bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidation of the melitidin biosynthesis pathway in pummelo
Authors: Shen Shuangqian , Wang Shouchuang , Yang Chenkun , Wang Chao , Zhou Qianqian , Zhou Shen , Zhang Ran , Li Yufei , Wang Zixuan , Dai Liupan , Peng Wenjv , Hao Yingchen , Guo Hao , Cao Guangping , Liu Xianqing , Yao Fan , Xu Qiang , Fernie Alisdair R. , Luo Jie
Published: September 2023

Specialized plant metabolism is a rich resource of compounds for drug discovery. The acylated flavonoid glycoside melitidin is being developed as an anti‐cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP‐glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti‐cholesterol statin drug candidate. Co‐expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites.
Kratom (Mitragyna speciosa): A Case Review of Use Before and During Pregnancy
Authors: Faucher Mary Ann , Morillos Stephanie , Cordova Polly , McNeil‐Santiel Jessica , Onisko Nancy , Adhikari Emily H. , Nelson David B.
Published: September 2023

Kratom (Mitragyna speciosa) is a plant‐based substance with psychoactive properties similar to opioids but is not currently classified as an opioid. One of its more prevalent uses is to treat opioid dependency and withdrawal symptoms. Opioid use disorder is a leading cause of pregnancy‐associated maternal mortality, and pregnant women may be using kratom as a substitute or alternative to opioids. Prevalence of kratom use is increasing rapidly, but scientific evidence specific to therapeutic and adverse effects is lacking overall, and the implications of its use in pregnancy and on the fetus‐newborn are limited to a few case reports. Kratom is a legal substance by federal law, although some states have banned its use. The lack of regulation is concerning. Significant illness and associated deaths have been reported with kratom use. Lack of disclosure by people using kratom and limited laboratory testing options are major challenges for health care providers and public health.
Inverse correlation between vitamin D and CRP levels in alopecia areata: A pilot study
Authors: Mokhtari Fatemeh , Ganjei Zakiye , Yazdanpanah Maral , Hosseini Mohsen
Published: September 2023

Introduction

Alopecia areata (AA) is an autoimmune non‐scarring hair loss. The role of micronutrients such as iron, zinc, and vitamins, especially vitamin D, on the natural hair cycle is well defined in literature. This study aims to evaluate the correlation between vitamin D and CRP levels in patients with alopecia areata.

Methods

This cross‐sectional study was performed from beginning of October 2020 until end of December 2021. Alopecia areata patients over 18 years of age gave their written consent to participate in the study. The severity of the patients' disease was assessed using the Severity of Alopecia Tool. Serum vitamin D and CRP levels were measured and CBC and LFT were also performed.

Results

There were significant differences between the patients with the localized form of AA and its universal form in the following variables: Vitamin D levels, SALT score, WBC, ALKP, and CRP. There was also a significant inverse correlation between CRP and vitamin D levels (p < 0.0001).

Conclusion

Vitamin D deficiency is associated with higher CRP levels, and patients with low serum vitamin D and high CRP levels are at a higher risk of developing the universalis form of AA; therefore, these patients should undergo more aggressive treatments.
Nurse‐led models of care for metabolic syndrome in primary care: A scoping review
Authors: Marzano Maryta , Caniano Lori , Abram Marissa D.
Published: September 2023

Aim

To identify and map out existing nurse‐led models of care for treatment and prevention of metabolic syndrome in primary care settings.

Design

A scoping review.

Methods

Conducted in accordance with the JBI methodology.

Data Sources

A search of the databases PubMed, CINAHL Complete, Cochrane Library, Scopus, handsearch and a grey literature search was conducted in June 2022 and updated in March 2023.

Results

Title and abstract screening was performed on 926 articles resulting in 40 articles for full text screening. Full text screening yielded seven articles that met inclusion criteria.

Conclusion

Additional research is needed on nursing models of care to prevent and treat metabolic syndrome. Future studies should concentrate on rigour with clearly defined objective inclusion criteria.

Implications to Clinical Practice

This review contributes a synthesis of the evidence on nurse‐led models for metabolic syndrome in primary care.

Impact

This scoping review addresses metabolic syndrome, the precursor to non‐communicable disease. The review mapped the evidence for nurse‐led models of care for metabolic syndrome in the primary care setting. These findings promote the development and evaluation of novel nurse‐led models of care which can mitigate the effect of the current epidemic.

Reporting Method

PRISMA checklist for scoping reviews.

No patient or public contribution was part of this study.

Protocol Registration: Open Science Framework accessible at:https://osf.io/jfpw7/.
Plurinational democracies in Europe: the quest for a profane constitutionalism
Authors: BENGOETXEA JOXERRAMON
Published: September 2023

How should we understand the claims on the right to decide on status made within plurinational member states of the European Union by actors and institutions seeking to protect the self‐government of sub‐state nations or peoples, or at least their right to consent to their ascribed status? Peaceful solutions to conflicts involving contested claims over territory, citizenship, and national sovereignty (authority) can be found when a conceptual or cultural transformation takes place towards a pluralist and bottom‐up or federal concept of plurinational democracy, recovering the centrality of self‐determination as the self‐assertion of a political community. Constitutional law based on the popular sovereignty of a majority nation within plurinational democracies often neglects the question of the definition of the demos as the prefigured constituency, and the existence of national or territorial minorities. If constitutions are interpreted as precluding any claim to self‐determination by a constituency, and any debate about that claim, then an undemocratic, sacralized model of militant constitutionalism may emerge. That model is not so much about protecting democracy as it is about imposing a national mould, a pre‐defined demos. This article revisits the claims of sovereignty made by national territorial minorities in Spain, against the background of the constitutional doctrine of the Spanish judiciary that precludes these constituencies from engaging in political debates on the right to decide. The resulting sacralization of the Constitution leads to a new version of the model of ‘militant democracy’, a militant nationalist constitutionalism, which can be countered by an alternative, secular, even profane approach to the Constitution.
Transnational constitutionalism – conflicts‐law constitutionalism – economic constitutionalism: the exemplary case of the European Union
Authors: JOERGES CHRISTIAN
Published: September 2023

