bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant treatment for renal cell carcinoma: current status and future
Authors: Leung David K.W. , Siu Brian W.H. , Teoh Jeremy Y.C. 
Published: September 2024

Purpose of review
Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized.

Recent findings
KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53–0.87; P = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44–0.87; P = 0.005). A number of other adjuvant ICI trials have though been negative.

Summary
Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted.
Hypertrophic nonunion management with distraction osteogenesis: a scoping review of the literature
Authors: Rouse Benjamin J. , Sheridan Gerard A. , Page Brian J. , Fragomen Austin T. , Rozbruch S. Robert 
Published: September 2024

Abstract

Introduction:
Traditionally, stiff hypertrophic nonunions have been managed with open preparation of the nonunion site, which is then secured with internal fixation. Alternative surgical options are available including distraction osteogenesis with an external fixator. There is currently a limited amount of literature pertaining to the use of distraction osteogenesis in the management of hypertrophic nonunion. The aim of this systematic review was to collate and assess the effectiveness of distraction osteogenesis (DO) in the management of hypertrophic nonunions and to evaluate the complications that are commonly reported in the literature.

Methods:
We searched for articles pertaining to the treatment of hypertrophic nonunion using distraction osteogenesis. Several electronic bibliographic databases and clinical trial registries were searched using the MeSH terms “hypertrophic non-union,” “distraction osteogenesis,” “stiff non-union,” and “External Fixation” in various combinations to return the maximal number of studies for review. We performed a systematic review and identified a total of 11 studies eligible for review.

Results:
The review of the literature demonstrated that this technique is highly effective in achieving bony union with minimal complications. The most common complication is mild superficial pin site infections, usually managed with oral antibiotics and effective wound hygiene. Other complications reported were deep pin tract infections, broken hardware, and deformity recurrence due to collapse of regenerate bone.

Conclusion:
The use of distraction osteogenesis with external fixator devices is an effective and safe method for producing bony union in hypertrophic nonunions. There were minimal associated complications.
Susceptibility Screening of HIV-1 Viruses to Broadly Neutralizing Antibodies, Teropavimab and Zinlirvimab, in People With HIV-1 Suppressed by Antiretroviral Therapy
Authors: Selzer Lisa , VanderVeen Laurie A. , Parvangada Aiyappa , Martin Ross , Collins Sean E. , Mehrotra Megha , Callebaut Christian 
Published: September 2024

Background:
HIV envelope (env) diversity may result in resistance to broadly neutralizing antibodies (bNAbs). Assessment of genotypic or phenotypic susceptibility to antiretroviral treatment is often performed in people with HIV-1 (PWH) and used for clinical trial screening for HIV-1 bNAb susceptibility. Optimal bNAb susceptibility screening methods are not yet clear.

Methods:
Phenotypic and genotypic analyses were conducted on 124 screening samples from a phase 1b study of bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS) administered with lenacapavir in virally suppressed PWH. Phenotypic analysis was conducted on integrated HIV-1 provirus and stimulated outgrowth virus, with susceptibility to bNAbs defined as 90% inhibitory concentration ≤2 μg/mL. The proviral DNA HIV env gene was genotyped using deep sequencing, and bNAb susceptibility predicted using published env amino acid signatures.

Results:
Proviral phenotypic results were reported for 109 of 124 samples; 75% (82/109) were susceptible to teropavimab, 65% (71/109) to zinlirvimab, and 50% (55/109) to both bNAbs. Phenotypic susceptibility of outgrowth viruses was available for 39 samples; 56% (22/39) were susceptible to teropavimab, and 64% (25/39) to zinlirvimab. Phenotypic susceptibilities correlated between these methods: teropavimab r = 0.82 (P < 0.0001); zinlirvimab r = 0.77 (P < 0.0001). Sixty-seven samples had genotypic and phenotypic data. Proviral genotypic signatures predicted proviral phenotypic susceptibility with high positive predictive value (68%–86% teropavimab; 63%–90% zinlirvimab).

