bluuebunny/crossref_metadata_2025 huggingface dataset:
Observations on the reproductive morphology of the female short‐beaked echidna, Tachyglossus aculeatus
Authors: Fenelon Jane C. , Ferrier Stephanie B. , Johnston Stephen D. , Renfree Marilyn B.
Published: September 2024

Although monotremes diverged from the therian mammal lineage approximately 187 million years ago, they retain various plesiomorphic and/or reptilian‐like anatomical and physiological characteristics. This study examined the morphology of juvenile and adult female reproductive tracts across various stages of the presumptive oestrous cycle, collected opportunistically from cadaver specimens submitted to wildlife hospitals during the breeding season. In adult females, ovaries had a convoluted cortex with follicles protruding from the ovarian surface. While protruding antral follicles were absent from the ovaries of juvenile echidnas, histological analysis identified early developing primordial and primary follicles embedded into the ovarian cortex. The infundibulum epithelial cells of the oviducts were secretory during the follicular phase but not at other stages, the ampulla region was secretory at all stages and is likely responsible for the mucoid layer deposited around the zona pellucida, and the isthmus region of the oviduct appeared to be responsible for initial deposition of the shell coat, as in marsupials. Female echidnas have two separate uteri, which never merge and enter separately into the urogenital sinus (UGS). This study confirmed that both uteri are functional and increase in glandular activity during the luteal phase. In the juvenile uteri, the endometrium was immature with minimal, small uterine glands. A muscular cervical region at the caudal extremity of each uterus, just before the cranial region of the UGS was defined by the absence of glandular tissue in all female echidnas, including the juveniles. There was no evidence of a definitive vaginal region. A clitoris was also detected that possessed a less developed but similar structural (homologous) anatomy to the male penis; urethral ducts while present did not appear to be patent.
Occurrence of Phytopythium helicoides Causing Root and Crown Rot of Blueberry in Mexico
Authors: Nuñez‐García Perla R. , Vieira Willie A. S. , Cruz‐Lachica Isabel , García‐Estrada Raymundo S. , Marquez‐Zequera Isidro , Márquez‐Licona Guillermo , Tovar‐Pedraza Juan M.
Published: September 2024

In August 2023, severe symptoms of crown and root rot were detected on blueberry plants in two commercial fields located in Guasave, Sinaloa, Mexico. Colonies with oomycete morphology were obtained and two isolates were purified. The causal agent was identified as Phytopythium helicoides by a combination of morphological studies, pathogenicity tests, and phylogenetic analysis including data from internal transcribed spacer and large subunit sequences. This is the first report of P. helicoides causing crown and root rot of blueberry worldwide.
Two for One: Tuberculid and Leukocytoclastic Vasculitis in an Adolescent
Authors: Bui Jordan K. , Baker Mairead , Habeshian Kaiane
Published: September 2024

A 13‐year‐old girl with fevers, abdominal pain, and vomiting for 4 days presented with a full body pruritic rash that began in the axilla and spread rapidly to the rest of the body. She was recently diagnosed with tuberculosis and had been on rifampin, isoniazid, pyrazinamide and ethambutol (RIPE) therapy for 1 month to treat this infection, raising concern for a severe drug reaction. On exam, there were pink to hemorrhagic crusted papules diffusely on the body; two skin biopsies from the right ankle and right arm showed leukocytoclastic vasculitis and tuberculid pathologies, respectively. Tuberculids are a cutaneous form of tuberculosis that represent a hypersensitivity reaction to Mycobacterium tuberculosis or its antigens. These rashes can mimic other common diseases, and this case highlights the importance of obtaining histopathology early in the disease course for accurate and prompt diagnosis.
Voluntary Turnover Rate Fluctuations, Human Resource Practices, and Innovation: A Within‐Organization Investigation
Authors: Li Yixuan , Huang Zhefan , Dineen Brian , Wang Mo , van Jaarsveld Danielle
Published: September 2024

Organizations constantly navigate voluntary employee departures to facilitate organizational effectiveness. To date, most studies on the implications of voluntary turnover rate have been conducted at the between‐organization level, comparing organizations with varying levels of voluntary turnover rates. Building upon complex adaptive system (CAS) theory, we develop within‐organization theorizing regarding the implications of voluntary turnover rate fluctuations for organizational innovation. We propose a U‐shape threshold model, where the relationship between voluntary turnover rate fluctuations and innovation takes a negative form when voluntary turnover rate fluctuations are within the normal range for an organization, and a positive form when voluntary turnover rate fluctuations surpass a critical threshold reflecting far‐from‐equilibrium conditions. Furthermore, we investigate how organizations may utilize human resource (HR) practices to shift the critical threshold. Specifically, we argue that increased reliance on interaction‐facilitating HR practices (employee participation and group‐based pay) lowers the threshold, while increased reliance on interaction‐inhibiting HR practices (individual‐based pay) raises the threshold. With firm‐fixed effects modeling, we found general support for our hypotheses using a large‐scale, multi‐level, longitudinal dataset from Statistics Canada (7110 workplace‐year observations from 1980 workplaces). We provide a novel theoretical lens to understand the nature and management of collective turnover.
Periodontal regeneration using platelet‐rich fibrin. Furcation defects: A systematic review with meta‐analysis
Authors: Miron Richard J. , Moraschini Vittorio , Estrin Nathan E. , Shibli Jamil Awad , Cosgarea Raluca , Jepsen Karin , Jervøe‐Storm Pia‐Merete , Sculean Anton , Jepsen Søren
Published: September 2024

