bluuebunny/crossref_metadata_2025 huggingface dataset:
Late gadolinium enhancement in mid infero-septal area after left bundle branch area pacing in the setting of bifascicular block and syncope: a case report
Authors: Redzepi Betim , Bengueddache Samir , Schwitter Juerg , Antiochos Panagiotis , Pruvot Etienne
Published: January 2025

Background

Conduction system pacing, which includes His bundle pacing and left bundle branch area pacing (LBBAP), is becoming increasingly common in clinical practice. His bundle pacing, introduced over two decades ago, continues to see growing use, while LBBAP is gaining traction due to its broader target area and shorter procedure times. However, complications such as septal perforation and lead-related issues may still arise. This case report explores the evaluation and management of recurrent syncope in the context of bifascicular block (BFB), highlighting the importance of thorough assessment, continuous ECG monitoring, and the potential need for permanent pacemaker implantation.

Case summary

A 60-year-old woman with a history of myocardial infarction, Type II diabetes, and dyslipidaemia presented with recurrent syncope and BFB, for which a LBBAP device was implanted in August 2023. In February 2024, she was admitted again due to recurrent syncope and frequent premature ventricular contractions. Cardiac magnetic resonance imaging revealed two localized myocardial scars: one at the basal anterior wall from the 2018 ischaemic event and another in the mid infero-septal wall at the site of the LBBAP lead. During her hospital stay, she experienced multiple episodes of near fainting due to orthostatic hypotension, indicative of underlying autonomic neuropathy.

Discussion

This narrative explores the evolving landscape of cardiac pacing techniques, with a focus on LBBAP, highlighting its advantages over traditional methods while also acknowledging potential complications. Additionally, it emphasizes the importance of a comprehensive workup for syncope and the need for tailored interventions that extend beyond pacemaker implantation.
From In(-)formation to Infrastructural Turns: The Digital Futures of Human Rights Law and Practice
Authors: Fisher Angelina
Published: January 2025

In his book, The Informational Logic of Human Rights: Network Imaginaries in the Cybernetic Age, Joshua Bowsher critiques the human rights movement’s preoccupation with informational practices. Tracing the evolution of informational preoccupation of human rights organizations to the rise of cybernetics and its enmeshment with the neo-liberal project, Bowsher argues that the resulting practice of creating violations as events through capturing, cutting and noise elimination has defanged and depoliticized rights. The quest for objective, stable and predictable knowledge has permeated even the turn to algorithms and machine learning. While denouncing the human rights movement’s resistance to critical and political forms of knowledge making that interrogate subjects, norms, values and power relations, Bowsher nonetheless sees potential for salvaging the promise of human rights. What is needed, Bowsher argues, is a reconfiguration of human rights information from an assemblage of ‘brute facts’ into positional, situated knowledge-making practice that would aim to forge connections between structures of oppression and domination and sufferings of ‘particularly situated human beings’. Picking up on Bowsher’s call for human rights in(-)formation, this review essay examines the infrastructural turn needed to effectuate knowledge-generating practices attuned to the polyvalency of the situated perspectives. Focusing particularly on the growing role of digital data and infrastructures, the essay seeks to illuminate promising paths forward for human rights advocates and practitioners.
The pollution fast-track to the Arctic: how southern wintering areas contribute to organochlorine loads in a migrant seabird breeding in the Arctic
Authors: Bustnes Jan Ove , Bårdsen Bård-Jørgen , Moe Børge , Herzke Dorte , Bemmelen Rob S A van , Tulp Ingrid , Schekkerman Hans , Hanssen Sveinn-Are
Published: January 2025

This study examines how southern wintering areas may contribute to organochlorine (OCs) loads in arctic seabirds during breeding. Light-sensitive geolocators (GLS loggers) were deployed on Arctic skuas (Stercorarius parasiticus) in one high arctic and two subarctic colonies. Hexcahlorobenzene (HCB), chlordanes, mirex, p,p′-dichlorodiphenyldichloro-ethylene (p,p′-DDE), and polychlorinated biphenyls (PCBs) were measured in the blood of breeding adults at the nest (58 individuals, a total of 128 samples) in northern Norway and Svalbard between 2009 and 2015. We compared OC concentrations and OC profiles among nesting skuas wintering in five Atlantic regions, determined by the GLS loggers: the coast of Argentina, the Caribbean, off West Africa, off the coast of southern Africa, and the Mediterranean Sea. As predicted, HCB, which is semi-volatile and has high long-range transport potential, showed high prevalence in birds wintering in all regions except the Mediterranean. Mirex showed the highest prevalence in birds wintering off the coasts of Argentina and southern Africa, in accordance with high background levels previously documented in the Southern Ocean. Chlordanes were particularly prevalent in skuas wintering off southern Africa, whereas p,p′-DDE seemed relatively evenly distributed among wintering areas. As predicted, the prevalence of PCBs was much higher in birds wintering in the Mediterranean Sea than in birds from other regions. This study thus suggests that the Mediterranean Sea and the mid- and southern Atlantic are essential sources of different OCs in the blood of Arctic skuas breeding in the European Arctic.
Trade-offs of different types of dose-responses following temporal gradients of Pb stress in Tillandsia usneoides
Authors: Tang Zhen , Liu Yuanyuan , Agathokleous Evgenios , Han Shuo , Zheng Guiling , Li Peng
Published: January 2025