Conclusions:
bNAb susceptibility was correlated among all 3 in vitro assays used to determine teropavimab and zinlirvimab susceptibility in virally suppressed PWH. These findings may help refine PWH selection criteria for eligibility for future studies.
FIBRINOLYTIC DYSFUNCTION AND ENDOTHELIOPATHY AFTER MAJOR THERMAL INJURY: CONSIDERATIONS NEEDED FOR NEW APPROACHES TO BURN SHOCK RESUSCITATION
Authors: Pusateri Anthony E. , Moffatt Lauren T. , Ho Dao H. , Neidert Leslie E. , Morgan Clifford G. , Tejiram Shawn , Cardin Sylvain , Shupp Jeffrey W. 
Published: September 2024

ABSTRACT
In recent years, it has become apparent that fibrinolytic dysfunction and endotheliopathy develop in up to 40% of patients during the first hours following thermal injury and are associated with poor outcomes and increased resuscitation requirements. Rapidly following burn injury, the fibrinolytic system is activated, with activation generally greater with increased severity of injury. Very high plasma concentrations of plasmin-antiplasmin complex (marker of activation) have been associated with mortality. Patients display hyperfibrinolytic, physiologic/normal, or hypofibrinolytic/fibrinolytic shutdown phenotypes, as assessed by viscoelastic assay. Phenotypes change in over 50% of patients during the acute burn resuscitation period, with some patterns (maladaptive) associated with increased mortality risk and others (adaptive, trending toward the physiologic phenotype) associated with survival. Endotheliopathy, as reflected in elevated plasma concentrations of syndecan-1 has also been associated with increased mortality. Here we review the incidence and effects of these responses after burn injury and explore mechanisms and potential interactions with the early inflammatory response. Available data from burn and nonburn trauma suggest that the fibrinolytic, endothelial, and inflammatory systems interact extensively and that dysregulation in one may exacerbate dysregulation in the others. This raises the possibility that successful treatment of one may favorably impact the others.
The genetic history of Portugal over the past 5,000 years
Authors: Roca-Rada Xavier , Davidson Roberta , Williams Matthew P. , Ravishankar Shyamsundar , Collen Evelyn , Haarkötter Christian , Taufik Leonard , Carvalho António Faustino , Villalba-Mouco Vanessa , Cuesta-Aguirre Daniel R. , Tente Catarina , Monge Calleja Álvaro M. , MacRoberts Rebecca Anne , Melo Linda , Purnomo Gludhug A. , Souilmi Yassine , Tobler Raymond , Cunha Eugénia , Tereso Sofia , Matos Vítor M. J. , Fernandes Teresa Matos , Mauer Anne-France , Silva Ana Maria , Carvalho Pedro C. , Llamas Bastien , Teixeira João C. 
Published: September 2024

AbstractBackgroundRecent ancient DNA studies uncovering large-scale demographic events in Iberia have focused primarily on Spain, with limited reports for Portugal, a country located at the westernmost edge of continental Eurasia. Here, we introduce the largest collection of ancient Portuguese genomic datasets (n = 68) to date, spanning 5,000 years, from the Neolithic to the 19thcentury.ResultsWe found evidence of patrilocality in Neolithic Portugal, with admixture from local hunter-gatherers and Anatolian farmers, and persistence of Upper Paleolithic Magdalenian ancestry. This genetic profile persists into the Chalcolithic, reflecting diverse local hunter- gatherer contributions. During the Bronze Age, local genetic ancestry persisted, particularly in southern Iberia, despite influences from the North Pontic Steppe and early Mediterranean contacts. The Roman period highlights Idanha-a-Velha as a hub of migration and interaction, with a notably diverse genetic profile. The Early Medieval period is marked by Central European ancestry linked to Suebi/Visigoth migrations, adding to coeval local, African, and Mediterranean influences. The Islamic and Christian Conquest periods show strong genetic continuity in northern Portugal and significant African admixture in the south, with persistent Jewish and Islamic ancestries suggesting enduring influences in the post-Islamic period.ConclusionsThis study represents the first attempt to reconstruct the genetic history of Portugal from the analysis of ancient individuals. We reveal dynamic patterns of migration and cultural exchange across millennia, but also the persistence of local ancestries. Our findings integrate genetic information with historical and archaeological data, enhancing our understanding of Iberia’s ancient heritage.
The Molecular Toll Pathway Repertoire in Anopheline Mosquitoes
Authors: Rhodes Victoria L. , Waterhouse Robert M. , Michel Kristin 
Published: September 2024