The objective of the study was to compare the treatment outcomes of periodontal furcation defects by using platelet‐rich fibrin (PRF) with other commonly utilized modalities. The eligibility criteria comprised randomized controlled trials (RCTs) comparing the clinical outcomes of PRF with those of other modalities for the treatment of furcation defects. Studies were classified into 11 categories in 3 different groups as follows: Group I (addition of PRF): (1) open flap debridement (OFD) alone versus OFD/PRF, (2) OFD/bone graft (OFD/BG) versus OFD/BG/PRF; Group II (comparative studies to PRF): (3) OFD/BG versus OFD/PRF, (4) OFD/collagen membrane versus OFD/PRF, (5) OFD/PRP versus OFD/PRF, (6) OFD/rhBMP2 versus OFD/PRF; and Group III (addition of biomaterial/biomolecule to PRF): OFD/PRF versus … (7) OFD/PRF/BG, (8) OFD/PRF/amniotic membrane (AM), (9) OFD/PRF/metformin, (10) OFD/PRF/bisphosphonates, (11) OFD/PRF/statins. Weighted means and forest plots were calculated for the reduction of probing pocket depth (PPD), gain of vertical and horizontal clinical attachment levels (VCAL and HCAL), gain in vertical and horizontal bone levels (VBL, HBL), and radiographic bone fill (RBF). From 45 articles identified, 21 RCTs reporting on class II furcations were included. The use of OFD/PRF and OFD/BG/PRF statistically significantly reduced PPD and improved VCAL and HCAL when compared to OFD or OFD/BG, respectively. The comparison between OFD/PRF alone versus OFD/BG, OFD/CM, OFD/PRP, or OFD/rhBMP2 led to similar outcomes for all investigated parameters, including a reduction in PPD, VCAL/HCAL gain, and RBF. The additional incorporation of a BG to OFD/PRF only mildly improved outcomes, whereas the addition of AM improved clinical outcomes. The addition of small biomolecules such as metformin, bisphosphonates, or statins all led to significant improvements in PPD, VCAL, and HCAL when compared to OFD/PRF alone. Noteworthy, a very high heterogeneity was found in the investigated studies. The use of PRF significantly improved clinical outcomes in class II furcation defects when compared to OFD alone, with similar levels being observed between OFD/PRF and/or OFD/BG, OFD/CM, OFD/PRP, or OFD/rhBMP2. Future research geared toward better understanding potential ways to enhance the regenerative properties of PRF with various small biomolecules may prove valuable for future clinical applications. Future histological research investigating PRF in human furcation defects is largely needed. The use of PRF in conjunction with OFD statistically significantly improved PPD, VCAL, and HCAL values, yielding comparable outcomes to commonly used biomaterials. The combination of PRF to bone grafts or the addition of small biomolecules may offer additional clinical benefits, thus warranting future investigation.
Returning home from exile? Arnold Cornelisz's ministerial networks and the religious landscape of the liberated Netherlands☆
Authors: Muylaert Silke
Published: September 2024

Scholars of the Dutch Reformation have attributed the rapid development of Reformed churches in the liberated areas of the Northern Netherlands after 1572 to the immigration of radical migrants from Flanders or returning exiles who learned the trade in the refugee churches outside the Low Countries. However, the impact of the networks, rather than the ideology, of a third transformative stream of migrants often gets overlooked. This article argues that a wider network of mobile ministers centred around the University of Heidelberg had a profound impact on the religious landscape of the Low Countries. It demonstrates this using a network analysis of the correspondence of one of the leading Reformed ministers in the liberated Netherlands after 1572, Arnold Cornelisz, combined with a prosopographical examination of the network. The idea that exile brought innovation through the formation of networks itself is not new. Yet, the article suggest that scholars should also take into account the interaction of exile with other forms of migration. Although Reformed ministers did not always recognize themselves as refugees or exiles, they were part of a large, transferable network that formed an innovative force after their return to the Low Countries.
Establishment of a Mouse Model for Porokeratosis Due to Mevalonate Diphosphate Decarboxylase Deficiency
Authors: Peng Kexin , Wong Wenghong , Zhang Qiaoan , La Yumeng , Tian Zhen , Sun Ruilin , Ho Loksi , Yang Kaihang , Pan Jiewen , Luan Jing , Niu Zhenmin , Zhang Zhenghua
Published: September 2024

Introduction

Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase (MVD) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis.

Materials and Methods

In this research, we constructed K14‐CreERT2‐Mvdfl/fl mice using the Cre‐LoxP system to create a mouse model for in‐depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA‐seq, and Western Blot analysis were performed.