The dose-response relationship between toxicants and organisms is the most fundamental principle in toxicological risk assessment. However, multiphasic non-linear responses are poorly understood and the underlying mechanisms remain elusive. In this study, we subjected the indicator plant Tillandsia usneoides to 5 or 10 time gradients of 1 mM Pb, and assessed the response patterns of five damage markers and eight resistance markers in the leaves. The results showed that in the assay with 5 time gradients, 10 out of 13 biomarkers showed biphasic responses and 2 biomarkers showed multiphasic responses. In the assay with 10 time gradients, 6 biomarkers showed biphasic responses and 5 biomarkers showed multiphasic responses. The results confirmed that increasing the number of dose gradients facilitates the detection of multiphasic dose responses. Additionally, the occurrence of non-linear responses was found to be a common phenomenon. Further analysis of the frequency of trade-offs showed that the occurrence frequency of trade-off 2 (toxicants do not affect one marker but stimulate other markers), was always higher than that of trade-off 1 (toxicants worsen one marker while stimulating other markers) for both damage and resistance markers, and that trade-off 2 was more likely to appear in resistance markers. This suggests that, as the duration of stress increases, the body produces more resistance substances, which coordinate with one another to maintain internal balance. This study suggests that the trade-off theory can be effectively used to elucidate the complex relationship between a toxicant and T. usneoides.
Emerging live sonar technologies in freshwater recreational fisheries: Issues and opportunities
Authors: Cooke Steven J , Neely Ben C , Hasler Caleb T , Schooley Jason D , Brownscombe Jacob W , LaRochelle Luc , Danylchuk Andy J , Hunt Taylor L , Norman Jacob D
Published: January 2025

Debate about the potential benefits and risks of live sonar technology (also known as live imaging sonar and forward-facing sonar) in freshwater recreational fisheries includes growing discussions regarding regulation. Synthesizing sparse literature, experiences of the coauthors, and observations from traditional and social media, we revealed a varied range of potential outcomes for fisheries when this technology is used. Of particular concern is the ability to find fish that were previously cryptic and to target them in ways that increase capture efficiency (e.g., through snagging where legal or more accurately presenting lures or baits); thus, increasing catchability. Conflicting views within the recreational fishing community about the “fair chase” aspect of this technology have prompted discussions regarding regulations. We anticipate continued debate around this topic and hope that this paper will inspire more empirical research (ecological and human dimensions) to provide resource managers and the recreational fishing community with insights and guidance on how to ensure that live sonar is used in ways that benefit fisheries management and stakeholder interests.
Signal Transduction Pathway Mediating Carotid Body Dependent Sympathetic Activation and Hypertension by Chronic Intermittent Hypoxia
Authors: Peng Ying-Jie , Nanduri Jayasri , Wang Ning , Su Xiaoyu , Hildreth Matthew , Prabhakar Nanduri R
Published: January 2025

Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and sympathetic nerve responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cyclic adenosine monophosphate (cAMP) contributes to CB and sympathetic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3, Cth (encoding CSE), and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked a persulfidation response to CIH, indicating that Adcy3 activation requires Olfr78 activation by H2S in CIH. CIH also enhanced glomus cell Ca2+ influx, an effect absent in Cnga2 (encoding cyclic nucleotide–gated channel alpha2 subunit) and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+ responses through cyclic nucleotide–gated channels. Furthermore, Adcy3 null mice did not exhibit either CB activation or sympathetic activation by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation, sympathetic activity and hypertension.
Tandem Repeats Provide Evidence for Convergent Evolution to Similar Protein Structures
Authors: Wright Erik S
Published: January 2025

