal fluid (CSF) testing in resource-limited settings are scarce.

Methods
Electronic records for patients with CSF tested in government facilities in Botswana between 2016 and 2022 were obtained from a central online repository as part of ongoing national meningitis surveillance. Samples were excluded from 1 site where Xpert MTB/RIF is performed universally. The proportion receiving TB-specific investigation on CSF and the number positive for Mycobacterium tuberculosis following increased Xpert MTB/RIF capacity were determined.

Results
The proportion of CSF samples receiving TB-specific investigation increased from 4.5% (58/1288) in 2016 to 29.0% (201/693) in 2022, primarily due to increased analysis with Xpert MTB/RIF from 0.9% (11/1288) to 23.2% (161/693). There was an overall decline in the annual number of CSF samples analyzed, but the proportion with microbiologically confirmed TBM increased from 0.4% to 1.2%. The proportion of samples tested for TB that were collected from health care facilities &gt;100 km from the National TB Reference Laboratory increased with Xpert MTB/RIF rollout from 65.9% (87/132) to 78.0% (494/633).

Conclusions
In Botswana, access to TB culture is challenging in remote populations; more accessible near-patient testing using Xpert MTB/RIF increased the number of patients receiving TB-specific testing on CSF and the number of confirmed TBM cases.
Immune checkpoint inhibitor infusion times and clinical outcomes in patients with melanoma
Authors: Fletcher Kylie , Rehman Saba , Irlmeier Rebecca , Ye Fei , Johnson Douglas 
Published: August 2024

ABSTRACT

Background
Circadian rhythms impact immune function; a previous study demonstrated that immunotherapy treatment times taking place later in the day correlated with poorer outcomes in patients with melanoma. However, this finding has not been replicated, and other infusion timing schemas are unexplored. The objective of this retrospective, cohort study was to determine if the time of immunotherapy infusion affects outcomes.

Materials and Methods
Five hundred and sixteen participants age ≥18 years diagnosed with cutaneous, acral, mucosal, or unknown primary melanoma treated with &gt;1 infusion of nivolumab, pembrolizumab, or combination ipilimumab/PD-1 inhibitors were included. Response rate, toxicity rate, overall survival (OS), and progression-free survival (PFS) were determined based on infusion timing.

Results
Patients with ≥1 late infusion (after 4 pm) among their first 4 infusions had slightly poorer objective response rate compared with only pre-4 pm infusions (39.7% vs 44.5%), but no significant associations with late infusions and PFS and OS (P = .23, .93, respectively). Multivariable analyses showed no statistically significant association with outcomes for patients with any post-4 pm infusion among the first 4; median infusion time was also not associated with outcomes. However, considering all infusion times, we found inferior PFS (median 10.6 vs 38.9 months, P &lt; .0001), and numerically inferior OS (median 54.6 vs 81.2 months, P = .19) in patients with ≥20% late infusions. Multivariable models had similarly inferior response and PFS for patients with ≥20% late infusions, and later median infusion times were associated with inferior response, PFS, and OS.

Conclusions
Late immunotherapy infusion times were associated with inferior outcomes when considering all infusions, but not when considering initial (first 4) infusions.
Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study
Authors: Borazanci Erkut H , Bahary Nathan , Chung Vincent , Huyck Timothy K , Kio Ebenezer A , Chiorean Elena Gabriela , Skeel Roland T , Alese Olatunji B , Cardin Dana B , Fountzilas Christos , Hanna Wahid T , Leal Alexis D , Lee Valerie , Noonan Anne M , Philip Philip A , Wainberg Zev A , Pashova Hristina , Mann Grace , Oberstein Paul E 
Published: August 2024

Abstract

Background
Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines.

Patients and Methods
In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed.

Results
Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest.

Conclusion
Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.
Task sharing for increasing access to obstetric ultrasonography: a formative qualitative study of nurse-led scanning with telemedicine review in Kenya
Authors: Kumar Meghan Bruce , Mulongo Caleb Mike , Pincerato Lucia , De Vita Maria Vittoria , Saidi Salima , Gakii Yvonne , Morino GianFranco , Kumar Pratap 
Published: August 2024

Abstract
The informal settlements of Nairobi have higher neonatal and infant mortality rates than the average for Nairobi. Universal access to important diagnostics like ultrasonography is poor and inequitable due to the high cost of devices and limited availability of skilled sonographers. Recent advances of mobile ultrasound probes connected to smartphones, with or without artificial intelligence support, have improved access to devices; but skills to perform and interpret scans continue to be limited. The SonoMobile intervention involved training nurse-midwives to conduct point-of-care obstetric ultrasound scans in antenatal care clinics in urban informal settlements. Scan data and images were shared, using telemedicine technology, with remote sonographers, who reviewed scan images and data, and provided reports. This study of 61 respondents from diverse stakeholder groups describes the acceptability, utility and considerations for sustainability of nurse-led, point-of-care obstetric ultrasonography with telemedicine review. Perceived value of nurse-led obstetric ultrasonography includes improving access and affordability of obstetric ultrasonography services, timely identification and referral of high-risk pregnancies, and improving awareness of appropriate antenatal care among underserved populations. The relative affordability of SonoMobile was described as a critical enabler for a business model targeting low- and middle-income segments of the population, and for increasing quality and equity of antenatal care coverage. Areas highlighted for improvement include strengthening supervision of nurse trainees, broadening the scope of nurse training and development of clear regulatory guidelines for nurse-led obstetric ultrasonography. The study highlights the complex task shifting required to provide universal access to a life-saving technology in a low- and middle-income country health system.
A Taxonomy for Set-Theoretic Potentialism
Authors: Sutto Davide 
Published: August 2024