Results

Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL‐17A and IL‐1β, and a decreased Loricrin level in epidermal Mvd‐deficient mice. Compared with the wild‐type (WT) group, Mvd deficiency activated the expression of lipid metabolism‐related proteins.

Conclusion

We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches.
How can soil data and information become actionable knowledge to advance sustainable land management?
Authors: Lobry de Bruyn Lisa , Prager Katrin
Published: September 2024

Promoting sustainable land management is key to addressing land degradation but its progress is impeded by the availability and accessibility of the ‘right’ soil data and information. We focus on government‐funded data collection or publicly collected soil data as it is central to effective soil governance. Taking a governance perspective, we discuss what soil information is created and used for, who are the actors involved and how soil information is contributing (or not) to the creation of actionable knowledge. We investigated two countries in depth through a desk‐based review and consultation with 40 key informants, collating which soil data and information is collected, analysed, stored, retrieved and used in the UK and Australia. We present a comprehensive overview of public soil databases, including location, year established, stated purpose, current governing institution, accessibility, digital product/s available, cycle of assessment, scale of sampling, soil data presented and depth of soil assessment. The analysis highlights that current shortcomings in soil governance are a result of not adequately valuing legacy soil data and information, and with the loss of human capital, diminished accessibility to soil information leads to disrupted information flows. A critical assessment suggests that available soil information plays a limited role in knowing the soil types of a locality, the condition of soil under various land uses and associated management, which limits its potential for informing sustainable land management. In both countries, there is a mismatch in scale and intention of use for the soil information between the provider and the user: information is currently held at the scale for regional‐ or nation‐level reporting on targets to meet national and international obligations rather than improving soil health or SLM at the farm scale. In addition, available soil data repositories only partially meet accessibility criteria (discoverability, language applicable to audience, open source and interpretative layer for land management implications). We outline steps to improve soil information and knowledge exchange embedded in effective governance arrangements to ensure that soil data and information can become actionable knowledge for SLM. Applying principles and strategies for facilitating knowledge exchange is of particular relevance to this process.
Uracil phosphoribosyltransferase is required to establish a functional cytochrome b6f complex
Authors: Scherer Vanessa , Bellin Leo , Schwenkert Serena , Lehmann Martin , Rinne Jannis , Witte Claus‐Peter , Jahnke Kathrin , Richter Andreas , Pruss Tobias , Lau Anne , Waller Lisa , Stein Sebastian , Leister Dario , Möhlmann Torsten
Published: September 2024

Arabidopsis uracil phosphoribosyltransferase (UPP) is an essential enzyme and plants lacking this enzyme are strongly compromised in chloroplast function. Our analysis of UPP amiRNA mutants has confirmed that this vital function is crucial to establish a fully functional photosynthesis as the RIESKE iron sulfur protein (PetC) is almost absent, leading to a block in photosynthetic electron transport. Interestingly, this function appears to be unrelated to nucleotide homeostasis since nucleotide levels were not altered in the studied mutants. Transcriptomics and proteomic analysis showed that protein homeostasis but not gene expression is most likely responsible for this observation and high light provoked an upregulation of protease levels, including thylakoid filamentation temperature‐sensitive 1, 5 (FtsH), caseinolytic protease proteolytic subunit 1 (ClpP1), and processing peptidases, as well as components of the chloroplast protein import machinery in UPP amiRNA lines. Strongly reduced PetC amounts were not only detected by immunoblot from mature plants but in addition in a de‐etiolation experiment with young seedlings and are causing reduced high light‐induced non‐photochemical quenching Φ(NPQ) but increased unregulated energy dissipation Φ(NO). This impaired photosynthesis results in an inability to induce flavonoid biosynthesis. In addition, the levels of the osmoprotectants raffinose, proline, and fumarate were found to be reduced. In sum, our work suggests that UPP assists in stabilization PetC during import, processing or targeting to the thylakoid membrane, or protects it against proteolytic degradation.
SlBTB19 interacts with SlWRKY2 to suppress cold tolerance in tomato via the CBF pathway
Authors: Xu Jin , Liu Sidi , Hong Jiachen , Lin Rui , Xia Xiaojian , Yu Jingquan , Zhou Yanhong
Published: September 2024

Cold stress restricts the metabolic and physiological activities of plants, thereby affecting their growth and development. Although broad‐complex, tramtrack, and bric‐à‐brac (BTB) proteins are essential for diverse biological processes and stress responses, the mechanisms underlying BTB‐mediated cold responses remain not fully understood. Here, we characterize the function of the cold‐induced SlBTB19 protein in tomato (Solanum lycopersicum). Overexpression of SlBTB19 resulted in increased plant sensitivity to cold stress, whereas SlBTB19 knockout mutants exhibited a cold‐tolerance phenotype. Further analyses, including protein–protein interaction studies and cell‐free degradation assays, revealed that SlBTB19 interacts with and destabilizes the transcription factor SlWRKY2. Using virus‐induced gene silencing (VIGS) to silence SlWRKY2 in both wild‐type and slbtb19 mutants, we provided genetic evidence that SlWRKY2 acts downstream of SlBTB19 in regulating cold tolerance. Importantly, we demonstrated that SlWRKY2 positively regulates cold tolerance in a CRT/DRE binding factor (CBF)‐dependent manner. Under cold stress, SlWRKY2 binds to the W‐box in the CBF1 and CBF3 promoters, directly activating their expression. In summary, our findings identify a SlBTB19‐SlWRKY2 module that negatively regulates the CBF‐dependent cold tolerance pathway in tomato.
Post‐Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient‐Limited Cancer Cells
Authors: Güleç Taşkıran Aliye Ezgi , Hüsnügil Hepşen H. , Soltani Zahra E. , Oral Göksu , Menemenli Nazlı S. , Hampel Chuanpit , Huebner Kerstin , Erlenbach‐Wuensch Katharina , Sheraj Ilir , Schneider‐Stock Regine , Akyol Aytekin , Liv Nalan , Banerjee Sreeparna
Published: September 2024

Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient‐limited cells; this translocation was mediated by a rapid post‐transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient‐limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient‐limited cells were treated with 5‐Fluorouracil (5‐FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.
Ultrasonographic diagnosis of a cecal mucocele in a cat
Authors: Louvet Arnaud , Duconseille Anne‐Carole , Gatineau Matthieu , Albert Audrey
Published: September 2024

A 3‐year‐old neutered male domestic medium‐hair cat presented for sudden onset of vomiting and anorexia. Ultrasonographically, severe distension of the cecum by hyperechoic material associated with variable posterior attenuation was identified. The cecum was surgically excised. A retention cyst cecal mucocele complicated by mucosal ulceration and inflammation was diagnosed. A literature review of this well‐described lesion in humans, once described in dogs but as yet undescribed in cats, is briefly presented.
Novel multi‐spectral short‐wave infrared imaging for assessment of human burn wound depth
Authors: Nunez Johanna , Mironov Sergey , Wan Bingchun , Hazime Alaa , Clark Audra , Akarichi Chiaka , Abdelfattah Kareem , Korlakunta Sneha , Mandell Samuel , Arnoldo Brett , Chan Rodney , Goverman Jeremy , Huebinger Ryan , Park Caroline , Evers Bret , Carlson Deborah , Berenfeld Omer , Levi Benjamin
Published: September 2024

Burn depth determination is critical for patient care but is currently lacking accuracy. Recent animal studies showed that Short Wave Infrared (SWIR) imaging can distinguish between superficial and deep burns. This is a first human study correlating reflectance of multiple SWIR bands using a SWIR assessment tool (SWAT) with burn depth classifications by surgeons and histology. Burns and adjacent normal skin in 11 patients with thermal injuries were imaged with visual and narrow bands centred at 1200, 1650, 1940 and 2250 nm and biopsies were taken from select areas. Reflectance intensities for each band in 273 regions of interest (ROI) were divided by the normal skin reflectance and combined into three Reflectance Indices (RIs). In addition, burns in ROIs and biopsies were classified by five surgeons and three pathologists, respectively, as superficial partial, deep partial, or full thickness. Results show that for burn depth increase classified by the surgeons, reflectance increased at 1200 and 2250, decreased at 1940, and didn't change at 1650 nm. In contrast, all three RIs increase with burn depth and predict the deep and full depths ROIs representing operable regions (Area Under Curve >0.6507, p < 0.0001). Pathologists' classification matched surgeons' classification of burn category only in eight of 21 biopsies (38.1%), but reflectance at all bands and one RI for all deep partial and full thickness biopsies were larger than in non‐biopsy normal and superficial partial thickness ROIs (p < 0.0118). In conclusion, multi‐spectral imaging with a new SWAT is a promising approach for evaluation of burn wound depth.
Tiling with monochromatic bipartite graphs of bounded maximum degree
Authors: Girão António , Janzer Oliver
Published: September 2024

We prove that for any , there exists a constant such that the following is true. Let be an infinite sequence of bipartite graphs such that and hold for all . Then, in any ‐edge‐coloured complete graph , there is a collection of at most monochromatic subgraphs, each of which is isomorphic to an element of , whose vertex sets partition . This proves a conjecture of Corsten and Mendonça in a strong form and generalises results on the multi‐colour Ramsey numbers of bounded‐degree bipartite graphs. It also settles the bipartite case of a general conjecture of Grinshpun and Sárközy.
Intrasession Caffeine Intake and Cycling Performance After Accumulated Work: A Field-Based Study
Authors: Sánchez-Redondo Iván R. , Alejo Lidia B. , Revuelta Carlos , de Pablos Raúl , Ibañez María , Pérez-López Alberto , Lucia Alejandro , Barranco-Gil David , Valenzuela Pedro L.
Published: September 2024