Transnational constitutionalism is both a sociological given and a legal challenge. We observe the emergence of ever more legally framed transnational arrangements with ever more power and impact. Do such arrangements deserve to be called legitimate rule in Habermasian terms? Is it at all conceivable that the proprium of law can be defended against the rise of its informal competitors? This article opts for a third way that listens to neither the siren songs on law beyond the state nor to the defences of nation‐state constitutionalism as the monopolist of legitimate rule. The proposed alternative suggests that transnational legal ordering of the European Union should build on its reconceptualization as a ‘three‐dimensional conflicts law’ with a democracy‐enhancing potential. This reconceptualization operationalizes the ‘united in diversity’ motto of the Draft Constitutional Treaty of 2004, preserves the essential accomplishments of Europe's constitutional democracies, provides for co‐operative problem solving of transnational regulatory tasks, and retains supervisory powers over national and transnational arrangements of private governance.
Family Ownership and Alliance Intensity
Authors: Bettinazzi Emanuele L. M. , Amore Mario Daniele , Reuer Jeffrey J.
Published: September 2023

In this paper, we study the relationship between family ownership and corporate alliance intensity. Theoretically, we propose that the tendency of family firms to pursue socioemotional wealth objectives exacerbates the level of information asymmetry they display vis‐à‐vis other firms, reducing their attractiveness as alliance partners. Based on a panel of US firms, we find that family firms join fewer alliances than non‐family firms. In line with our arguments, we also find that analyst and media coverage, and the presence of dedicated institutional investors mitigate the negative relationship between family ownership and alliance intensity. By highlighting the role of family ownership in alliances, we provide new insights into the debate on the ability of family firms to develop. Moreover, we contribute to research on the antecedents of alliances by introducing the role of owners’ attributes and identifying a set of mechanisms that mitigate the informational hazards that family firms present to prospective partners.
Biomechanical effects of different materials for an occlusal device on implant‐supported rehabilitation in a tooth clenching situation: A 3D finite element analysis
Authors: Andrade Carla Souza , de Abreu Costa Luy , Menechelli Luana Gonçalves , Lemos Cleidiel A. A. , Okamoto Roberta , Verri Fellippo R. , de Souza Batista Victor Eduardo
Published: September 2023

Purpose

The purpose of this 3D finite element analysis was to evaluate the biomechanical effects of different materials used to fabricate occlusal devices to achieve stress distribution in simulated abutment screws, dental implants, and peri‐implant bone tissue in individuals who clench their teeth.

Materials and Methods

Eight 3D models simulated a posterior maxillary bone block with three external hexagon implants (Ø4.0 × 7.0 mm) supporting a 3‐unit screw‐retained metal‐ceramic prosthesis with different crown connection (splinting), and the use of an occlusal device (OD). The OD was modeled to be 2‐mm thick. ANSYS 19.2 software was used to generate the finite‐element models in the pre‐and post‐processing phases. Simulated abutment screws and dental implants were evaluated by von Mises stress maps, and simulated bone was evaluated by maximum principal stress and microstrain maps by using a finite element software program.

Results

The highest stress values in the dental implants and screws were observed in single crowns without OD (M1). Furthermore, the highest stress values and bone tissue strain were found in single crowns without OD (M1). The simulated material for the OD did not cause many discrepancies in terms of the stress magnitude in the simulated dental implant and abutment screw for both single and splinted crowns; however, more rigid materials exhibited lower stress values.

Conclusion

The use of OD was effective in reducing stress in the simulated implants and abutment screws and stress and strain in the simulated bone tissue. The material used to simulate the OD influenced the biomechanical behavior of implant‐supported fixed prostheses, whereas splints with rigid materials such as PEEK and PMMA exhibited better biomechanical behavior.
Longitudinal effects of oral administration of antimicrobial drugs on fecal microbiota of horses
Authors: Gomez Diego , Toribio Ramiro , Caddey Benjamin , Costa Marcio , Vijan Stephanie , Dembek Katarzyna
Published: September 2023

Background

Antimicrobial drug‐associated diarrhea (AAD) is the most common adverse effect in horses receiving antimicrobials. Little information on how oral administration of antimicrobials alters intestinal microbiota in horses is available.

Objective

Investigate changes of the fecal microbiota in response to oral administration of antimicrobials.

Animals

Twenty healthy horses.

Methods

Prospective, longitudinal study. Horses were randomly assigned to 4 groups comprising 4 horses each: group 1 (metronidazole); group 2 (erythromycin); group 3 (doxycycline); group 4 (sulfadiazine/trimethoprim, SMZ‐TMP); and group 5 (control). Antimicrobials were administered for 5 days. Fecal samples were obtained before (day 0) and at 1, 2, 3, 4, 5, 6, and 30 days of the study period. Fecal microbiota was characterized by high throughput sequencing of the V4 region of the 16S rRNA.