Homology is a key concept underpinning the comparison of sequences across organisms. Sequence-level homology is based on a statistical framework optimized over decades of work. Recently, computational protein structure prediction has enabled large-scale homology inference beyond the limits of accurate sequence alignment. In this regime, it is possible to observe nearly identical protein structures lacking detectable sequence similarity. In the absence of a robust statistical framework for structure comparison, it is largely assumed similar structures are homologous. However, it is conceivable that matching structures could arise through convergent evolution, resulting in analogous proteins without shared ancestry. Large databases of predicted structures offer a means of determining whether analogs are present among structure matches. Here, I find that a small subset (∼2.6%) of Foldseek clusters lack sequence-level support for homology, including ∼1% of strong structure matches with template modeling score ≥ 0.5. This result by itself does not imply these structure pairs are nonhomologous, since their sequences could have diverged beyond the limits of recognition. Yet, strong matches without sequence-level support for homology are enriched in structures with predicted repeats that could induce spurious matches. Some of these structural repeats are underpinned by sequence-level tandem repeats in both matching structures. I show that many of these tandem repeat units have genealogies inconsistent with their corresponding structures sharing a common ancestor, implying these highly similar structure pairs are analogous rather than homologous. This result suggests caution is warranted when inferring homology from structural resemblance alone in the absence of sequence-level support for homology.
A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator
Authors: Lee Matthew A , Hatcher Charlie A , Hazelwood Emma , Goudswaard Lucy J , Tsilidis Konstantinos K , Vincent Emma E , Martin Richard M , Smith-Byrne Karl , Brenner Hermann , Cheng Iona , Kweon Sun-Seog , Le Marchand Loic , Newcomb Polly A , Schoen Robert E , Peters Ulrike , Gunter Marc J , Van Guelpen Bethany , Murphy Neil
Published: January 2025

Background

Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.

Methods

Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist–hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity–CRC association.

Results

BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity–protein (2628 unique circulating proteins) and 33 protein–CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI–CRC association for GREM1, effect estimates were attenuated—suggestive of a potential mediating role—most strongly for the BMI–overall CRC association in women.

Conclusion

Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI–CRC association, particularly in women.
P24 In vitro activity of cefepime/enmetazobactam, and comparators, against OXA carbapenemase-positive Acinetobacter baumannii
Authors: Ward Jon , Dunkel Nathalie , Quevedo Juan , Morrisey Ian , Santerre Henriksen Anne
Published: January 2025

Background

Cefepime/enmetazobactam (FEP/META) is a new β-lactam/β-lactamase inhibitor combination with broad-spectrum activity against MDR Enterobacterales (including OXA-48-producing isolates) which has demonstrated superiority to piperacillin/tazobactam for the treatment of complicated urinary tract infections. This study was conducted to evaluate the activity of cefepime/enmetazobactam against a collection of Acinetobacter baumannii isolates positive for characterized OXA carbapenemases.

Methods

The MICs of cefepime, FEP/META (META tested at a fixed concentration of 8 mg/L) and other relevant agents were determined by broth microdilution according to EUCAST guidelines against a panel of 120 OXA-positive A. baumannii collected globally (30 isolates each positive for OXA-23, OXA-24, OXA-51 and OXA-58 carbapenemases).

Results

The A. baumannii isolates producing class D carbapenemases were 0.8% susceptible to ciprofloxacin or meropenem, and 22.5% susceptible to gentamicin. At the proposed FEP/META breakpoint of 8 mg/L, the susceptibility of OXA-positive A. baumannii isolates was 31.7% showing synergy compared with FEP alone. FEP/META had a limited in vitro activity against the most common carbapenem resistant A. baumannii (OXA-23 or OXA-24 producers), but it showed promising activity against OXA-58 and OXA-51 producers.

Conclusions

Enmetazobactam displayed a capacity to restore cefepime activity against clinical isolates of OXA-51 and OXA-58 carbapenemase producing A. baumannii, rendering many of the isolates that were resistant to commercial comparators susceptible to FEP/META.
Exoskeleton Robot Training in Two Patients with an Electrical Burn and Septic Arthritis: A Case Report
Authors: Lee Seung Yeol , Seo Cheong Hoon , Ch Yoon Soo , Kim Youngmin , Yoon Youngsuh , Joo So Young
Published: January 2025

Septic arthritis (SA) is rare in patients with burns, but delayed treatment can result in irreversible joint destruction. Early diagnosis and immediate treatment are necessary to prevent joint destruction. Robot training in patients with musculoskeletal diseases and burns can improve joint range of motion (ROM), muscle strength, and lower extremity function. The aim of this report is to present robot training utility in patients with lower extremity electrical burns and associated SA. Rebless (H-Robotics, Korea) for ROM and strength training can operate in passive or active modes in knee or ankle flexion and extension. Rebless works by providing visual feedback on angles during flexion and extension training. Two participants, diagnosed with SA after burns and unable to walk before training because of joint pain, limited ROM, and muscle weakness, underwent 30 min of robot training using Rebless with 30-min conventional therapy, 5 days a week for 8 weeks. After training, the gait function, muscle strength, and pain scores of the participants improved without adverse effects on joint ROM. This report is the first to demonstrate that robot training has a positive effect on gait function, pain, muscle strength with no soft tissue contractures, or other complications in a patient with burn injury and SA.
On-farm evaluation of swede midge (Diptera: Cecidomyiidae) susceptibility among popular kale varieties
Authors: Izzo Victor M , Lewins Scott A , Nouri-Aiin Maryam
Published: January 2025

