bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment Effectiveness and Recurrence of Extracranial Arteriovenous Malformations Following Surgical Operations
Authors: Shiraishi Makoto , Narushima Mitsunaga , Banda Chihena Hansini , Moriwaki Yuta , Fujisawa Kou , Nakajima Mayuri , Yamagata Kosuke , Kondo Chizuki , Okada Yoshimoto , Mitsui Kohei , Hashimoto Kohei , Danno Kanako , Hosomi Kento , Ishiura Ryohei , Kurita Masakazu , Okazaki Mutsumi
Published: May 2024

Background

At present, there is no golden standard for treatment of extracranial arteriovenous malformations (AVMs) and recurrence remains a major challenge with limited available evidence on the associated factors. This study aimed to evaluate the effectiveness of surgical treatment options, in terms of size reduction, symptoms, and early recurrence in patients treated surgically for AVMs.

Methods

A retrospective cohort study was conducted to evaluate patients with AVMs following surgical treatment in 2 centers from 2005 to 2020. Posttreatment lesion size and symptoms, as well as recurrence, were assessed. Multiple regression analysis was performed to identify factors associated with recurrence.

Results

Forty-four surgical treatment cases in 31 patients were assessed with a mean follow-up duration period of 67.9 ± 39.5 months. Treatment included total resection in 26 cases (59.1%) and partial resection 18 (40.9%), with free flap coverage used in 19 cases (43.2%). No acute exacerbation following treatment was observed in our cohort. Total resection significantly reduced posttreatment lesion size (P < 0.001), symptoms (P < 0.001), and recurrence (20.0%, P = 0.03). The recurrence rate was significantly higher after partial resection (73.7%, P = 0.03). Total resection was identified as an associated factor for significantly reduced AVM recurrence (odds ratio: 0.12; 95% confidence interval: 0.03, 0.52). However, the use of free flaps did not significantly reduce recurrence, post treatment size or improve AVM symptoms.

Conclusions

Total resection is the optimal treatment for AVMs. Free flaps are useful in covering large defects but the regulative effect of free flap remains controversial.
Defining Benchmarks for Pelvic Exenteration Surgery
Authors: Brown Kilian G. M. , Solomon Michael J. , Koh Cherry E. , Sutton Paul A. , Aguiar Samuel , Bezerra Tiago S. , Clouston Hamish W. , Desouza Ashwin , Dozois Eric J. , Ersryd Amanda L. , Frizelle Frank , Funder Jonas A. , Garcia-Aguilar Julio , Garfinkle Richard , Glyn Tamara , Heriot Alexander , Kanemitsu Yukihide , Kong Chia Y. , Kristensen Helle Ø , Malakorn Songphol , Mens David M. , Nilsson Per J. , Palmer Gabriella J. , Pappou Emmanouil , Quinn Martha , Quyn Aaron J. , Sahakitrungruang Chucheep , Saklani Avanish , Solbakken Arne M. , Tiernan Jim P. , Verhoef Cornelis , Steffens Daniel
Published: May 2024

Objective:

To establish globally applicable benchmark outcomes for pelvic exenteration (PE) in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC), using outcomes achieved at highly specialised centres.

Background data:

PE is established as the standard of care for selected patients with LARC and LRRC. There are currently no available benchmarks against which surgical performance in PE can be compared for audit and quality improvement.

Methods:

This international multicentre retrospective cohort study included patients undergoing PE for LARC or LRRC at 16 highly experienced centres between 2018 and 2023. Ten outcome benchmarks were established in a lower-risk subgroup. Benchmarks were defined by the 75th percentile of the results achieved at the individual centres.

Results:

763 patients underwent PE, of which 464 patients (61%) had LARC and 299 (39%) had LRRC. 544 patients (71%) who met predefined lower risk criteria formed the benchmark cohort. For LARC patients, the calculated benchmark threshold for major complication rate was ≤44%; comprehensive complication index (CCI): ≤30.2; 30-day mortality rate: 0%; 90-day mortality rate: ≤4.3%; R0 resection rate: ≥79%. For LRRC patients, the calculated benchmark threshold for major complication rate was ≤53%; CCI: ≤34.1; 30-day mortality rate: 0%; 90-day mortality rate: ≤6%; R0 resection rate: ≥77%.