Results

Horses remained healthy throughout the study. Richness and diversity in doxycycline, erythromycin, and metronidazole, but not SMZ‐TMP groups, was significantly lower (P < .05) at multiple time points after administration of antimicrobials compared with samples from day 0. Main changes in the microbiota were observed during the time of antimicrobial administration (day 2‐5; weighted and unweighted UniFrac PERMANOVA P < .05). Administration of erythromycin, doxycycline and, to a lesser extent, metronidazole produced a pronounced alteration in the microbiota compared with day 0 samples by decreasing the abundance of Treponema, Fibrobacter, and Lachnospiraceae and increasing Fusobacterium and Escherichia‐Shigella.

Conclusions and Clinical Importance

Oral administration of antimicrobials alters the intestinal microbiota of healthy horses resembling horses with dysbiosis, potentially resulting in intestinal inflammation and predisposition to diarrhea.
MOCOS‐associated renal syndrome in a Brown Swiss cattle
Authors: Jacinto Joana G. P. , Küchler Leonore Bettina , Peters Laureen M. , Van der Vekens Elke , Gurtner Corinne , Seefried Franz R. , Meylan Mireille , Drögemüller Cord
Published: September 2023

Background

A recessive form of MOCOS‐associated xanthinuria type II is described in Tyrolean grey cattle. A similar case was identified in a 5‐month‐old Brown Swiss calf with hoof overgrowth, rough coat, urine sediment, and pneumonia.

Hypothesis/Objectives

To characterize the disease phenotype, to evaluate its genetic etiology, and to determine the prevalence of the deleterious allele in the Brown Swiss population.

Animals

An affected calf, its parents, and 65 441 Swiss dairy cattle.

Methods

The affected animal was clinically examined and necropsied. Microarray genotyping was used to determine the genotypes and to assess the frequency of the MOCOS allele in a Brown Swiss control cohort.

Results

Ultrasonography revealed hyperechoic renal pyramids with multifocal distal shadowing and echogenic sediment in the urinary bladder. Necropsy revealed suppurative bronchopneumonia and urolithiasis. Histology revealed numerous nephroliths with multifocal chronic lymphohistiocytic interstitial infiltrates, fibrosis, tubular degeneration, chronic multifocal glomerulonephritis with sclerosis, and bilateral hydronephrosis. Dysplastic changes were observed in the corium of the claw and the cornea. Genetic testing identified the homozygous presence of a known MOCOS frameshift variant in the case. Both parents were heterozygous and the prevalence of carriers in genotyped Brown Swiss cattle was 1.4% (342/24337).

Conclusions and Clinical Importance

The findings were consistent with the diagnosis of a recessive renal syndrome similar to xanthinuria type II described in Tyrolean grey cattle. The prevalence of the deleterious MOCOS allele is low in the Brown Swiss breed. However, mating of carriers should be avoided to prevent further losses.
Longitudinal examination of urine pH, specific gravity, protein, culture, and antimicrobial resistance profiles in healthy dogs
Authors: McGlynn Andrew , Mrofchak Ryan , Madan Rushil , Madden Christopher , Jahid Mohammad Jawad , Mollenkopf Dixie , Wittum Thomas , Justice Sheryl S. , Rudinsky Adam , Hokamp Jessica , Hale Vanessa
Published: September 2023

Background

Urine is routinely evaluated in dogs to assess health. Reference ranges for many urine properties are well established, but the scope of variation in these properties over time within healthy dogs is not well characterized.

Objectives

Longitudinally characterize urine properties in healthy dogs over 3 months.

Animals

Fourteen healthy client‐owned dogs.

Methods

In this prospective study, dogs were evaluated for health; then, mid‐stream free‐catch urine was collected from each dog at 12 timepoints over 3 months. Urine pH, urine specific gravity (USG), protein, cultures, and antimicrobial resistance profiles were assessed at each timepoint.

Results

Urine pH varied within and between dogs over time (Friedman's test: within P = .03; between P < .005). However, USG, protein, and bacterial diversity of urine were consistent within dogs over time, and only varied between dogs (Kruskal‐Wallis: between all P < .005). Antimicrobial resistant isolates were identified in 12 out of 14 dogs with 34 of 48 of the isolates demonstrating resistance to amoxicillin.

Conclusions and Clinical Importance

Urine pH should be assessed at multiple timepoints via pH meter before making clinical decisions. Mid‐stream free‐catch urine with high concentrations of bacteria (>105 CFU/mL) should not be considered the only indicator of urinary tract infection. Bacterial isolates from dogs in this study had widespread resistance to amoxicillin/oxacillin underscoring the need for antimicrobial stewardship.
A missense variant in DGKG as a recessive functional variant for hepatic fibrinogen storage disease in Wagyu cattle
Authors: Jacinto Joana G. P. , Wohlsein Peter , Häfliger Irene M. , Karl Michael , Pohlers Michael , Plobner Lutz , Grünberg Walter , Drögemüller Cord
Published: September 2023