Background: Preexercise caffeine intake has proven to exert ergogenic effects on cycling performance. However, whether these benefits are also observed under fatigue conditions remains largely unexplored. We aimed to assess the effect of caffeine ingested during prolonged cycling on subsequent time-trial performance in trained cyclists. Methods: The study followed a triple-blinded, randomized, placebo-controlled cross-over design. Eleven well-trained junior cyclists (17 ± 1 years) performed a field-based 8-min time trial under “fresh” conditions (i.e., after their usual warm-up) or after two work-matched steady-state cycling sessions (total energy expenditure∼20 kJ/kg and ∼100 min duration). During the latter sessions, participants consumed caffeine (3 mg/kg) or a placebo ∼60 min before the time trial. We assessed power output, heart rate, and rating of perceived exertion during the time trial and mood state (Brunel Mood Scale) before and after each session. Results: No significant condition effect was found for the mean power output attained during the time trial (365 ± 25, 369 ± 31, and 364 32 W for “fresh,” caffeine, and placebo condition, respectively; p = .669). Similar results were found for the mean heart rate (p = .100) and rating of perceived exertion (p = 1.000) during the time trial and for the different mood domains (all p > .1). Conclusions: Caffeine intake during prolonged exercise seems to exert no ergogenic effects on subsequent time-trial performance in junior cyclists. Future studies should determine whether significant effects can be found with larger caffeine doses or after greater fatigue levels.
A host-adapted auxotrophic gut symbiont induces mucosal immunodeficiency
Authors: Lu Qiuhe , Hitch Thomas C. A. , Zhou Julie Y. , Dwidar Mohammed , Sangwan Naseer , Lawrence Dylan , Nolan Lila S. , Espenschied Scott T. , Newhall Kevin P. , Han Yi , Karell Paul E. , Salazar Vanessa , Baldridge Megan T. , Clavel Thomas , Stappenbeck Thaddeus S.
Published: September 2024

Harnessing the microbiome to benefit human health requires an initial step in determining the identity and function of causative microorganisms that affect specific host physiological functions. We show a functional screen of the bacterial microbiota from mice with low intestinal immunoglobulin A (IgA) levels; we identified a Gram-negative bacterium, proposed as
Tomasiella immunophila
, that induces and degrades IgA in the mouse intestine. Mice harboring
T. immunophila
are susceptible to infections and show poor mucosal repair.
T. immunophila
is auxotrophic for the bacterial cell wall amino sugar N-acetylmuramic acid. It delivers immunoglobulin-degrading proteases into outer membrane vesicles that preferentially degrade rodent antibodies with kappa but not lambda light chains. This work indicates a role for symbionts in immunodeficiency, which might be applicable to human disease.
How wet must a wetland be to have federal protections in post-
Sackett
US?
Authors: Gold Adam C.
Published: September 2024

In 2023, the US Supreme Court’s majority ruled in
Sackett
v.
Environmental Protection Agency
that only wetlands that are “indistinguishable” from federally protected waters “due to a continuous surface connection” are federally protected. This study estimates the potential impact of interpretations of the ruling on federal wetlands protections, using a qualitative measure of wetland “wetness” as a proxy for the new requirement. An estimated area ranging from ~17 million acres (19%) to nearly all 90 million acres of nontidal wetlands in the conterminous United States could be without federal protections, and variability in state protections creates hotspots of risk. The high-level estimates provided here represent a first step toward understanding the long-term impacts of
Sackett
v.
Environmental Protection Agency
on federal wetlands protections and highlight the uncertainty introduced by the ruling.
Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1
Authors: Lu Yi , Yue Chen-Xi , Zhang Li , Yao Deqiang , Xia Ying , Zhang Qing , Zhang Xinchen , Li Shaobai , Shen Yafeng , Cao Mi , Guo Chang-Run , Qin An , Zhao Jie , Zhou Lu , Yu Ye , Cao Yu
Published: September 2024

Precise regulation of intracellular phosphate (Pi) is critical for cellular function, with xenotropic and polytropic retrovirus receptor 1 (XPR1) serving as the sole Pi exporter in humans. The mechanism of Pi efflux, activated by inositol pyrophosphates (PP-IPs), has remained unclear. This study presents cryo–electron microscopy structures of XPR1 in multiple conformations, revealing a transmembrane pathway for Pi export and a dual-binding activation pattern for PP-IPs. A canonical binding site is located at the dimeric interface of Syg1/Pho81/XPR1 (SPX) domains, and a second site, biased toward PP-IPs, is found between the transmembrane and SPX domains. By integrating structural studies with electrophysiological analyses, we characterized XPR1 as an inositol phosphates (IPs)/PP-IPs–activated phosphate channel. The interplay among its transmembrane domains, SPX domains, and IPs/PP-IPs orchestrates the conformational transition between its closed and open states.
Mental programming of spatial sequences in working memory in the macaque frontal cortex
Authors: Tian Zhenghe , Chen Jingwen , Zhang Cong , Min Bin , Xu Bo , Wang Liping
Published: September 2024