Conclusions:

The reported benchmarks for PE in patients with LARC and LRRC represent the best available care for this patient group globally and can be used for rigorous assessment of surgical quality and to facilitate quality improvement initiatives at international exenteration centres.
Evaluation of urological and gynecological surgeons as force multipliers for mass casualty trauma care
Authors: Andreatta Pamela B. , Graybill John Christopher , Bradley Matthew J. , Gross Kirby R. , Elster Eric A. , Bowyer Mark W.
Published: May 2024

BACKGROUND

The clinical demands of mass casualty events strain even the most well-equipped trauma centers and are especially challenging in resource-limited rural, remote, or austere environments. Gynecologists and urologists care for patients with pelvic and abdominal injuries, but the extent to which they are able to serve as “force multipliers” for trauma care is unclear. This study examined the abilities of urologists and gynecologists to perform 32 trauma procedures after mentored training by expert trauma educators to inform the potential for these specialists to independently care for trauma patients.

METHODS

Urological (6), gynecological surgeons (6), senior (postgraduate year 5) general surgery residents (6), and non–trauma-trained general surgeons (8) completed a rigorous trauma training program (Advanced Surgical Skills Exposure in Trauma Plus). All participants were assessed in their trauma knowledge and surgical abilities performing 32 trauma procedures before/after mentored training by expert trauma surgeons. Performance benchmarks were set for knowledge (80%) and independent accurate completion of all procedural components within a realistic time window (90%).

RESULTS

General surgery participants demonstrated greater trauma knowledge than gynecologists and urologists; however, none of the specialties reached the 80% benchmark. Before training, general surgery, and urology participants outperformed gynecologists for overall procedural abilities. After training, only general surgeons met the 90% benchmark. Post hoc analysis revealed no differences between the groups performing most pelvic and abdominal procedures; however, knowledge associated with decision making and judgment in the provision of trauma care was significantly below the benchmark for gynecologists and urologists, even after training.

CONCLUSION

For physiologically stable patients with traumatic injuries to the abdomen, pelvis, or retroperitoneum, these specialists might be able to provide appropriate care; however, they would best benefit trauma patients in the capacity of highly skilled assisting surgeons to trauma specialists. These specialists should not be considered for solo resuscitative surgical care.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Impact of pre-copulatory sexual cannibalism on genetic diversity and efficacy of selection
Authors: Martínez Villar Mauro , Bechsgaard Jesper , Bilde Trine , Albo Maria Jose , Tomasco Ivanna H.
Published: May 2024

Factors that increase reproductive variance among individuals act to reduce effective population size (Ne), which accelerates the loss of genetic diversity and decreases the efficacy of purifying selection. These factors include sexual cannibalism, offspring investment and mating system. Pre-copulatory sexual cannibalism, where the female consumes the male prior to mating, exacerbates this effect. We performed comparative transcriptomics in two spider species, the cannibalistic
Trechaleoides biocellata
and the non-cannibalistic
T. keyserlingi
, to generate genomic evidence to support these predictions. First, we estimated heterozygosity and found that genetic diversity is relatively lower in the cannibalistic species. Second, we calculated dN/dS ratios as a measure of purifying selection; a higher dN/dS ratio indicated relaxed purifying selection in the cannibalistic species. These results are consistent with the hypothesis that sexual cannibalism impacts operational sex ratio and demographic processes, which interact with evolutionary forces to shape the genetic structure of populations. However, other factors such as the mating system and life-history traits contribute to shaping Ne. Comparative analyses across multiple contrasting species pairs would be required to disentangle these effects. Our study highlights that extreme behaviours such as pre-copulatory cannibalism may have profound eco-evolutionary effects.
A qualitative analysis of an Aβ-monomer model with inflammation processes for Alzheimer’s disease
Authors: Ciuperca Ionel , Pujo-Menjouet Laurent , Matar-Tine Leon , Torres Nicolas , Volpert Vitaly
Published: May 2024

We introduce and study a new model for the progression of Alzheimer’s disease (AD) incorporating the interactions of Aβ-monomers, oligomers, microglial cells and interleukins with neurons through different mechanisms such as protein polymerization, inflammation processes and neural stress reactions. To understand the complete interactions between these elements, we study a spatially homogeneous simplified model that allows us to determine the effect of key parameters such as degradation rates in the asymptotic behaviour of the system and the stability of equilibrium. We observe that inflammation appears to be a crucial factor in the initiation and progression of AD through a phenomenon of hysteresis with respect to the oligomer degradation rated. This means that depending on the advanced state of the disease (given by the value of the Aβ-monomer degradation rated: large value for an early stage and low value for an advanced stage) there exists a critical threshold of initial concentration of interleukins that determines if the disease persists or not in the long term. These results give perspectives on possible anti-inflammatory treatments that could be applied to mitigate the progression of AD. We also present numerical simulations that allow us to observe the effect of initial inflammation and monomer concentration in our model.
Post-Imbrium Pb–Pb isochron ages for Apollo basaltic impact melt samples 14078 and 68415
Authors: Snape Joshua F. , Nemchin Alexander A. , Whitehouse Martin J. , Li Qiu-Li , Liu Yu , Timms Nicholas E. , Erickson Timmons , Benedix Gretchen K.
Published: May 2024