Hepatic fibrinogen storage disease (HFSD) was diagnosed in a 5‐month‐old Wagyu calf with a history of recurrent respiratory disease. It was characterized by lethargy, dehydration, acidemia, and increased liver enzyme activities. Histologically, disseminated hepatocytes were swollen and showed a single, sharply demarcated, faintly eosinophilic cytoplasmic inclusion with a ground‐glass appearance, with the nucleus in an eccentric position. Cytoplasmic inclusions did not stain with the periodic acid‐Schiff (PAS) reaction. Using a rabbit polyclonal antibody against fibrinogen, the cytoplasmic vacuoles in the hepatocytes stained intensely. Electron microscopy disclosed hepatocytes with membrane‐bound cytoplasmic inclusions filled with fine granular material interspersed with a few coarse‐grained electron‐dense granules. A trio whole‐genome sequencing approach identified a deleterious homozygous missense variant in DGKG (p.Thr721Ile). The allele frequency in 209 genotyped Wagyu was 7.2%. This is a report of a DGKG‐related recessive inherited disorder in cattle and adds DGKG to the list of candidate genes for HFSD in other species.
Petrology and shock history of the first depleted‐like poikilitic shergottite Asuka 12325
Authors: Takenouchi Atsushi , Yamaguchi Akira , Mikouchi Takashi , Greenwood Richard , Yamazaki Sojiro
Published: September 2023

Asuka (A) 12325 is the first poikilitic shergottite having a depleted pattern in light rare earth elements (REE). Compared with known poikilitic shergottites, A 12325 has smaller but more abundant pyroxene oikocrysts with remarkable Fe‐rich pigeonite rims, indicating that A 12325 cooled relatively faster at a shallower part of the crust. The redox condition (logfO2 = IW + 0.6‐IW + 1.7) and Fe‐rich chemical compositions of each mineral in A 12325 are close to enriched shergottites. The intermediate shergottites could not form by a simple mixing between parent magmas of A 12325 and enriched shergottites. Although A 12325 contains various high‐pressure minerals such as majorite and ringwoodite, plagioclase is only partly maskelynitized. Therefore, the maximum shock pressure may be within 17–22 GPa. Thermal conduction and ringwoodite growth calculation around a shock vein revealed that the shock dwell time of A 12325 is at least 40 ms. The weaker shock pressure and longer shock dwell time in A 12325 may be attained by an impact event similar to those of nakhlites and Northwest Africa (NWA) 8159. Such a weak shock ejection event may be as common on Mars as a severe shock event recorded in shergottites. Alteration of sulfide observed in A 12325 may imply the presence of magmatic fluid in its reservoir on Mars. A 12325 expands a chemical variety of Martian rocks and has a unique shock history among poikilitic shergottites while A 12325 also implies that poikilitic shergottites are common rocks on Mars regardless of their sources.
A conserved extracellular Ribo1 with broad‐spectrum cytotoxic activity enables smut fungi to compete with host‐associated bacteria
Authors: Ökmen Bilal , Katzy Philipp , Huang Luyao , Wemhöner Raphael , Doehlemann Gunther
Published: September 2023

Ribotoxins are secreted ribonucleases that specifically target and cleave the universally conserved sarcin–ricin loop sequence of rRNA, which leads to inhibition of protein biosynthesis and subsequently to cell death. We have identified and characterized a secreted Ribo1 protein of plant pathogenic smut fungi.

Heterologous expression in different model systems showed that smut Ribo1 has cytotoxic activity against bacteria, yeast, host and nonhost plants.

Recombinant expression of Ribo1 in Nicotiana benthamiana induced plant cell death; however, an active site mutant induced cell death only when expressed as a secreted protein. In the maize smut Ustilago maydis, transcription of Ribo1 is specifically induced in early infection stages. While a knockout mutant revealed that Ribo1 is dispensable for U. maydis virulence, the overexpression of Ribo1 in planta had a strong dominant negative effect on virulence and induced host defense responses including cell death.

Our findings suggest a function of Ribo1 during the epiphytic development rather than for invasive colonization of the host. Accordingly, in the presence of the biocontrol bacteria Pantoea sp., which were isolated from maize leaves, the ribo1 knockout mutant was significantly impaired in virulence. Together, we conclude that Ribo1 enables smut fungi to compete with host‐associated bacteria during epiphytic development.
Limits of thermal and hydrological tolerance in a foundation tree species (Populus fremontii) in the desert southwestern United States
Authors: Moran Madeline E. , Aparecido Luiza M. T. , Koepke Dan F. , Cooper Hillary F. , Doughty Christopher E. , Gehring Catherine A. , Throop Heather L. , Whitham Thomas G. , Allan Gerard J. , Hultine Kevin R.
Published: September 2023

Populus fremontii is among the most dominant, and ecologically important riparian tree species in the western United States and can thrive in hyper‐arid riparian corridors. Yet, P. fremontii forests have rapidly declined over the last decade, particularly in places where temperatures sometimes exceed 50°C.

We evaluated high temperature tolerance of leaf metabolism, leaf thermoregulation, and leaf hydraulic function in eight P. fremontii populations spanning a 5.3°C mean annual temperature gradient in a well‐watered common garden, and at source locations throughout the lower Colorado River Basin.

Two major results emerged. First, despite having an exceptionally high Tcrit (the temperature at which Photosystem II is disrupted) relative to other tree taxa, recent heat waves exceeded Tcrit, requiring evaporative leaf cooling to maintain leaf‐to‐air thermal safety margins. Second, in midsummer, genotypes from the warmest locations maintained lower midday leaf temperatures, a higher midday stomatal conductance, and maintained turgor pressure at lower water potentials than genotypes from more temperate locations.