How the brain mentally sorts a series of items in a specific order within working memory (WM) remains largely unknown. We investigated mental sorting using high-throughput electrophysiological recordings in the frontal cortex of macaque monkeys, who memorized and sorted spatial sequences in forward or backward orders according to visual cues. We discovered that items at each ordinal rank in WM were encoded in separate rank-WM subspaces and then, depending on cues, were maintained or reordered between the subspaces, accompanied by two extra temporary subspaces in two operation steps. Furthermore, the cue activity served as an indexical signal to trigger sorting processes. Thus, we propose a complete conceptual framework, where the neural landscape transitions in frontal neural states underlie the symbolic system for mental programming of sequence WM.
Impact of obesity on clinical outcomes of methicillin-susceptible
Staphylococcus aureus
bloodstream infections
Authors: Wasielewski Anthony S. , Casapao Anthony M. , Jankowski Christopher A. , Isache Carmen L. , Ravi Malleswari , Kunz Coyne Ashlan J.
Published: September 2024

Obesity affects over one-third of U.S. adults and complicates the treatment of methicillin-susceptible
Staphylococcus aureus
(MSSA) bloodstream infections (BSI). A study at the University of Florida Health Centers compared clinical outcomes between 233 obese and non-obese patients receiving cefazolin for MSSA BSI. No significant differences were found in clinical success (81.9% vs 82.7%), mortality (7.2% vs 5.3%), or adverse events (3.6% vs 3.3%). However, obese patients took longer to clear blood cultures (4.62 vs 4.01 days,
P
= 0.017).
Parametric and nonparametric population pharmacokinetic analysis of fluconazole in critically ill patients and dosing simulations for
Candida
infections
Authors: Matusik Elodie , Vassal Olivia , Conrad Anne , Ferry Tristan , Millet Aurélien , Dupont Damien , Grandjean Lola , Guitton Jérôme , Roux Sandrine , Bienvenu Anne-Lise , Bohé Julien , Friggeri Arnaud , Goutelle Sylvain
Published: September 2024

Large pharmacokinetic (PK) variability of fluconazole has been reported in critically ill patients, but the implications for fluconazole dosing remain unclear. The objectives of this study were to evaluate the population PK of fluconazole and identify appropriate dosage regimens by simulations. This was a retrospective analysis of fluconazole PK data from patients hospitalized in critical care and infectious disease departments. Both parametric and nonparametric population approaches were used. Various loading and maintenance fluconazole doses were evaluated by simulations, with computation of the probabilities of PK/pharmacodynamic (PD) target attainment (PTA) and cumulative fractions of response (CFR) based on international and local minimum inhibitory concentration (MIC) distributions of
Candida
sp. Data from 36 critically ill patients and 16 non-critically ill patients were available for model building (
n
= 202 concentrations). The final model adequately described the data, including the external data set (13 patients). After 24 h of therapy, 65% and 74% of patients had trough and area under the concentration-time curve values below the usual targets. Standard dosages were associated with low PTA for MIC >1 mg/L at 24 h. Higher loading doses administered two times daily improved PTA. CFR were >90% for
C. albicans
with standard dosages, while they were very low for
C. glabrata
, even with high dosages.
Candida
species and associated MIC distributions strongly influence fluconazole dosage requirements. Higher loading doses may be necessary for the achievement of PK/PD targets up to MIC breakpoints. The use of fluconazole for invasive
C. glabrata
infection should be discouraged because of poor PK/PD target attainment.
WNV and SLEV coinfection in avian and mosquito hosts: impact on viremia, antibody responses, and vector competence
Authors: Gallichotte Emily N. , Fitzmeyer Emily A. , Williams Landon , Spangler Mark Cole , Bosco-Lauth Angela M. , Ebel Gregory D.
Published: September 2024

West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are closely related flaviviruses that can cause encephalitis in humans and related diseases in animals. In nature, both are transmitted by
Culex
, with wild birds, including jays, sparrows, and robins, serving as vertebrate hosts. WNV and SLEV circulate in the same environments and have recently caused concurrent disease outbreaks in humans. The extent that coinfection of mosquitoes or birds may alter transmission dynamics, however, is not well characterized. We therefore sought to determine if coinfection alters infection kinetics and virus levels in birds and infection rates in mosquitoes. Accordingly, American robins (
Turdus migratorius
), two species of mosquitoes, and vertebrate and invertebrate cells were infected with WNV and/or SLEV to assess how simultaneous exposure may alter infection outcomes. There was variable impact of coinfection in vertebrate cells, with some evidence that SLEV can suppress WNV replication. However, robins had comparable viremia and antibody responses regardless of coinfection. Conversely, in
Culex
cells and mosquitoes, we saw a minimal impact of simultaneous exposure to both viruses on replication, with comparable infection, dissemination, and transmission rates in singly infected and coinfected mosquitoes. Importantly, while WNV and SLEV levels in coinfected mosquito midguts were positively correlated, we saw no correlation between them in salivary glands and saliva. These results reveal that while coinfection can occur in both avian and mosquito hosts, the viruses minimally impact one another. The potential for coinfection to alter virus population structure or the likelihood of rare genotypes emerging remains unknown.