The Apollo 14 and 16 missions returned several samples commonly interpreted as crystalline impact melt, with ages of approximately 3800–3850 Ma. Previous work has suggested that these rocks formed in one or more pre-Imbrium basin forming impact(s). By contrast, recent ages determined for a range of lunar breccias provide compelling evidence that the Imbrium basin was formed at approximately 3920 Ma. Using an approach previously demonstrated in lunar basalts, Pb–Pb isochron ages are determined for two of these proposed impact melt samples (14078: 3848 ± 4 Ma; and 68415: 3834 ± 11 Ma). In the case of 14078, the least radiogenic Pb isotopic compositions measured here are interpreted as representing the initial Pb isotopic composition of the sample. This value indicates derivation from a source (or sources) with high
238
U/
204
Pb ratios (approx. 2400), similar to those predicted for the Apollo 14 high-Al and very high-K basalts. It was not possible to determine an equivalent initial Pb isotopic composition for 68415, but Pb isotope evolution models indicate that the sample would have been derived from lithologies with lower
238
U/
204
Pb source ratios (approx. 1000). In both cases, the samples are interpreted as having been formed by impacts local to the Apollo 14 and Apollo 16 landing sites.
Isospectral open cavities and gratings
Authors: Cominelli Sebastiano , Vial Benjamin , Guenneau Sébastien , Craster Richard V.
Published: May 2024

Open cavities are often an essential component in the design of ultra-thin subwavelength metasurfaces and a typical requirement is that cavities have precise, often low frequency, resonances while simultaneously being physically compact. To aid this design challenge, we develop a methodology to allow isospectral twinning of reference cavities with either smaller or larger ones, enforcing their spectra to coincide so that open resonators are identical in terms of their complex eigenfrequencies. For open systems, the spectrum is not purely discrete and real, and we pay special attention to the accurate twinning of leaky modes associated with complex-valued eigenfrequencies with an imaginary part orders of magnitude lower than the real part. We further consider twinning of two-dimensional gratings, and model these with Floquet–Bloch conditions along one direction and perfectly matched layers in the other one; complex eigenfrequencies of special interest are located in the vicinity of the positive real line and further depend upon the Bloch wavenumber. The isospectral behaviour is illustrated, and quantified, throughout by numerical simulation using finite-element analysis.
Life-long music and dance relationships inform impressions of music- and dance-based movement therapies in individuals with and without mild cognitive impairment
Authors: Kazanski Meghan E. , Dharanendra Sahrudh , Rosenberg Michael C. , Chen Danyang , Brown Emma Rose , Emmery Laura , McKay J. Lucas , Kesar Trisha M. , Hackney Madeleine E.
Published: May 2024

Background

No effective therapies exist to prevent degeneration from Mild Cognitive Impairment (MCI) to Alzheimer’s disease. Therapies integrating music and/or dance are promising as effective, non-pharmacological options to mitigate cognitive decline.

Objective

To deepen our understanding of individuals’ relationships (i.e., histories, experiences and attitudes) with music and dance that are not often incorporated into music- and dance-based therapeutic design, yet may affect therapeutic outcomes.

Methods

Eleven older adults with MCI and five of their care partners/spouses participated (4M/12F; Black: n=4, White: n=10, Hispanic/Latino: n=2; Age: 71.4±9.6). We conducted focus groups and administered questionnaires that captured aspects of participants’ music and dance relationships. We extracted emergent themes from four major topics, including: (1) experience and history, (2) enjoyment and preferences, (3) confidence and barriers, and (4) impressions of music and dance as therapeutic tools.

Results

Thematic analysis revealed participants’ positive impressions of music and dance as potential therapeutic tools, citing perceived neuropsychological, emotional, and physical benefits. Participants viewed music and dance as integral to their lives, histories, and identities within a culture, family, and/or community. Participants also identified lifelong engagement barriers that, in conjunction with negative feedback, instilled persistent low self-efficacy regarding dancing and active music engagement. Questionnaires verified individuals’ moderately-strong music and dance relationships, strongest in passive forms of music engagement (e.g., listening).