Taken together, results suggest that under well‐watered conditions, P. fremontii can regulate leaf temperature below Tcrit along the warm edge of its distribution. Nevertheless, reduced Colorado River flows threaten to lower water tables below levels needed for evaporative cooling during episodic heat waves.
The role of indices in predicting disease severity and outcomes of multisystem inflammatory syndrome in children
Authors: Coşkun Serkan , Güngörer Vildan , Öner Nimet , Sezer Müge , Karagöl Cüneyt , Tekin Zahide Ekici , Tekgöz Pakize Nilüfer , Kaplan Melike Mehveş , Polat Merve Cansu , Çelikel Elif , Acar Banu Çelikel
Published: September 2023

Background

The aim of this study was to evaluate the role of the systemic immune inflammation index (SII), C‐reactive protein/albumin ratio (CAR), the monocyte/lymphocyte ratio (MLR), and the neutrophil/lymphocyte ratio (NLR) in predicting disease severity, treatment, and prognosis in multisystem inflammatory syndrome in children (MIS‐C).

Methods

This medical record review retrospectively evaluated the clinical and laboratory findings of 191 MIS‐C patients followed in the Department of Pediatric Rheumatology at Ankara City Hospital, Turkey. The patients were grouped by disease severity: mild, moderate, and severe. SII, CAR, MLR, and NLR were calculated for each group.

Results

All patients had fever at the time of admission; 153 (80.1%) had gastrointestinal tract involvement, 74 (38.7%) had rash, 63 (33%) had conjunctivitis, 107 (56%) had cardiac involvement, 32 (15.6%) had renal involvement, and 143 (74.9%) had hematological involvement. According to logistic regression analysis, SII, NLR, MLR, and CAR were found to be predictive indexes for disease severity, need for intensive care, need for inotropes, and anakinra treatment in MIS‐C.

The cut‐off values of ≥1605.3 for SII, ≥9.1 for NLR, and ≥3.9 for CAR increased the risk of severe disease by 3.4, 7.1, and 5.7 times, respectively.

Conclusion

NLR, SII, MLR, and CAR are effective and useful for predicting the severity of MIS‐C, the need for intensive care, and the need for anakinra treatment.
Robust condition‐based production and maintenance planning for degradation management
Authors: Sun Qiuzhuang , Chen Piao , Wang Xin , Ye Zhi‐Sheng
Published: September 2023

We study the robust production and maintenance control for a production system subject to degradation. A periodic maintenance scheme is considered, and the system production rate can be dynamically adjusted before maintenance, serving as a proactive way of degradation management. Optimal control of the degradation rate aims to strike a balance between the risk of failure and the production profit. We first consider the scenario in which the degradation rate increases linearly with the production rate. Different from the existing literature that posits a parametric stochastic degradation process, we suppose that the degradation increment during a period lies in an uncertainty set, and our objective is to minimize the maintenance cost in the worst case. The resulting model is a robust mixed‐integer linear program. We derive its robust counterpart and establish structural properties of the optimal production plan. These properties are then used for real‐time condition‐based control of the production rate through reoptimization. The model is further generalized to the nonlinear production–degradation relation. Based on a real production–degradation dataset from an extruder system, we conduct comprehensive numerical experiments to illustrate the application of the model. Numerical results show that our model significantly outperforms existing methods in terms of the mean and variance of cost rate when degradation model misspecification is presented.
Twenty‐five years of recombinant human growth factors rhPDGF‐BB and rhBMP‐2 in oral hard and soft tissue regeneration
Authors: Galarraga‐Vinueza Maria Elisa , Barootchi Shayan , Nevins Marc L. , Nevins Myron , Miron Richard J. , Tavelli Lorenzo
Published: September 2023

Contemporary oral tissue engineering strategies involve recombinant human growth factor approaches to stimulate diverse cellular processes including cell differentiation, migration, recruitment, and proliferation at grafted areas. Recombinant human growth factor applications in oral hard and soft tissue regeneration have been progressively researched over the last 25 years. Growth factor‐mediated surgical approaches aim to accelerate healing, tissue reconstruction, and patient recovery. Thus, regenerative approaches involving growth factors such as recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB) and recombinant human bone morphogenetic proteins (rhBMPs) have shown certain advantages over invasive traditional surgical approaches in severe hard and soft tissue defects. Several clinical studies assessed the outcomes of rhBMP‐2 in diverse clinical applications for implant site development and bone augmentation. Current evidence regarding the clinical benefits of rhBMP‐2 compared to conventional therapies is inconclusive. Nevertheless, it seems that rhBMP‐2 can promote faster wound healing processes and enhance de novo bone formation, which may be particularly favorable in patients with compromised bone healing capacity or limited donor sites. rhPDGF‐BB has been extensively applied for periodontal regenerative procedures and for the treatment of gingival recessions, showing consistent and positive outcomes. Nevertheless, current evidence regarding its benefits at implant and edentulous sites is limited. The present review explores and depicts the current applications, outcomes, and evidence‐based clinical recommendations of rhPDGF‐BB and rhBMPs for oral tissue regeneration.
Not all seed transfer zones are created equal: using fire history to identify seed needs in the Cold Deserts of the western United States
Authors: Barga Sarah C. , Kilkenny Francis F. , Jensen Scott , Kulpa Sarah M. , Agneray Alison C. , Leger Elizabeth A.
Published: September 2023