The swede midge, Contarinia nasturtii Kieffer (Diptera:Cecidomyiidae), is a gall-forming insect pest that targets cruciferous plants. Since its introduction to North America in the early 2000s, the midge has expanded its range to include farming regions in Quebec and the Northeastern USA. In this study, we evaluated the susceptibility of 4 popular kale varieties—Green Curly—(Vates), Red Russian, Red Curly (RedBor), and Lacinato/Tuscan—to swede midge infestation in on-farm trials conducted over consecutive years. Our results indicate substantial variability in susceptibility among varieties, with Red Russian kale consistently exhibiting the highest damage incidence across both years. These findings provide valuable insights for developing effective integrated pest management (IPM) strategies tailored to organic and small-scale vegetable farming contexts, emphasizing the role of crop genetic resources in pest mitigation and sustainable agriculture. In addition, this study highlights the potential of non-chemical approaches for managing swede midge, leading to a more diverse and adaptable IPM toolbox for growers.
Teleost IgM+ plasma-like cells: beyond antibody secretion
Authors: Wu Liting , Morel Esther , Simón Rocío , Perdiguero Pedro , Zhang Yong-An , Ye Jianmin , Tafalla Carolina
Published: January 2025

Upon antigen encounter, B cells start a differentiation process toward antibody-secreting cells (ASCs), initially plasmablasts, and eventually long-lived plasma cells. All these ASCs specialize in secreting important amounts of antibodies and usually lose other functionalities of naïve B cells. This differentiation process is scarcely characterized in teleost fish, in which B cells have been shown to share many functional and phenotypic characteristics of mammalian B1 innate subsets. In this context, we were prompted to investigate further the functionalities of ASCs in teleosts, using rainbow trout (Oncorhynchus mykiss) as a model. Our results demonstrate that IgM+ plasma-like cells in the rainbow trout head kidney exhibit a strong IgM secreting capacity along with phagocytic and antigen-presenting capacities, even higher than those of naïve B cells. These IgM+ plasma-like cells were capable of surviving in vitro for 2 wk secreting IgM. Interestingly, they retained a functional B cell receptor that responded to TNP conjugated to lipopolysaccharide, a thymus-independent model antigen, which also rendered these cells more reactive to B cell receptor crosslinking. These findings shed light on the differentiation process of teleost B cells, demonstrating that teleost plasma-like cells conserve other phenotypical attributes beyond immunoglobulin secretion, being capable of directly responding to antigens. These findings point to an exclusive differentiation process of teleost B cells, which might provide mechanistic insights on how mammalian innate subsets such as B1 cells or IgM-expressing plasma cells differentiate.
PVR exposure influences the activation, adhesion, and protein expression of human CD8+ T cells, including the CD96-mediated transfer of PVR
Authors: Huang Xueting , Pawge Girija , Snicer Christina E , Hsiao Chia-Hung Christine , Wiemer Andrew J
Published: January 2025

Poliovirus receptor (PVR) ligands have gained attention as immunotherapy targets, yet their regulation remains unclear. Here, we examine the impact of PVR exposure on primary human CD8+ T cells. We used flow cytometry and Western blot analysis to quantify expression of PVR and its ligands in naïve and effector T cells and used adhesion assays and enzyme-linked immunosorbent assay (ELISA) to assess the impact of PVR on T cell adhesion and cytokine production. Stimulation with phytohemagglutinin P strongly increased DNAM-1 expression and caused a less robust and more variable increase in TIGIT expression. Exposure to PVR-Fc enhanced the CD8+ T cell adhesion to ICAM-1–coated plates in a dose-dependent manner, while exposure to PVR-expressing K32 cells mildly decreased CD8+ T cell interferon γ release. However, PVR exposure strongly decreased the expression of DNAM-1, TIGIT, and CD96. The reduction of DNAM-1, TIGIT, and CD96 induced by PVR was dominant to the increase caused by T cell receptor signaling. The impact of PVR on their expression was completely abolished by the Q63R and F128R point mutations of PVR, while DNAM-1 was partially rescued by inhibitors of Src and protein kinase C. Additionally, PVR exposure along with T cell receptor signaling promoted the transfer of surface proteins including PVR from K32 cells to CD8+ T cells. This PVR transfer was mediated by the IgV domain of PVR and CD96 on CD8+ T cells and required cellular contact. Our findings collectively demonstrate that PVR engagement has a mild antagonistic effect on interferon γ production but strongly impacts CD8+ T cell adhesion and protein expression.
Topoisomerase 1 is required for the development and function of thymus
Authors: Kumar Amit , Choubey Pallawi , Kaur Harshdeep , Muralidhara Prerana , Bansal Kushagra
Published: January 2025