ABSTRACTInnate immunity in mosquitoes has received much attention due to its potential impact on vector competence for vector-borne disease pathogens, including malaria parasites. The nuclear factor (NF)-κB-dependent Toll pathway is a major regulator of innate immunity in insects. In mosquitoes, this pathway controls transcription of the majority of the known canonical humoral immune effectors, mediates anti-bacterial, anti-fungal and anti-viral immune responses, and contributes to malaria parasite killing. However, besides initial gene annotation of putative Toll pathway members and genetic analysis of the contribution of few key components to immunity, the molecular make-up and function of the Toll pathway in mosquitoes is largely unexplored. To facilitate functional analyses of the Toll pathway in mosquitoes, we report here manually annotated and refined gene models of Toll-like receptors and all putative components of the intracellular signal transduction cascade across 19 anopheline genomes, and in two culicine genomes. In addition, based on phylogenetic analyses, we identified differing levels of evolutionary constraint across the intracellular Toll pathway members, and identified a recent radiation of TOLL1/5 within theAn. gambiaecomplex. Together, this study provides insight into the evolution of TLRs and the putative members of the intracellular signal transduction cascade within the genusAnopheles.
Endothelial miR-34a deletion guards against aneurysm development despite endothelial dysfunction
Authors: Kopacz Aleksandra , Kloska Damian , Bar Anna , Targosz-Korecka Marta , Cysewski Dominik , Chlopicki Stefan , Jozkowicz Alicja , Grochot-Przeczek Anna 
Published: September 2024

AbstractObjectivesOur previous study reported a reciprocal link between NRF2, a stress-responsive cytoprotective transcription factor, and aortic and endothelial cell (EC) ageing. We also found that NRF2 transcriptional knockout (tKO) mice are prone to abdominal aortic aneurysm (AAA) development. Given that miRNA-34a is a marker of ageing, in this study we explored its relationship with NRF2 and its role in vascular function and AAA formation.Approach and resultsThe experiments were performed in primary human aortic endothelial cells (HAECs) from young and aged donors and mice devoid of NRF2 transcriptional activity and endothelial miR-34a. The normolipidemic mice were challenged with angiotensin II (Ang II) to develop AAA. We show that premature NRF2-dependent aging of aortic endothelial cells (ECs) depends on miR-34a. Infusion of hypertensive Ang II in mice increases miR-34a in the aortic endothelial layer and serum, especially in mice which develop AAA. Mice deficient in endothelial miR-34a (miR-34aΔEC) display severe EC dysfunction. Despite that, such mice are protected from AAA development, also on the NRF2 tKO background. Ang II infusion increases proliferation of intimal ECs in these mice. The protective effect of endothelial miR-34a deletion on AAA formation is reversed by rapamycin that suppresses EC proliferation. MTA2, but not SIRT1, is a direct target of miR-34a abrogating Ang II-induced EC proliferation.ConclusionsThese findings reveal that AAA development in NRF2 tKO mice relies on endothelial miR-34a overexpression. Deletion of endothelial miR-34a protects mice from AAA despite inducing endothelial cell dysfunction. The fine-tuning of EC proliferation may play a therapeutic role in the treatment of aneurysm.
Interaction between facial expression and color in modulating ERP P3
Authors: Hasegawa Yuya , Tamura Hideki , Nakauchi Shigeki , Minami Tetsuto 
Published: September 2024