Restoration planning requires a reliable seed supply, yet many projects occur in response to unplanned events. Identifying regions of greater disturbance risk could efficiently guide seed procurement. Using fire in U.S. Cold Deserts as an example, we demonstrate how historic disturbance can inform seed production choices. We compared differences in fire frequency, area burned, and percent of area burned among different management areas, identifying regions of particular need. We also present a case study focused on fire occurrence within important wildlife habitat, specifically looking at the greater sage‐grouse priority areas for conservation (PACs) within the Northern Basin and Range ecoregion. We used geospatial seed transfer zones as our focal management areas. We broadly considered generalized provisional seed transfer zones, created using climate and stratified by ecoregion, but also present results for empirical seed transfer zones, based on species‐specific research, as part of our case study. Historic fire occurrence was effective for prioritizing seed transfer zones: 23 of 132 provisional seed transfer zones burned every year, and, within each ecoregion, two provisional seed transfer zones comprised ≧50% of the total area burned across all years. Fire occurrence within PACs largely reflected the seed transfer zone priorities found for the ecoregion as a whole. Our results demonstrate that historic disturbance can be used to identify regions that encounter regular or large disturbance. This information can then be used to guide seed production, purchase, and storage, create more certainty for growers and managers, and ultimately increase restoration success.
Long‐term effects of extreme smoke exposure on COVID‐19: A cohort study
Authors: Lane Tyler J. , Carroll Matthew , Borg Brigitte M. , McCaffrey Tracy A. , Smith Catherine L. , Gao Caroline X. , Brown David , Poland David , Allgood Shantelle , Ikin Jillian , Abramson Michael J.
Published: September 2023

Background

In 2014, the Hazelwood coalmine fire shrouded the regional Australian town of Morwell in smoke and ash for 6 weeks. One of the fire's by‐products, PM2.5, is associated with an increased risk of COVID‐19 and severe disease. However, it is unclear whether the effect persisted for years after exposure. In this study, we surveyed a cohort established prior to the pandemic to determine whether PM2.5 from the coalmine fire increased long‐term vulnerability to COVID‐19 and severe disease.

Methods

From August to December 2022, 612 members of the Hazelwood Health Study's adult cohort, established in 2016/17, participated in a follow‐up survey that included standardized items to capture COVID‐19 cases, as well as questions about hospitalization and vaccinations. Associations were evaluated in crude and adjusted logistic regression models.

Results

A total of 268 (44%) participants self‐reported or met symptom criteria for having had COVID‐19 at least once. All models found a positive association, with odds of COVID‐19 increasing by between 4% and 30% for a 10 μg/m3 increase in coalmine fire‐related PM2.5 exposure. However, the association was significant in only 2 of the 18 models. There were insufficient hospitalizations to examine severity (n = 7; 1%).

Conclusion

The findings are inconclusive on the effect of coalmine fire‐related PM2.5 exposure on long‐term vulnerability to COVID‐19. Given the positive association that was robust to modelling variations as well as evidence for a causal mechanism, it would be prudent to treat PM2.5 from fire events as a long‐term risk factor until more evidence accumulates.
Anti‐caries Streptococcus spp.: A potential preventive tool for special needs patients
Authors: Mato Eliane García , Montaño‐Barrientos Bitalio J. , Rivas‐Mundiña Berta , Aneiros Iván Varela , López Lucía Sande , Posse Jacobo Limeres , Lamas Lucía Martínez
Published: September 2023

Introduction

Probiotics are living microorganisms that act on the host‐microbiome interface to restore the microbiota's physiological homeostasis. Numerous probiotics have been marketed with inhibitory activity against Streptococcus mutans and consequently with a potential anti‐caries effect, mainly of the genera Lactobacillus and Bifidobacterium, whose main disadvantage is their limited ability to settle in the oral cavity.

Methods

This narrative review describes the main Streptococcus spp. with probiotic anti‐Streptococcus mutans activity, whose substantivity is greater than that of Lactobacillus spp. and consequently with anti‐caries potentiality. We performed a literature review in the PubMed, Science Direct and Google Scholar databases of articles published in English (without time restriction) related to caries and probiotics.

Results

The potential identified anti‐caries probiotics included Streptococcus spp. A12, Streptococcus oralis (AJ3), Streptococcus oligofermentans, Streptococcus salivarius (K12, M18, JH, LAB813, 24SMB), Streptococcus spp. with arginolytic activity (S. sanguinis, S. gordonii, S. ratti, S. parasanguinis, S. intermedius, S. australis, and S. cristatus), Streptococcus rattus (JH145), Streptococcus dentisani and Streptococcus downii.

Conclusions

The possibility of using these Streptococcus spp. as probiotics that inhibit the growth of dental plaque and the development of carious lesions represents a potential tool of particular interest for individuals with physical or intellectual disabilities that impede the routine and effective application of mechanical dental plaque removal techniques.
Vitamin B
6
is governed by the local compartmentalization of metabolic enzymes during growth
Authors: Franco Carolina N. , Seabrook Laurence J. , Nguyen Steven T. , Yang Ying , Campos Melissa , Fan Qi , Cicchetto Andrew C. , Kong Mei , Christofk Heather R. , Albrecht Lauren V.
Published: September 2023