Thymus organogenesis is critical for proper maturation of developing T cells. In this study, we identified Top1 as a novel gene involved in thymus development and function. We created a mouse line with deletion of Top1 in thymic epithelial cells (TECs), and our results demonstrate that biallelic loss of Top1 in TECs causes congenital thymic aplasia, precipitating T cell immunodeficiency. Transcriptomic analysis provides insights into the molecular mechanism of Top1 in thymus development as we identify key genes involved in thymus organogenesis as the transcriptional targets of Top1 in TECs. Analysis of peripheral immunological compartments revealed severe loss of αβ T cells complemented with a disproportionate accumulation of γδ T cells and myeloid cells upon deletion of Top1 in TECs. The residual αβ T cells in Top1 knockout mice were effector and oligoclonal in nature highlighting their self-reactivity. These results reveal a previously unknown role of Top1 in thymus development and T cell homeostasis. We propose Top1 as a genetic target for altered thymic development and T cell lymphopenia.
Suppression of NF-κB and downstream XBP1 by DcR3 contributes to a decrease in antibody secretion
Authors: Liu Po-Chun , Huang Szu-Ying , Lin Kuo-I , Hsieh Shie-Liang , Leu Chuen-Miin
Published: January 2025

Decoy receptor 3 (DcR3), a soluble receptor in the tumor necrosis factor receptor superfamily, regulates the functions of monocytes, macrophages, dendritic cells, and T cells. Previous studies have demonstrated that DcR3 suppresses B cell proliferation in vitro and ameliorates autoimmune diseases in animal models; however, whether and how DcR3 regulates antibody production is unclear. Using a DcR3 transgenic mouse model, we found that DcR3 impaired the T cell–dependent antigen-stimulated antibody response. The number of Ag-specific antibody-secreting cells was transiently reduced, but the concentration of specific antibodies continued to decrease in the DcR3 transgenic mice, implying a direct suppression of antibody production by DcR3. In vitro assays showed that the DcR3-Fc fusion protein attenuated T cell–dependent induced antibody production and reduced the expression of secretory Igh and Xbp1. We found that nuclear factor κB (NF-κB) activity was essential for the expression of Xbp1 in activated B cells. DcR3-Fc attenuated anti-CD40-induced NF-κB activity and Xbp1 promoter activity. Furthermore, DcR3-Fc decreased the expression of Xbp1 in Blimp1+ antibody-secreting cells. Restoration of spliced XBP1 (X-box binding protein 1) in DcR3-treated B cells increased the secretory Ighg1 transcript levels, suggesting that reducing XBP1 is one of the mechanisms by which DcR3 regulates antibody production both in vitro and in vivo. Collectively, these results indicate that in addition to blocking proliferation, DcR3 impairs NF-κB activation, subsequently decreasing the expression of Xbp1, eventually leading to a reduction in antibody secretion.
Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells
Authors: Miller-Handley Hilary , Harper Gavin , Pham Giang , Turner Lucien H , Shao Tzu-Yu , Russi Abigail E , Erickson John J , Ford Mandy L , Araki Koichi , Way Sing Sing
Published: January 2025

Organ transplant recipients require continual immune-suppressive therapies to sustain allograft acceptance. Although medication nonadherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here, we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune-suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells. Uninterrupted immune-suppressive therapy is required because drug discontinuation triggers allograft rejection, replicating the requirement for immune-suppressive therapy adherence in transplant recipients. Graft-specific CD8+ T cells in allograft-accepted mice show diminished effector differentiation and cytokine production, with reciprocally increased PD1 expression. Allograft acceptance–induced PD1 expression is essential, as PDL1 blockade reinvigorates graft-specific CD8+ T cell activation with ensuing allograft rejection despite continual immune-suppressive therapy. Thus, PD1 sustained CD8+ T cell inhibition is essential for allograft acceptance maintained by tacrolimus plus mycophenolate. This necessity for PD1 in sustaining allograft acceptance explains the high rates of rejection in transplant recipients with cancer administered immune checkpoint inhibitors targeting PD1/PDL1, highlighting shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection.
Noise reduction of low-dose electron holograms using the wavelet hidden Markov model
Authors: Tomita Yuto , Midoh Yoshihiro , Tamaoka Takehiro , Murakami Yasukazu
Published: January 2025