Conclusions

Our findings support that individuals’ music and dance relationships and the associated perceptions toward music and dance therapy may be valuable considerations in enhancing therapy efficacy, participant engagement and satisfaction for individuals with MCI.
Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction
Authors: Hara Naoko , Raclawska Dorota S. , Morgan Leslie E. , NeeDell James C. , Dao Lucie , Kato Ayako , Jaramillo Ana M. , Hume Patrick S. , Holguin Fernando , Janssen William J. , Vladar Eszter K. , Evans Christopher M.
Published: May 2024

Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma, and it contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Due to the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2 (Fut2).Fut2gene deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model that may help improve therapeutic targeting of airway mucus.
Epigenetic upregulation of carotid body angiotensin signaling increases blood pressure
Authors: Zhu Fengli , Wang Zhuqing , Davis Kayla , McSwiggin Hayden , Zyuzin Jekaterina , Liu Jie , Yan Wei , Rehan Virender K. , Jendzjowsky Nicholas
Published: May 2024

Epigenetic changes can be shaped by a wide array of environmental cues as well as maternal health and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and in particular, hypertension. Increased basal carotid body activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to carotid body activity induced by perinatal nicotine exposure resulting in carotid body-mediated hypertension. Using a rodent model of perinatal nicotine exposure, we show that angiotensin II type 1 receptor is upregulated in the carotid bodies of nicotine-exposed offspring. These changes were attributed to an upregulation of genetic promotion as DNA methylation of angiotensin II type 1 receptor occurred within intron regions, exemplifying an upregulation of genetic transcription for these genes. Nicotine increased angiotensin signalingin vitro. Carotid body reactivity to angiotensin was increased in perinatal nicotine-exposed offspring compared to control offspring. Further, carotid body denervation reduced arterial pressure as a result of suppressed efferent sympathetic activity in perinatal nicotine-exposed offspring. Our data demonstrate that perinatal nicotine exposure adversely affects carotid body afferent sensing, which augments efferent sympathetic activity to increase vasoconstrictor signaling and induce hypertension. Targeting angiotensin signaling in the carotid bodies may provide a way to alleviate hypertension acquired by adverse maternal uterine environments in general and perinatal nicotine exposure in particular.
Antibiotic use in early life subsequently impairs MAIT cell-mediated immunity
Authors: Sobel Adam L. , Melamed Jonathan , Haas Dominic , LeBlanc Gabrielle , Cirone Aiko , Constantinides Michael G.
Published: May 2024

Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.
Application of Multiomics Approach to Investigate the Therapeutic Potentials of Stem Cell-derived Extracellular Vesicle Subpopulations for Alzheimer’s Disease
Authors: Abyadeh Morteza , Kaya Alaattin
Published: May 2024

Alzheimer’s disease (AD) presents a complex interplay of molecular alterations, yet understanding its pathogenesis remains a challenge. In this study, we delved into the intricate landscape of proteome and transcriptome changes in AD brains compared to healthy controls, examining 788 brain samples revealing common alterations at both protein and mRNA levels. Moreover, our analysis revealed distinct protein-level changes in aberrant energy metabolism pathways in AD brains that were not evident at the mRNA level. This suggests that the changes in protein expression could provide a deeper molecular representation of AD pathogenesis. Subsequently, using a comparative proteomic approach, we explored the therapeutic potential of mesenchymal stem cell-derived extracellular vehicles (EVs), isolated through various methods, in mitigating AD-associated changes at the protein level. Our analysis revealed a particular EV-subtype that can be utilized for compensating dysregulated mitochondrial proteostasis in the AD brain. By using network biology approaches, we further revealed the potential regulators of key therapeutic proteins. Overall, our study illuminates the significance of proteome alterations in AD pathogenesis and identifies the therapeutic promise of a specific EV subpopulation with reduced pro-inflammatory protein cargo and enriched proteins to target mitochondrial proteostasis.

Graphical Abstract

The cross-comparison of transcriptomics and proteomics data from AD brain samples and MSCs-derived EVs uncovers the therapeutic potential of a subpopulation targeting mitochondrial proteostasis and inflammation.
Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet
Authors: Amioka Naofumi , Franklin Michael K. , Kukida Masayoshi , Zhu Liyuan , Moorleghen Jessica J. , Howatt Deborah A. , Katsumata Yuriko , Mullick Adam E. , Yanagita Motoko , Martinez-Irizarry Michelle M. , Sandoval Ruben M. , Dunn Kenneth W. , Sawada Hisashi , Daugherty Alan , Lu Hong S.
Published: May 2024

Background

Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice.