Vitamin B
6
is a vital micronutrient across cell types and tissues, and dysregulated B
6
levels contribute to human disease. Despite its importance, how B
6
vitamer levels are regulated is not well understood. Here, we provide evidence that B
6
dynamics are rapidly tuned by precise compartmentation of pyridoxal kinase (PDXK), the rate-limiting B
6
enzyme. We show that canonical Wnt rapidly led to the accumulation of inactive B
6
by shunting cytosolic PDXK into lysosomes. PDXK was modified with methyl-arginine Degron (MrDegron), a protein tag for lysosomes, which enabled delivery via microautophagy. Hyperactive lysosomes resulted in the continuous degradation of PDXK and B
6
deficiency that promoted proliferation in Wnt-driven colorectal cancer (CRC) cells. Pharmacological or genetic disruption of the coordinated MrDegron proteolytic pathway was sufficient to reduce CRC survival in cells and organoid models. In sum, this work contributes to the repertoire of micronutrient-regulated processes that enable cancer cell growth and provides insight into the functional impact of B
6
deficiencies for survival.
Mycobacterium tuberculosis
carrying the rifampicin drug-resistance-conferring
rpoB
mutation H445Y is associated with suppressed immunity through type I interferons
Authors: Bobba Suhas , Howard Nicole C. , Das Shibali , Ahmed Mushtaq , Tang Linrui , Thirunavukkarasu Shyamala , Larsen Michelle H. , Mathema Barun , Divangahi Maziar , Khader Shabaana A.
Published: September 2023

Tuberculosis (TB) is one of the leading causes of death due to an infectious disease. The rise of multi-drug resistance (MDR) in
Mycobacterium tuberculosis
(
Mtb
), the causative agent of TB, presents a significant obstacle to TB control. While human studies report dysregulated immune responses during MDR TB, a clear understanding of the host-pathogen interactions of MDR
Mtb
is lacking. Here, we studied the immune responses induced by
Mtb
strains carrying two of the most common rifampicin drug-resistance (RDR)-conferring single-nucleotide polymorphisms (SNPs) in the RNA polymerase gene of
Mtb
, which accounts for nearly 90% of drug-resistance mutations found clinically in
Mtb
. During
Mtb
infection of primary human macrophages, we found that pro-inflammatory cytokine production was reduced upon infection with
Mtb
carrying the H445Y SNP but not the S450L SNP. Using a mouse model, we also characterized the host immune response
in vivo
following infection. Despite similar establishment of
Mtb
infection in the lung and dissemination to the peripheral organs, we show that infection with the RDR
Mtb rpoB
-H445Y strain, but not with the
rpoB
-S450L strain, resulted in a suppressed lung myeloid and lymphoid immune responses through type I IFN-dependent pathways, relative to
wt Mtb
. This suppressed host immunity had functional consequences in limiting control of RDR
Mtb
strains harboring
rpoB
-H445Y and led to worse pathology during chronic TB disease. Collectively, our results suggest that disease pathogenesis may be associated with specific RDR mutations in
Mtb
, which may differentially regulate immune responses.

IMPORTANCE

This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to
Mycobacterium tuberculosis
(
Mtb
), the causative agent of tuberculosis (TB). Clinical reports have previously suggested that multi-drug-resistant) TB patients exhibit altered peripheral immune responses as compared with their drug-sensitive TB counterparts. The murine model of infection with
Mtb
strains carrying drug-resistance-conferring mutations recapitulated these findings and allowed us to mechanistically interrogate the pathways responsible for driving the divergent immune responses. Our findings underscore the need for greater investigation into bacterial heterogeneity to better appreciate the diversity in host-pathogen interactions during TB disease.
Circulation of enterotoxigenic
Escherichia coli
(ETEC) isolates expressing CS23 from the environment to clinical settings
Authors: Calderon Toledo Carla , von Mentzer Astrid , Agramont Jorge , Thorell Kaisa , Zhou Yingshun , Szabó Miklós , Colque Patricia , Kuhn Inger , Gutiérrez-Cortez Sergio , Joffré Enrique
Published: September 2023

Enterotoxigenic
Escherichia coli
(ETEC) is one of the leading causes of infant diarrhea in low- and middle-income countries (LMICs). Diarrheal pathogens are transmitted through environmental reservoirs; however, the bacterial clones that spread across the human-environment interface remain unexplored. We aimed to determine the relationship and clonal dissemination of ETEC between children with diarrhea and polluted water samples from a local river in La Paz, Bolivia. By using WGS and the PhenePlates phenotypic system to analyze ETEC strains, we showed that ST218 and ST410 LT+STh ETEC expressing the colonization factor (CF) CS23 were found with high frequency in both samples. The CS23 ETEC isolates were found within several STs,
E. coli
phylogroups, and across ETEC lineages. Comparative genomic evaluation and PhenePlate screening of globally distributed clinical ETEC strains suggest that the CS23 gene is likely carried on plasmids acquired independently of the bacterial chromosomal background. Clinical strains were more often multidrug-resistant (MDR) than environmental isolates and harbored the class 1 integron-integrase gene
intI1
next to the MDR cassettes. Retrospective analysis of antibiotic resistance in ETEC revealed a high frequency of MDR in clinical isolates. The LT+STh CS23 environmental ETEC isolates, showed an increased biofilm ability at environmental temperature, equal cytotoxicity, and significantly lower adherence to human epithelial cells compared to ETEC expressing other CFs. Together, we suggest that CS23 is more prevalent in ETEC than previously estimated, and the Choqueyapu River is a reservoir for LT+STh CS23 ETEC containing strains capable of causing diarrheal cases in children.