The precision in electron holography studies on electrostatic and magnetic fields depends on the image quality of an electron hologram. Enhancing the image quality of electron holograms is essential for the comprehensive analysis of weak electromagnetic fields; however, extended electron beam irradiation can lead to undesirable radiation damage and contamination. Recent studies have demonstrated that noise reduction using the wavelet hidden Markov model (WHMM) can improve the precision of phase analysis for limited thin-foiled crystals. In this study, we examine the effects of WHMM-based denoising on the electron holography data of weakly charged nanoparticles collected under low-electron-dose conditions. The results indicate that effective noise reduction with the WHMM allows for a reduction in the magnitude of the electron dose by approximately half relative to data collection without WHMM denoising, while maintaining the same level of charge determination precision: less than one elementary charge. Notably, at a low electron dose of 0.40 e−/pixel, WHMM denoising enables the clear visualization of a weak stray electric field outside a charged latex sphere. This method offers significant advantages for electron holography studies of electron-beam-sensitive materials requiring minimal time for electron exposure.
Abdominal visceral and subcutaneous adipose tissue associations with postmenopausal breast cancer incidence
Authors: Bea Jennifer W , Ochs-Balcom Heather M , Valencia Celina I , Chen Zhao , Blew Robert M , Lind Kimberly E , Caan Bette J , Roe Denise J , Rohan Thomas E , Reeves Katherine W , Manson JoAnn E , Ballinger Tarah , Reding Kerryn W , Follis Shawna , Ziller Shelby G , Odegaard Andrew O
Published: January 2025

Background

Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear.

Methods

We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27 years follow-up (N = 9950), during which all new cancers were adjudicated. Dual-energy X-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa.

Results

Participants averaged 63.3 ± 7.4 years of age and a BMI of 28.20 ± 5.72 kg/m2 at baseline. The models included 738 incident BCa cases (N = 593 invasive; N = 145 in situ). Baseline VAT and SAT area were associated with significantly increased BCa risk, by 36% and 19% respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, though not significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared to Q1 was 1.49 (95% CI: 1.18, 1.87).

Conclusion

Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample.(NCT00000611)
Warming inhibited new soil organic carbon formation with higher bacterial necromass contribution
Authors: Liao Chang , Zhai Deping , Cheng Xiaoli
Published: January 2025

Warming has been consistently observed to reduce soil carbon (C) storage by accelerating soil organic matter (SOM) decomposition. While soil C fraction may differentially respond to warming, and microbial necromass has been considered an important contributor to persistent soil C pool. However, how warming regulates microbial necromass formation and their potential contribution to new soil organic carbon (SOC) fractions is not fully understood. In this study, we examined the effects of elevated temperature on newly formed amino sugar C (i.e., indicative of fungal and bacterial-derived microbial necromass C) and its allocation in particulate organic matter (POM) and mineral-associated organic matter (MAOM) fractions in alpine soils of Southwest China, based on 37-day incubation experiments at 15 ℃ and 25 ℃ by adding 13C labeled glucose and oxalic acid. The results showed that warming significantly reduced the formation of new SOC by lowering the incorporation of new C into both POM and MAOM fractions. Glucose addition was found to enhance new SOC formation more effectively than oxalic acid addition regardless of temperature. Warming also significantly decreased the new microbial necromass in both soil fractions with more bacterial necromass associated with mineral particles, which was primarily attributed to a higher abundance of bacterial community. In addition, glucose addition significantly promoted the fungal necromass contribution to newly formed SOC. Overall, this study revealed that warming significantly altered the allocation of newly-formed SOC and microbial necromass, highlighting the different microbial responses in soil C sequestration with implications for predicting and managing soil C stocks in forest ecosystems under climate change.
Suggested Dosing of Select Beta-lactam Agents for the Treatment of Antimicrobial-Resistant Gram-Negative Infections in Children
Authors: Lockowitz Christine R , Hsu Alice J , Chiotos Kathleen , Bio Laura L , Dassner Aimee M , Gainey Andrew B , Girotto Jennifer E , Iacono Denise , Morrisette Taylor , Stimes Grant , Tran M Tuan , Wilson William S , Tamma Pranita D
Published: January 2025