Methods

FemaleLrp2f/f mice were bred with maleNdrg1-Cre ERT2+/0 mice to develop PTC-LRP2 +/+ and −/− littermates. To study atherosclerosis, all mice were bred to an LDL receptor −/− background and fed a Western diet to induce atherosclerosis.

Results

PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor −/− mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 −/− mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 −/− mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. In contrast, female PTC-LRP2 −/− mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney.

Conclusions

PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
Climate resilience conserved in global germplasm repositories: Picking the most promising parents for agile plant breeding
Authors: Campbell Quinn , Castaneda-Alvarez Nora , Domingo Ryan , Bishop-von Wettberg Eric , Runck Bryan , Nandkangre Herve , McCormick Anna , Fumia Nathan , Neyhart Jeffrey , Kilian Benjamin , Wambugu Peterson , Nyamongo Desterio , Hubner Sariel , Sitar Sidney , Thompson Addie , Rieseberg Loren , Gore Michael A. , Kantar Michael B.
Published: May 2024

Crop diversity is an essential resource for national and international breeding programs aimed at preparing global agriculture for a changing climate to ensure global food security. To do this there are related risks that need to be evaluated (1) does the genetic diversity needed for climate adaptation exist somewhere? And (2) is such genetic diversity accessible? To evaluate these risks, we consider the test case of publicly available genotyped and georeferenced sorghum landraces (n = 1,937) to ask if diversity is sufficient to support breeding for climate change adaptation. Answering these questions allows for characterization of the best potential parents and the geographies that harbor the most potentially promising genetypes for crop improvement. We subset this data into national, regional, and global geographic regions, and complete/mini core collections to understand the potential for climate adaptation in regional germplasm. Study accessions were given a future climate resilience score based on future climatic projections and a genomic adaptive capacity score using genomic estimated adaptive values (GEAVs) generated from environmental genomic selection - EGS) to ask whether this accessible diversity stored in germplasm repositories is potentially sufficient to meet forecasted changes in growing environments under climate change. We find that genomic resilience capacity is highly variable among countries and regions. High geographical variability was also found for climate resilience. To equitably adapt agriculture to future climate conditions, increased accessibility to plant genetic resources is essential.
Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia
Authors: Rodems Benjamin J. , Sharma Sonali , Baker Cameron D. , Kaszuba Christina M. , Ito Takashi , Liesveld Jane L. , Calvi Laura M. , Becker Michael W. , Jordan Craig T. , Ashton John M. , Bajaj Jeevisha
Published: May 2024

Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified1–6, concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR basedin vivoLSC dependency map7to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemiasin vivoby downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax8, 9to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.
Novel Oral Adjuvant to Enhance Cytotoxic Memory-Like NK Cell Responses in an HIV Vaccine Platform
Authors: Alles Mario , Gunasena Manuja , Isckarus Christina , De Silva Ilmini , Board Sarah , Mulhern Will , Collins Patrick L. , Demberg Thorsten , Liyanage Namal P.M.
Published: May 2024

Antibody-dependent cell-mediated cytotoxicity, mediated by natural killer (NK) cells and antibodies, emerged as a secondary correlate of protection in the RV144 HIV vaccine clinical trial, the only vaccine thus far demonstrating some efficacy in human. Therefore, leveraging NK cells with enhanced cytotoxic effector responses may bolster vaccine induced protection against HIV. Here, we investigated the effect of orally administering indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, as an adjuvant to an RV144-like vaccine platform in a mouse model. We demonstrate the expansion of KLRG1-expressing NK cells induced by the vaccine together with I3C. This NK cell subset exhibited enhanced vaccine antigen-specific cytotoxic memory-like features. Our study underscores the potential of incorporating I3C as an oral adjuvant to HIV vaccine platforms to enhance antigen-specific (memory-like) cytotoxicity of NK cells against HIV-infected cells. This approach may contribute to enhancing the protective efficacy of HIV preventive vaccines against HIV acquisition.
Testing the coordination hypothesis: incompatibilities in the absence of a single-cell bottleneck in an experimentally evolved social amoeba.
Authors: Jahan Israt , Scott Trey J , Strassmann Joan E , Queller David C
Published: May 2024