IMPORTANCE

The importance of clean water cannot be overstated. It is a vital resource for maintaining health and well-being. Unfortunately, water sources contaminated with fecal discharges from animal and human origin due to a lack of wastewater management pose a significant risk to communities, as they can become a means of transmission of pathogenic bacteria like enterotoxigenic
E. coli
(ETEC). ETEC is frequently found in polluted water in countries with a high prevalence of diarrheal diseases, such as Bolivia. This study provides novel insights into the circulation of ETEC between diarrheal cases and polluted water sources in areas with high rates of diarrheal disease. These findings highlight the Choqueyapu River as a potential reservoir for emerging pathogens carrying antibiotic-resistance genes, making it a crucial area for monitoring and intervention. Furthermore, the results demonstrate the feasibility of a low-cost, high-throughput method for tracking bacterial pathogens in low- and middle-income countries, making it a valuable tool for One Health monitoring efforts.
Functional characterization of genes encoding cadmium pumping P
1B
-type ATPases in
Aspergillus fumigatus
and
Aspergillus nidulans
Authors: Vig Ildikó , Benkő Zsigmond , Gila Barnabás Cs. , Palczert Zoltán , Jakab Ágnes , Nagy Fruzsina , Miskei Márton , Lee Mi-Kyung , Yu Jae-Hyuk , Pócsi István , Emri Tamás
Published: September 2023

Several P
1B
-type ATPases are important Cd
2+
/Cu
2+
pumps in
Aspergillus
species, and they are tightly associated with the heavy metal stress tolerance of these ascomycetous fungi. To better understand the roles of the two P
1B
-type ATPases,
Aspergillus nidulans
CrpA Cd
2+
/Cu
2+
pump (orthologue of the
Candida albicans Crp1
Cd
2+
/Cu
2+
pump) and
Aspergillus fumigatus
PcaA Cd
2+
pump (orthologue of the
Saccharomyces cerevisiae
Pca1 Cd
2+
pump), we have generated individual mutants and characterized their heavy metal susceptibilities. The deletion of CrpA in
A. nidulans
has led to the increased sensitivity of the fungus to stresses induced by Zn
2+
, Fe
2+
, or the combination of oxidative-stress-inducing menadione sodium bisulfite and Fe
3+
. Heterologous expression of
A. fumigatus
PcaA in the
S. cerevisiae pca1
deletion mutant has resulted in enhanced tolerance of the yeast to stresses elicited by Cd
2+
or Zn
2+
but not by Fe
2+
/Fe
3+
or Cu
2+
. Mammalian host immune defense can attack microbes by secreting Zn
2+
or Cu
2+
, and the oxidative stress induced by host immune systems can also disturb metal (Cu
2+
, Fe
2+
, and Zn
2+
) homeostasis in microbes. In summary, PcaA and CrpA can protect fungal cells from these complex stresses that contribute to the virulence of the pathogenic
Aspergillus
species. Moreover, due to their presence on the fungal cell surface, these P
1B
-type ATPases may serve as a novel drug target in the future.

IMPORTANCE

Mammalian host immune defense disrupts heavy metal homeostasis of fungal pathogens. P1B-type ATPase of
Aspergillus fumigatus
and
Aspergillus nidulans
may help to cope with this stress and serve as virulence traits. In our experiments, both
A. nidulans
Cd2+/Cu2+ pump CrpA and
A. fumigatus
Cd2+ pump PcaA protected fungal cells from toxic Zn2+, and CrpA also decreased Fe2+ susceptibility most likely indirectly. In addition, CrpA protected cells against the combined stress induced by the oxidative stressor menadione and Fe3+. Since P1B-type ATPases are present on the fungal cell surface, these proteins may serve as a novel drug target in the future.
DegQ is an important policing link between quorum sensing and regulated adaptative traits in
Bacillus subtilis
Authors: Danevčič Tjaša , Spacapan Mihael , Dragoš Anna , Kovács Ákos T. , Mandic-Mulec Ines
Published: September 2023

Quorum sensing (QS) is a widespread bacterial communication system that controls important adaptive traits in a cell density-dependent manner. However, mechanisms by which QS-regulated traits are linked within the cell and mechanisms by which these links affect adaptation are not well understood. In this study,
Bacillus subtilis
was used as a model bacterium to investigate the link between the ComQXPA QS system, DegQ, surfactin and protease production in planktonic and biofilm cultures. The work tests two alternative hypotheses predicting that hypersensitivity of the QS signal-deficient mutant (
comQ::kan
) to exogenously added ComX, resulting in increased surfactin production, is linked to an additional genetic locus, or alternatively, to overexpression of the ComX receptor ComP. Results are in agreement with the first hypothesis and show that the P

srfAA

hypersensitivity of the
comQ::kan
mutant is linked to a 168 strain-specific mutation in the P

degQ

region. Hence, the markerless Δ
comQ
mutant lacking this mutation is not overresponsive to ComX. Such hyper-responsiveness is specific for the P

srfAA

and not detected in another ComX-regulated promoter, the P

aprE

, which is under the positive control by DegQ. Our results suggest that DegQ by exerting differential effect on P

srfAA

and P

aprE

acts as a policing mechanism and the intracellular link, which guards the cell from an overinvestment into surfactin production.

IMPORTANCE

DegQ levels are known to regulate surfactin synthesis and extracellular protease production, and DegQ is under the control of the ComX-dependent QS. DegQ also serves as an important policing link between these QS-regulated processes, preventing overinvestment in these costly processes. This work highlights the importance of DegQ, which acts as the intracellular link between ComX production and the response by regulating extracellular degradative enzyme synthesis and surfactin production.