Abstract
Set-theoretic potentialism is one of the most lively trends in the philosophy of mathematics. Modal accounts of sets have been developed in two different ways. The first, initiated by Charles Parsons, focuses on sets as objects. The second, dating back to Hilary Putnam and Geoffrey Hellman, investigates set-theoretic structures. The paper identifies two strands of open issues, technical and conceptual, to clarify these two different, yet often conflated, views and categorize the potentialist approaches that have emerged in the contemporary debate. The final outcome is a taxonomy that should help researchers navigate the rich landscape of modal set theories.
Missing-Mass Measurement of the 12C(K-, K+) Reaction at 1.8 GeV/c with the Superconducting Kaon Spectrometer
Authors: Ichikawa Yudai , Ahn Jung Keun , Akazawa Yuya , Aoki Kanae , Botta Elena , Ekawa Hiroyuki , Evtoukhovitch Petr , Feliciello Alessandro , Fujita Manami , Gogami Toshiyuki , Hasegawa Shoichi , Hasegawa Tomoyuki , Hayakawa Shuhei , Hayakawa Tomonori , Honda Ryotaro , Hosomi Kenji , Imai Ken’ichi , Jung Wooseung , Kanatsuki Shunsuke , Kim Shin Hyung , Kinbara Shinji , Kobayashi Kazuya , Lee Jaeyong , Marcello Simonetta , Miwa Koji , Moon Taejin , Nagae Tomofumi , Nakada Yoshiyuki , Nakagawa Manami , Nanamura Takuya , Naruki Megumi , Sakaguchi Atsushi , Sako Hiroyuki , Sasaki Yuki , Sato Susumu , Shirotori Kotaro , Sugimura Hitoshi , Takahashi Toshiyuki , Tamura Hirokazu , Tanida Kiyoshi , Tsamalaidze Zviadi , Ukai Mifuyu , Yamamoto Takeshi O 
Published: August 2024

Abstract
We performed a measurement of the inclusive missing-mass spectrum of the $^{12}$C$(K^-, K^+)$ reaction at an incident beam momentum of 1.8 GeV/c. This measurement was carried out by using the Superconducting Kaon Spectrometer (SKS) and the K1.8 beamline spectrometer at the Hadron Experimental Facility in J-PARC. From the missing-mass of the $^{12}$C$(K^-, K^+)$ reaction, the binding energy of a $\Xi ^-$ hyperon in a core $^{11}$B nucleus, $B_{\Xi ^-}$, can be calculated. Our experimental setup yielded a good energy resolution of 8.2 MeV (full width at half maximum), which allowed us to observe significant enhancements in the proximity of the $^{12}_{\Xi }$Be production threshold region. In order to extract information from the missing-mass spectrum, we employed several fitting parameters assumptions. A good agreement with the spectrum shape was obtained by adding two Gaussian functions, with the constant experimental resolution for the $\Xi$-hypernuclear states, to the background distribution. The peak positions were obtained to be $B_{\Xi ^-} = 8.9 \pm 1.4$ (stat.) $^{+3.8}_{-3.1}$ (syst.) MeV and $B_{\Xi ^-} = -2.4 \pm 1.3$ (stat.) $^{+2.8}_{-1.2}$ (syst.) MeV. Another model assumption, one Breit–Wigner function with $B_{\Xi ^-} = -2.7 \pm 2.2$ (stat.) $^{+0.5}_{-0.7}$ (syst.) MeV and $\Gamma = 4.1 \pm 2.1$ (stat.) $^{+1.2}_{-0.7}$ (syst.) MeV, also yielded a similar $\chi ^2$ value.
Cowper’s Pauses
Authors: Turner Joseph 
Published: August 2024

Abstract
This essay is about the status and significance of pauses in the poetry of William Cowper. The pause, it argues, is not only a formal feature of that poetry, manifest in caesurae and line-endings, but a human experience with which Cowper displays a richly vexed fascination. Consideration of Cowper’s prose writings reveals his sense that the proper management of pauses is a crucial and distinguishing characteristic of blank verse as against rhyming couplets. Attending to Cowper’s pauses, it is argued, can help us better to understand the distinctive mode of attention that his verse demands of its readers, especially in the long poem The Task (1785). Cowper’s complicated and ambivalent sense of the value of pausing is related, on the one hand, to a Protestant tradition of temporal improvement, and, on the other, to eighteenth-century debates about the nature of blank verse. Cowper’s sense of religious experience, the essay suggests, cannot properly be separated from the way in which he chose to write poetry. At their ambiguous best, Cowper’s pauses place the reader in a position akin to that in which the poet found himself as a Christian believer, doubtfully poised between election and reprobation, between salvation and damnation, and uncertain of what the future holds.
Assessment of radiation dose values in common orthopaedic trauma examinations performed under X-ray fluoroscopy guidance
Authors: Genetay Tristan , Gamulin Axel , Lorimier Arnaud , Sans Merce Marta 
Published: August 2024

Abstract
This study aims to provide radiation reference levels in orthopaedic surgery. A total of 753 procedures were collected within 1 y. Categories containing several similar procedures were created based on four criteria: same anatomical area, same level of complexity, only single procedures, and at least 10 cases per category. Exposure was defined in terms of air kerma-area product, fluoroscopy time, and air kerma at the patient entrance reference point. For common procedures, median effective doses to patient were calculated using the Monte Carlo Software PCXMC. Most irradiating procedure in this study i.e. intramedullary nailing of the proximal femur was equivalent to an air kerma at the patient entrance reference point of 37.1 mGy, which is ~50 times lower than the threshold for acute deterministic effects of radiation. Optimization remains a must to reduce the dose while maintaining the image quality and reducing the likelihood of stochastic effects.