Multicellular organisms that form by aggregation of cells arguably do not achieve high levels of complexity. Conflict among the cells is a widely accepted explanation for this, but an alternative hypothesis is that mixing cells of different genotypes leads to failures of coordination, which we call the coordination hypothesis. We empirically tested the coordination hypothesis in the social amoeba Dictyostelium discoideum. We mixed D. discoideum clones that had evolved in isolation for generations and accumulated mutations that have not been tested against each other by selection. To quantify the effect of incompatibilities, we measured performance in terms of the developmental traits of slug migration and spore production. Importantly, kin recognition incompatibilities were avoided by mixing lines evolved from the same ancestor under conditions that would not select for the evolution of de novo recognition. Our results show no evidence of incompatibilities in coordinated movement of slugs towards light in the social amoeba. Spore production was higher than expected in mixtures, in apparent contradiction to the coordination hypothesis. However, we found support for coordination incompatibilities in an interaction between migration and spore production: in mixtures, fewer cells succeeded at migrating and becoming spores.
Spatiotemporal control of subcellular O-GlcNAc signaling using Opto-OGT
Authors: Ong Qunxiang , Lim Rachel , Goh Cameron , Liao Yilie , Chan Sher En , Lim Crystal , Kam Valerie , Yap Jerome , Tseng Tiffany , Desrouleaux Reina , Wang Loo Chien , Ler Siok Ghee , Lim Siew Lan , Kim Sunyee , Sobota Radoslaw M , Bennett Anton M. , Han Weiping , Yang Xiaoyong
Published: May 2024

The posttranslational modification of intracellular proteins through O-linked β-N-acetylglucosamine (O-GlcNAc) is a conserved regulatory mechanism in multicellular organisms. Catalyzed by O-GlcNAc transferase (OGT), this dynamic modification plays an essential role in signal transduction, gene expression, organelle function, and systemic physiology. Here we present Opto-OGT, an optogenetic probe that allows for precise spatiotemporal control of OGT activity through light stimulation. By fusing a photosensitive cryptochrome protein to OGT, Opto-OGT can be robustly and reversibly activated with high temporal resolution by blue light and exhibits minimal background activity without illumination. Transient activation of Opto-OGT results in mTORC activation and AMPK suppression which recapitulate nutrient-sensing signaling. Furthermore, Opto-OGT can be customized to be localized at specific subcellular sites. By targeting OGT to the plasma membrane, we demonstrate downregulation of site-specific AKT phosphorylation and signaling outputs in response to insulin stimulation. Thus, Opto-OGT is a powerful tool to define the role of O-GlcNAcylation in cell signaling and physiology.
The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38
Authors: Tan Sijie , Dengler Alisa Susan , Darawsheh Rami Zahi , Kory Nora
Published: May 2024

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.
Specific Mitotic Events Drive Cytoskeletal Remodeling Required for Left-Right Organizer Development
Authors: Wu Yan , Lan Yiling , Ononiwu Favour , Poole Abigail , Rasmussen Kirsten , Da Silva Jonah , Shamil Abdalla Wael , Jao Li-En , Hehnly Heidi
Published: May 2024

Cellular proliferation is vital for tissue development, including the Left-Right Organizer (LRO), a transient organ critical for establishing the vertebrate LR body plan. This study investigates cell redistribution and the role of specific progenitor cells in LRO formation, focusing on cell lineage and behavior. Using zebrafish as a model, we mapped all mitotic events in Kupffer’s Vesicle (KV), revealing an FGF-dependent, anteriorly enriched mitotic pattern. With a KV-specific fluorescent microtubule (MT) line, we observed that mitotic spindles align along the KV’s longest axis until the rosette stage, spindles that form after spin, and are excluded from KV. Early aligned spindles assemble cytokinetic bridges that point MT bundles toward a tight junction where a rosette will initially form. Post-abscission, repurposed MT bundles remain targeted at the rosette center, facilitating actin recruitment. Additional cells, both cytokinetic and non-cytokinetic, are incorporated into the rosette, repurposing or assembling MT bundles before actin recruitment. These findings show that initial divisions are crucial for rosette assembly, MT patterning, and actin remodeling during KV development.
Proving a negative; estimating species ‘Confidence in Absence for Decision-Making’ (CIADM) using environmental DNA monitoring
Authors: Griffiths Nathan P. , Hänfling Bernd , Cattaneo Marco , Wright Rosalind M. , Macarthur James A. , Peixoto Sara , Bolland Jonathan D.
Published: May 2024

Policy-driven decision-making is an important aspect of environmental management globally, often focused on protecting priority species. However, declining trends in freshwater biodiversity have resulted in a lack of up-to-date knowledge regarding the distribution of rare and elusive species. Furthermore, when dealing with priority species, it is sometimes more important to provide a confident assessment of absence, than merely confirm their presence. Without such confident assessments, resource intensive management plans may be misplaced, and not adequately targeted to conserve important remaining populations.

Here, we present a framework to estimate confidence in absence, referred to as “Confidence in Absence for Decision-Making” (CIADM), based on single-visit environmental DNA metabarcoding data obtained from water samples. It uses a case study of European eel presence / absence upstream of 44 water pumping stations, given their critically endangered status and the legislative drivers for remediation (EC Eel Regulation 1100/2007, Eels (England and Wales) Regulation 2009). Through a high degree of biological (sample) and technical (PCR) replication, we retrospectively assigned ‘confidence in absence’ values and proposed various strategies to achieve the required confidence levels in future surveys.

Our findings indicate that 17 out of 44 pumping stations tested positive for eel, and we were able to assign a >99% confidence level that the remaining 27 sites were negative for eel DNA at the time of sampling. Increasing both biological and technical replication increased ‘confidence in absence’ values. For example, using three PCR replicates per sample, required four replicate biological samples to achieve >95% and six to achieve >99% confidence in eel absence given non-detection. However, we estimate that by using seven PCR replicates per sample a >99% confidence in eel absence following non-detection could be achieved with only three replicate biological samples. Furthermore, we found that eel positive sites had significantly higher species richness, and fish communities differed between eel positive and eel negative sites.

This study highlights the importance of optimising workflow specific replication, and provides an adaptable framework to produce confidence estimations of priority species absence given non-detection.
Metagenomics to Metabolomics: Integrating Genomic Insights for Mulberry Crop Protection and Enhancement
Authors: Niranjan Vidya , Lavanya C , Pooja H V , Bhat Shreya Satyanarayan , Kulkarni Spoorthi R
Published: May 2024

Indian Mulberry (Morus indica) is vital in sericulture, with their leaves serving as the primary food source for silkworms. The soil microbiome surrounding mulberry trees plays a pivotal role in nutrient cycling and ecosystem functioning. This study utilizes metagenomic analysis to explore the taxonomic diversity and functional potential of microbial communities in mulberry soil, particularly focusing on the rhizosphere. Key bacterial species such asPseudomonas, Frankia, Azosipirulumare identified, highlighting their importance in mulberry health and disease dynamics. The abundance distribution of these bacterial populations reveals significant trends, offering insights into mulberry agroecosystem microbial ecology. Understanding garden soil-derived microbial consortia provides a foundation for exploring their role in nutrient cycling and plant health. The study reveals the intricate web of interactions between mulberry and their surrounding soil microbiota and identification of metabolites. Leveraging high-throughput sequencing and bioinformatics, the research identifies potential metabolites as biofertilizers and biopesticides, aiming to improve agricultural sustainability. The findings underscore the critical role of soil microbes in maintaining soil fertility, supporting plant health, and enhancing ecosystem resilience. Despite limitations and gaps, the study contributes to advancing eco-friendly agricultural practices and promoting soil health in mulberry cultivation. Ultimately, the research transcends the laboratory, resonating with stakeholders as it unravels the genetic blueprints of soil life and sows’ seeds of sustainable progress.
Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2
Authors: Bashore Frances M. , Min Sophia M. , Chen Xiangrong , Howell Stefanie , Rinderle Caroline H. , Morel Gabriel , Silvaroli Josie A. , Wells Carrow I. , Bunnell Bruce A. , Drewry David H. , Pabla Navjot S. , Ultanir Sila K. , Bullock Alex N. , Axtman Alison D.
Published: May 2024

Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound9was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound16was designed as a negative control to be used alongside compound9in experiments to interrogate CDKL2-mediated biology. A solved co-crystal structure of compound9bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound9in cells resulted in inhibition of its activity. When used at relevant concentrations, compound9does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial–mesenchymal transition.
The yolk sac vasculature in early avian embryo provides a novel model for the analysis of cancer extravasation
Authors: Morita Mizuki , Fujii Ryo , Ryuno Asuka , Morimoto Manami , Inoko Akihito , Inoue Takahiro , Ikenouchi Junichi , Atsuta Yuji , Hayashi Yoshiki , Teramoto Takayuki , Saito Daisuke
Published: May 2024