IMPORTANCE

West Nile virus (WNV) and St. Louis encephalitis virus (SLEV) are closely related viruses that are transmitted by the same mosquitoes and infect the same birds in nature. Both viruses circulate in the same regions and have caused concurrent outbreaks in humans. It is possible that mosquitoes, birds, and/or humans could be infected with both WNV and SLEV simultaneously, as has been observed with Zika, chikungunya, and dengue viruses. To study the impact of coinfection, we experimentally infected vertebrate and invertebrate cells, American robins, and two
Culex
species with WNV and/or SLEV. Robins were efficiently coinfected, with no impact of coinfection on virus levels or immune response. Similarly, in mosquitoes, coinfection did not impact infection rates, and mosquitoes could transmit both WNV and SLEV together. These results reveal that WNV and SLEV coinfection in birds and mosquitoes can occur in nature, which may impact public health and human disease risk.
Innate cells and STAT1-dependent signals orchestrate vaccine-induced protection against invasive
Cryptococcus
infection
Authors: Wang Keyi , Espinosa Vanessa , Wang Yina , Lemenze Alexander , Kumamoto Yosuke , Xue Chaoyang , Rivera Amariliz
Published: September 2024

Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies, we determined that a heat-killed,
Cryptococcus neoformans
fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2
+
monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2
+
cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c
+
cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against
Cryptococcus
infection.

IMPORTANCE

The number of patients susceptible to invasive fungal infections across the world continues to rise at an alarming pace yet current antifungal drugs are often inadequate. Immune-based interventions and novel antifungal vaccines hold the promise of significantly improving patient outcomes. In previous studies, we identified a
Cryptococcus neoformans
mutant strain (Fbp1-deficient) as a potent, heat-inactivated vaccine candidate capable of inducing homologous and heterologous antifungal protection. In this study, we used a combination of methods together with a cohort of conditional knockout mouse strains to interrogate the roles of innate cells in the orchestration of vaccine-induced antifungal protection. We uncovered novel roles for neutrophils and monocytes as coordinators of a STAT1-dependent cascade of responses that mediate vaccine-induced protection against invasive cryptococcosis. This new knowledge will help guide the future development of much-needed antifungal vaccines.
Aspergillus nigeras a rare cause of postarthroscopy knee septic arthritis in a healthy patient
Authors: Agathangelidis Filon , Nikopoulou Anna , Vyzantiadis Timoleon-Achilleas , Baxevanou Maria , Givissis Panagiotis , Chalidis Byron
Published: September 2024

This case report outlines the diagnostic and therapeutic challenges encountered in a man in his 70s suffering from knee septic arthritis caused byAspergillus niger. It is the second published case in the literature with osteoarticular infection fromA. nigerand the first one in the last 40 years. Following knee arthroscopy, the patient experienced persistent pain, swelling and discomfort, prompting further investigation. Postoperative knee cultures were negative for infection, but symptoms were not ameliorated. Therefore, an arthroscopic debridement was performed that revealed severe joint inflammation and degeneration. Cultures from the synovial fluid and tissue samples identified infection fromA. nigersp. Antimicrobial treatment with voriconazole finally led to significant clinical improvement and eradication of infection. This case highlights the intricacies involved in diagnosing and managing fungal osteoarticular infections in healthy patients without concomitant medical diseases or comorbidities.
Topiramate-induced acute eosinophilic pneumonia
Authors: Tyagi Rahul , Aggarwal Monika , Suyal Utkarsh , Pandey Indramani
Published: September 2024

A man in his 40s with a known history of alcohol dependence syndrome was admitted with presenting symptoms of alcohol withdrawal. During his admission, he developed breathlessness, cough and wheezing. Investigations revealed raised absolute eosinophil count and serum IgE levels. Chest imaging showed ill-defined opacities and fibreoptic bronchoscopy with bronchoalveolar lavage confirmed eosinophilic pneumonia. Extensive workup for the cause of eosinophilia was negative. The patient’s medicines were reviewed, and it was realised that the onset of eosinophilia occurred after starting topiramate for an alcohol withdrawal seizure. The drug was stopped, leading to the complete resolution of symptoms and radiological abnormalities. This case highlights the importance of considering drug-induced causes of eosinophilic pneumonia.
Importance of immunosuppression in haemophagocytic lymphohistiocytosis caused by miliary tuberculosis
Authors: Nielsen Tine , Dimitrijevic Andreja , Dahl Sørensen Mia , Johansen Isik Somuncu , Hansen Dennis Lund
Published: September 2024

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome with an abnormal activation of the immune system and is associated with a high mortality even with treatment. We present a case of a woman in her mid-50s who developed HLH triggered by miliary tuberculosis (TB) while receiving a tumour necrosis factor alpha inhibitor.

The patient was admitted with a high fever and respiratory pain. Her condition deteriorated despite empirical treatment. Diagnosis of HLH was established based on clinical presentation, H-score and HLH-04 criteria. Concurrently, miliary TB was identified as the trigger. She was treated with anti-tuberculous therapy and HLH-directed treatment with dexamethasone, etoposide and anakinra. Initial improvement was observed, leading to the withholding of HLH-orientated treatment. However, several relapses occurred, necessitating prolonged HLH treatment.