The Infectious Diseases Society of America (IDSA) publishes annual guidance on the treatment of antimicrobial-resistant (AMR) gram-negative infections. Within the AMR guidance, suggested dosages of antibiotics for adults infected with AMR pathogens are provided. This document serves as a companion document to the IDSA guidance to assist pediatric specialists with dosing β-lactam agents for the treatment of AMR infections in children. A panel of 13 pediatric infectious diseases specialists, including 11 pharmacists and 2 physicians, reviewed existing pharmacokinetic/pharmacodynamic, animal, and clinical data for newer β-lactam agents that are available in the United States and suggested for the treatment of AMR infections (ie, cefiderocol, ceftazidime-avibactam, ceftazidime-avibactam and aztreonam, ceftolozane-tazobactam, imipenem-cilastatin-relebactam, meropenem-vaborbactam, sulbactam-durlobactam). Suggested dosing for ampicillin-sulbactam is also provided, given complexities in dosing for carbapenem-resistant Acinetobacter baumannii infections. Consensus-based suggested dosing for β-lactam agents used to treat AMR infections in neonates, infants, children, and adolescents and relevant supporting evidence are provided. Content is up to date as of December 1, 2024. Gaps and limitations to existing data are discussed. Optimizing antibiotic dosing is critical to improving the outcomes of children with AMR infections.
Convergent pairs of highly transcribed genes restrict chromatin looping in Dictyostelium discoideum
Authors: Zhegalova Irina V , Ulianov Sergey V , Galitsyna Aleksandra A , Pletenev Ilya A , Tsoy Olga V , Luzhin Artem V , Vasiluev Petr A , Bulavko Egor S , Ivankov Dmitry N , Gavrilov Alexey A , Khrameeva Ekaterina E , Gelfand Mikhail S , Razin Sergey V
Published: January 2025

Dictyostelium discoideum is a unicellular slime mold, developing into a multicellular fruiting body upon starvation. Development is accompanied by large-scale shifts in gene expression program, but underlying features of chromatin spatial organization remain unknown. Here, we report that the Dictyostelium 3D genome is organized into positionally conserved, largely consecutive, non-hierarchical and weakly insulated loops at the onset of multicellular development. The transcription level within the loop interior tends to be higher than in adjacent regions. Loop interiors frequently contain functionally linked genes and genes which coherently change expression level during development. Loop anchors are predominantly positioned by the genes in convergent orientation. Results of polymer simulations and Hi-C-based observations suggest that the loop profile may arise from the interplay between transcription and extrusion-driven chromatin folding. In this scenario, a convergent gene pair serves as a bidirectional extrusion barrier or a ‘diode’ that controls passage of the cohesin extruder by relative transcription level of paired genes.
Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC
Authors: Corbett Ryan J , Gullickson Cricket C , Geng Zhuangzhuang , Brown Miguel A , Zhang Bo , Zhong Chuwei , Van Kuren Nicholas , Chroni Antonia , Blackden Christopher , Naqvi Ammar S , Plisiewicz Alexa , McHugh Sean , Drake Emmett , Lehmann Kaitlin , Davidson Tom B , Prados Michael , Storm Phillip B , Resnick Adam C , Waanders Angela J , Waszak Sebastian M , Mueller Sabine , Rokita Jo Lynne , Kline Cassie
Published: January 2025

Background

Central nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied, but is limited.

Methods

We performed genetic ancestry prediction in 1,452 pediatric patients with paired normal and tumor whole genome sequencing from the Open Pediatric Cancer (OpenPedCan) project to evaluate the influence of reported race and ethnicity and ancestry-based genetic superpopulations on tumor histology, molecular subtype, survival, and treatment.

Results

Predicted superpopulations included African (AFR, N=153), Admixed American (AMR, N=222), East Asian (EAS, N=67), European (EUR, N=968), and South Asian (SAS, N=42). Reported race and ethnicity and ancestry-based genetic superpopulations were non-randomly associated (p<0.001). Patients with an atypical teratoid rhabdoid tumor or meningioma were enriched for AFR ancestry (OR=2.6, FDR=0.01; OR=2.9, FDR=0.01, respectively). Among KIAA1549::BRAF fusion-positive low-grade glioma (LGG) diagnoses, EAS and SAS patients disproportionately harbored exon 15:09 breakpoints (FDR<0.05), and AMR patients demonstrated rare breakpoints, which were associated with lesser degree of surgical resection and worse event free survival (EFS) versus other breakpoints (HR=4.6, p=0.03). Non-EUR and AMR patients with germ cell tumors and SHH-activated medulloblastoma, respectively, exhibited worse EFS relative to EUR patients (HR=12.1, p<0.01; HR=5.2, p=0.03) and AFR patients with LGG (HR=16.4, p<0.01) or ependymoma (HR=5.5, p=0.02) had worse overall survival compared to EUR patients. We observed higher frequency of clinical trial enrollment among AMR patients across tumor histologies (OR=2.0, p=<0.01), but increased utilization of photon versus proton radiation relative to other superpopulations (OR=0.55, p=0.04).

Conclusions

Genetic ancestry-associated differences exist across pediatric CNS tumor histological and molecular subtypes from PBTA and PNOC. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.
Cannabis use among Dutch patients with a primary brain tumor
Authors: Belgers Vera , Rietveld Niek A , de Witt Hamer Philip C , Niers Johanna M
Published: January 2025

Background

Cancer patients commonly use cannabis to improve symptoms or for presumed anti-cancer effects. However, the extent and type of cannabis use among Dutch primary brain tumor patients, along with their motivations, remains unclear. This study aims to determine the prevalence of prior or current cannabis use in patients with a primary brain tumor, the type of cannabis used, their motivation, how they perceived the effects of the cannabis, and what adverse effects they noticed.

Methods

We conducted a cross-sectional survey of adult primary brain tumor patients who visited the neuro-oncology outpatient clinic at Amsterdam UMC between August and October 2023.

Results

Of 100 responding patients, 51% had ever used cannabis and 14% currently used cannabis. Of the total group, 19% currently or previously used cannabis for tumor-related reasons including symptom relief (n = 14; 74%) and presumed effect on the tumor (n = 8; 42%), indicating that some patients used it for multiple therapeutic purposes. Patients favored cannabidiol (CBD) over Δ9-tetrahydrocannabinol (THC). Self-reported sleep, anxiety, worrying, and depressive symptoms most frequently improved due to cannabis use, and the most common self-reported adverse events included drowsiness, dry mouth, and dizziness.

Conclusions

A considerable amount of primary brain tumor patients use cannabis, often for symptom relief or presumed anti-tumor effects. The user rate underscores a demand for clinical research into the therapeutic efficacy of cannabis, particularly concerning its impact on symptoms like sleep disturbances, depressive symptoms, and anxiety/worrying, as well as its tumor-inhibiting capabilities.
Fifteen Years of NOVA Food-Processing Classification: “Friend or Foe” Among Sustainable Diet Indicators? A Scoping Review
Authors: Tompa Orsolya , Kiss Anna , Soós Sándor , Lakner Zoltán , Raner Ana , Kasza Gyula , Szakos Dávid
Published: January 2025

It has been 15 years since the introduction of the NOVA food-processing classification. While it was designed to identify ultra-processed foods linked to noncommunicable diseases, the NOVA system has a holistic concept that fits with sustainable nutrition. However, NOVA’s connection to other sustainable diet indicators has not been thoroughly explored. The aim was to summarize the research and methodological context of using the NOVA system with other sustainable diet indicators and to investigate NOVA’s synergies and discordance with them. A scoping review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews (PRISMA-ScR). Studies published between 2009 and 2023 were collected from the Web of Science, Scopus, and PubMed databases. 1612 studies were initially screened; in the selected studies (n = 77), the NOVA system was applied in addition to other sustainable diet indicator(s). The studies were analyzed within a qualitative data analysis framework. 77 studies were analyzed in which healthiness (n = 66), environmental pressure (n = 9), affordability (n = 11), other processing classifications (n = 6), and other sustainable diet indicators (n = 10) were applied with NOVA. Among them, the identified relationships between the NOVA system and other healthfulness indicators were synergistic in the majority of studies (n = 70/93). For environmental pressure indicators, a mixed picture was observed; the NOVA classification was predominantly synergistic with greenhouse gas emissions (n = 8/13), while it was mostly discordant with fresh water use (n = 8/12). Economic affordability was also found to be discordant with the NOVA classification in the majority of studies (n = 10/16). To complete the NOVA classification with nutrient profiling would be beneficial to identify healthy diets. In the case of the integration of NOVA into sustainable nutrition research, environmental pressure and economic affordability indicators should be controlled to reach optimal trade-offs for more sustainable diets. The application of NOVA is gaining relevance; thus, its methodological adaptation to sustainable nutrition research is necessary.
Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction
Authors: Chung Vincent , Alistar Angela , Becerra Carlos , Kasi Anup , Borazanci Erkut , Jameson Gayle S , Roe Denise J , Wertheim Betsy C , Cridebring Derek , Truitt Morgan , Downes Michael , Barrett Michael T , Korn Ron , Lee Keehoon , Han Haiyong , Evans Ronald , Von Hoff Daniel D
Published: January 2025

Lessons learned

Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life.

Background

Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade.

Methods

This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS).

Results

There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms.

Conclusions and relevance

Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity.

Trial Registration

Clinicaltrials.gov, ID: NCT03331562.
Why High-Level Explanations Exist
Authors: Strevens Michael
Published: January 2025

High-level explanation would be impossible without a certain kind of independence of high-level behavior from low-level behavior. This partial autonomy has been characterized in various ways by scientists and philosophers; the present chapter advances a particular characterization deemed ‘semi-detachment’. The main business of the chapter is to pose and suggest an answer to the question why semi-detachment should be so widespread, enabling the existence of explanatory scientific disciplines—evolutionary biology, sociology, economics—that operate almost entirely separately from the disciplines that study their lower-level substrates (microbiology and psychology, for example). The approach explored here turns on low-level details' propensity to cancel or balance out in much the same way that the outcomes produced by a simple chance setup such as a coin toss balance out to produce stable frequencies. Such ‘canceling out’ considerations, it is argued, provide at least a partial account of why high-level explanations in the sciences should be, not merely possible, but plentiful.