AbstractThe relationships between facial expression and color affect human cognition functions such as perception and memory. However, whether these relationships influence attention remains unclear. Additionally, whether facial expressions affect selective attention is unknown; for example, reddish angry faces increase negative social evaluation or emotion intensity, but it is unclear whether selective attention is similarly enhanced. To investigate these questions, we examined whether event-related potentials for faces vary depending on facial expression and color by recording electroencephalography (EEG) data. We conducted an oddball task using stimuli that combined facial expressions (angry, neutral) and facial colors (original, red, green). The participants counted the number of times a rarely appearing target face stimulus appeared among the standard face stimuli. The results indicated that the difference in P3 amplitudes for the target and standard faces depended on the combinations of facial expressions and facial colors; the P3 amplitudes for red angry faces were greater than those for red neutral faces. Additionally, there was no significant main effect or interaction effect of facial expression or facial color on P1 amplitudes for the target, and there were significant main effects of facial expression only on the N170 amplitude. These findings suggest that the intensity of a human’s selective attention to facial expressions varies according to the higher-order semantic processing of the relationship between emotion and color rather than simple facial expression or facial color effects individually. Our results support the idea that red color increases the human response to anger from an EEG perspective.Significance StatementIt remains unclear whether selective attention to faces is modulated by the relationships between facial expression and color. Using an oddball task and recording EEGs, we showed that the event-related potentials reflecting selective attention are modulated by the interaction between facial expression and facial color, although the interaction was not found at earlier ERP stages. These findings suggest that the intensity of selective attention to facial expressions is influenced more by the interaction between facial expression and facial color than by facial expression or facial color alone and that the interaction occurs as a higher-order processing step than facial expression or color recognition. Our results provide EEG evidence supporting the idea that red color increases the human response to anger.
Structural insight into the nuclear transportation mechanism of PPARγ by Transportin-1
Authors: Toma-Fukai Sachiko , Nakamura Yutaro , Kawamoto Akihiro , Shimizu Hikaru , Hayama Koki , Kojima Ruri , Yoshimura Kanami , Ishii Masaki , Hirose Mika , Teratani Toshiaki , Ohata Shinya , Kato Takayuki , Kamikubo Hironari , Itoh Toshimasa , Tomita Kengo , Shimizu Toshiyuki 
Published: September 2024

AbstractThe spatial and temporal control of protein is essential for normal cellular function. Proteins working in the nucleus have nuclear localization signal (NLS) sequences and are escorted into the nucleus by cognate nuclear transport receptors. A wealth of experimental data about NLS has been accumulated, and nuclear transportation mechanisms are established at the biochemical and structural levels.The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that control various biological responses. We recently reported that the transportation of PPARγ is mediated by Transportin-1, but PPARγ lacks a typical NLS sequence recognized by Transportin-1. Moreover, the recognition mechanism remains largely unknown.In this study, we determined the Cryo-EM structure of PPARγ in complex with Transportin-1 and revealed that Transportin-1 gripped the folded DNA binding domain and the Hinge region of PPARγ, indicating that PPARγ recognizes a folded domain with an extended region as a nuclear localization signal, not a canonical unstructured signal sequence, confirmed by the mutation analyses in vitro and in cultured cells. Our study is the first snapshot structure working in nuclear transportation, not in transcription, of PPARγ.
Expansion ofDrosophilahaemocytes using a conditionalGeneSwitchdriver affects larval haemocyte function, but does not modulate adult lifespan or survival from infection
Authors: Hayman Dan J , Morrin Lola M , Halder Sudipta , Phillips Eleanor J , Simons Mirre J P , Evans Iwan R 
Published: September 2024