A literature review corroborated the importance of combined anti-tuberculous and immunosuppressive therapy for managing HLH. This case underscores the necessity of timely and comprehensive management of HLH-oriented treatment.
Extrahepatic gallstones and abscess formation post-cholecystostomy: a rare complication in high-risk acute cholecystitis management
Authors: MacDonald-Nethercott Meiling , Ahmed Naeem , Tanner Nicola , Finch Guy
Published: September 2024

This intriguing case report explores an interesting complication following percutaneous cholecystostomy for the management of acute cholecystitis in an elderly female with multiple comorbidities. Despite initial improvement, she later presented with recurrent symptoms, due to a collection of gallstones, that had migrated through the cholecystostomy tract, requiring exploration, stone retrieval and abscess drainage. While percutaneous cholecystostomy remains an effective treatment for managing acute cholecystitis in high-risk surgical candidates, this case highlights the rare yet critical risk of extrahepatic gallstones and abscess formation. It emphasises the necessity for vigilance in detecting and managing complications associated with percutaneous transhepatic cholecystostomy, ensuring timely diagnosis and effective treatment.
Impact of the COVID-19 pandemic on psychotropic prescribing: a systematic review
Authors: Mahesarajah Swettha , El Asmar Marie Line , Irwin Ryan , Vallejo-Vaz Antonio J , Mastellos Nikolaos , Dharmayat Kanika I
Published: September 2024

Objectives

The global prevalence of mental health disorders has risen significantly since the beginning of the COVID-19 pandemic. The pandemic has additionally caused disruption to mental health services, leading to a shift from in-person to remote service delivery. Given its long-term impact, it has become critical to evaluate whether changes in health delivery during the pandemic have had an effect on prescribing patterns for commonly prescribed psychotropic drugs. This study aims to assess the impact of the COVID-19 pandemic on changes in psychotropic prescribing patterns in adults, as well as differences in prescribing in different healthcare delivery approaches across various geographical contexts.

Design and eligibility requirements

Systematic review of cohort, interrupted time-series and cross-sectional studies examining prescribing trends for at least one commonly prescribed psychotropic drug during and after COVID-19 in accessing care remotely or face to face between 1 January 2020 and 17 June 2022.

Data sources

MEDLINE, EMBASE, CINAHL, HMIC and PsycINFO databases were searched in addition to citation chaining of relevant reviews.

Extraction and analysis

Study screening, data extraction and quality assessment were completed by two independent reviewers. The PECO strategy was used to devise the systematic review and findings were synthesised narratively.

Results

16 studies were eligible for inclusion. Studies documenting changes in psychotropic prescribing trends provided very conflicting findings. There were no stark differences in prescribing outcomes between different healthcare delivery methods (ie, face-to-face consultations vs remote consultations). A noteworthy finding was that the prescribing rate of benzodiazepines was higher in women than men. No particular trends were observed for the prescription rates of hypnotics, antidepressants or antipsychotics.

Conclusions

Findings support mixed trends in the prescription of psychotropic medications in a range of settings, hindering conclusive statements on COVID-19’s impact on prescribing. In areas where remote consultations are in use, more comprehensive research is required to assess the safety of prescribing in these settings to inform public health policy and assess if the observed trends in our systematic review persist over time (given the increased consideration of remote and telehealth care in delivering services), particularly the safe and effective deployment of these services.
Disparities in the real-world prescription pattern of oral anticoagulants for US Medicare beneficiaries: a geospatial analysis
Authors: Zou Jingrui , Liang Dong , Zhu Yong
Published: September 2024

Objectives

This study was conducted to examine urban–rural differences in the real-world prescribing pattern of oral anticoagulants and geographic variations in the prescribing pattern among clinicians serving Medicare beneficiaries in the USA.

Design

A cross-sectional study.

Setting

A real-world setting.

Participants

232 665 clinicians who prescribed oral anticoagulants for Medicare beneficiaries from the 2020 Medicare Provider Utilisation and Payment Data were classified as warfarin only, direct oral anticoagulants (DOACs) only or warfarin+DOAC prescribers.

Main outcome measures

Urban–rural differences in the prescribing patterns were examined using multivariate multinominal logistic regression analysis. A geospatial analysis was conducted to estimate standardised prescriber ratios (SPR) for DOAC only or warfarin only prescribers versus warfarin+DOAC prescribers to illustrate hot and cold spots for DOAC adoption in the USA.

Results

92% of clinicians who prescribed oral anticoagulants prescribed DOAC in 2020. Clinicians from rural regions were more likely to prescribe warfarin only (adjusted OR=1.335, 95% CI=(1.281 to 1.391)) and DOAC only (adjusted OR=2.052, 95% CI=(1.999 to 2.106)), compared with clinicians from urban regions. Hot spots for SPR of DOAC only versus warfarin+DOAC prescribers were mostly found in California, southern and southeastern states; cold spots were mostly found in Minnesota and Iowa. Hot spots for SPR of warfarin only versus warfarin+DOAC prescribers were mostly found in several metropolitan areas on the west coast and in Midwest; cold spots were mostly found on the east coast.

Conclusions

Urban–rural status of clinicians was associated with their prescribing patterns of oral anticoagulants. The study identifies geographical heterogeneity in DOAC adoption and highlights gaps that may need to be addressed for increased accessibility of DOAC for patients in need.