Hematogenous metastasis, a key trait of cancer cells, involves a complex sequence of cell migration steps, including intravasation, circulation, arrest in capillary vessels, and extravasation. Among these steps, extravasation is challenging to image in amniotes like humans and mice due to its unpredictable timing and location, limiting our understanding of cellular and molecular mechanisms through imaging. Establishing a new cancer carrier model with high-resolution imaging capabilities in amniotes is crucial. In this study, we investigated the yolk sac vasculature (YSV) of early avian embryos (chickens and quail) as a new model for studying extravasation, offering excellent imaging capabilities. We examined the YSV structure and attempted fluorescent labeling to enhance visibility. We then injected mCherry-labeled HT-1080 cells into YSV and observed their behavior, revealing distinct morphologies and extravasation dynamics. Our findings suggest that the YSV model holds promise as a novel cancer carrier model for elucidating cellular and molecular mechanisms through imaging-based approaches.
Coming out of the ashes we rise: Culturally and linguistically diverse international nursing students during the COVID-19 pandemic
Authors: Lim Eric , Ng Linda , Zhou Huaqiong , Nair Ambili , Kalembo Fatch
Published: May 2024

Background and aim

Research on international students conducted during the COVID-19 pandemic has persistently highlighted the vulnerabilities and challenges that they experienced when staying in the host country to continue with their studies. The findings from such research can inevitably create a negative image of international students and their ability to respond to challenges during unprecedented times. Therefore, this paper took a different stance and reported on a qualitative study that explored culturally and linguistically diverse (CaLD) international nursing students who overcame the challenges brought about by the pandemic to continue with their studies in Australia.

Method

A descriptive qualitative research design guided by the processes of constructivist grounded theory was selected to ascertain insights from participants’ experiences of studying abroad in Australia during the COVID-19 pandemic.

Results

Three themes emerged from the collected data that described the participants’ lived experiences, and they were: 1)Viewing international education as the pursuit of a better life, 2)Focusing on personal growth, and 3)Coming out of the ashes we rise.

Discussion

The findings highlight the importance of recognising the investments and sacrifices that CaLD international students and their families make in pursuit of international tertiary education. The findings also underscore the importance of acknowledging the qualities that CaLD international students have to achieve self-growth and ultimately self-efficacy as they stay in the host country during a pandemic.

Conclusion

Future research should focus on identifying strategies that are useful for CaLD international nursing students to experience personal growth and ultimately self-efficacy and continue with their studies in the host country during times of uncertainty such as a pandemic.
Combinatorial Wnt signaling determines wing margin color patterns of the swallowtail butterfly ground plan
Authors: Mazo-Vargas Anyi , Liang Alan , Liang Brian , McDonald Jeanne M.C. , Martin Arnaud , Reed Robert D.
Published: May 2024

The intricate wing patterns of butterflies are thought to derive from a morphological ground plan that anchors homology relationships between individual color pattern elements and serves as an archetype for comparative analysis. These patterns undergo modifications that drive the diverse morphologies observed in nature. While brush-footed butterflies (Nymphalidae) have been well studied, assigning homologies with other lepidopteran families remains challenging due to substantial divergence. Here, we focus on swallowtails (Papilionidae), an early-diverging butterfly lineage known for its outstanding diversity in wing shapes and patterns but lacking a developmental framework. Through qualitative and phylogenetic analyses, CRISPR perturbation assays, andin situexpression experiments, we investigate homologies between papilionid butterflies, offering phylogenetic and molecular characterization of the Papilionidae wing ground plan. Our results highlight the roles ofWntAandWnt6in patterning papilionid signature wing elements, such as the glauca and the Submarginal spots. Notably, the nymphalids’ distinct Central Symmetry System is either reduced or absent in the family, with marginal systems expanding proximally. Our data illuminate a highly adaptable patterning system driven by Wnt signaling pathways in developing butterfly wings.
Y chromosome linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues
Authors: Gorashi Rayyan M. , Baddour Talia , Chittle Sarah J. , Vélez Nicole E. Félix , Wenning Michaela A. , Anseth Kristi S. , Mestroni Luisa , Peña Brisa , Guo Peng , Aguado Brian A.
Published: May 2024

Aortic valve stenosis (AVS) is a progressive disease wherein males more often develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and produce calcium nanoparticles, driving valve calcification in males. We hypothesized the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing, Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a novel role of UTY in the regulation of calcification processes in males during AVS progression.