AbstractMacrophages are responsible for diverse and fundamental functions in vertebrates. Fruit flies harbour an innate immune system of which the most populous blood cell (haemocyte) type bears striking homology to the vertebrate macrophage. The importance of these cells has been demonstrated previously, where immune and developmental phenotypes have been observed upon haemocyte ablation using pro-apoptotic transgenes driven by theHmlpromoter.Here we show that, as well as ablatingHml-positive cellsin vivousing the pro-apoptotic transgenebax, we can also increaseHml-positive cell numbers using a constitutively-active form ofras. However, in adults, compared to larvae, total blood cell numbers were not significantly affected by experimental expansion or ablation. This therefore implies the existence of feedback mechanisms which regulate the number of haemocytes.No effect on lifespan was observed from drivingrasandbaxinHml-positive cells using a conditional genetic system (Hml-GeneSwitch). Using a constitutive driver system, we did observe differences in lifespan, however we attribute this to differences in genetic background that could have led to spurious conclusions. Additionally, no effect of either transgene was observed upon infection with two different bacterial species, although a striking pupal lethality phenotype was observed upon expansion ofHml-positive cells in the context of a self-encapsulation mutant genetic background. The latter confirms that the change inHml-positive cell number does result in a phenotype. The lack of adult phenotypes could be due to the strength of our experimental manipulation or due to compensation via feedback mechanisms that operate to maintain total blood cell numbers. Our study demonstrates the importance of a conditional approach to modulate haemocyte cell numbersin vivowhich allows for more precise study of innate immune system function. This approach could be especially fruitful to uncover the mechanisms that regulate total blood cell numbers across development and ageing.
Targeting the untargeted: Uncovering the chemical complexity of root exudates
Authors: Möller Katrin , Ritter Annalena , Stobinsky Phillip J. , Jensen Kai , Meier Ina C. , Subrahmaniam Harihar Jaishree 
Published: September 2024

AbstractThe chemical complexity of root exudates has garnered significant attention in recent years, yet critical gaps remain in understanding the full scope of root exudate chemical variation across the plant kingdom. To address this, we conducted a systematic review of 57 studies, comprising 124 experiments, aimed at evaluating current methodologies and findings in untargeted root exudate chemical analysis. Our review revealed that hydroponic (44%) and soil-hydroponic hybrid (32%) sampling approaches, primarily utilising water as the collection medium, were the most common experimental setups. Liquid chromatography-mass spectrometry (LC-MS) was the predominant analytical technique used in 54% of the studies, followed by gas chromatography-mass spectrometry (GC-MS) in 31%. The average number of metabolites identified per analysis was 960, though the number of annotated metabolites varied considerably. Shikimates, phenylpropanoids, and carbohydrates were the most frequently identified classes, with their relative abundances varying widely. Several methodological challenges were highlighted, including inconsistencies in sampling techniques, underrepresentation of non-crop plants, and incomplete chemical annotation. To address these limitations, we propose a framework emphasising the need for representative exudate sampling, the use of multiple analytical approaches, the development of advanced bioinformatics tools, and the integration of these findings to enhance our understanding of root exudates and their ecological functions.
Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells
Authors: Acharya Prashun , Thapa Garima , Liao Xiayi , Matoo Samaneh , Graves Maura J. , Atallah Sarah Y. , Tipirneni Ashna K. , Nguyen Tram , Chhabra Niki. M. , Maschack Jaden , Herod Mackenzie R. , Ohaezu Favour A. , Robison Alder , Mudaliyar Ashwini , Bharaj Jasvinder , Roeser Nicole , Holmes Katherine , Nayak Vishwaas , Alsayed Rayah , Perrin Benjamin J. , Crawley Scott W. 
Published: September 2024

SUMMARYMyosin-7A (Myo7A) is a motor protein crucial for the organization and function of stereocilia, specialized actin-rich protrusions on the surface of inner ear hair cells that mediate hearing. Mutations in Myo7A cause several forms of genetic hearing loss, including autosomal dominant DFNA11 deafness. Despite its importance, the structural elements of Myo7A that control its motor activity within cells are not well understood. In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells. Our findings reveal that Myo7A is regulated by specific IQ motifs within its lever arm, and that this regulation can function at least partially independent of its tail sequence. Importantly, we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness.