bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships among symptoms of gastroparesis to those of avoidant/restrictive food intake disorder in patients with gastroparesis
Authors: Hollis Erin , Murray Helen Burton , Parkman Henry P.
Published: December 2023

Background

Patients with symptoms of gastroparesis (Gp) often reduce food intake in attempt to manage their symptoms. Up to 40% of adults with Gp have been reported to have symptoms of a non‐body image‐based eating disorder, avoidant/restrictive food intake disorder (ARFID). However, whether ARFID symptoms precede or follow the diagnosis of Gp is unknown.

Methods

From January 2021 to January 2022, consecutive adult patients with Gp at an academic center completed self‐report surveys for Gp symptom severity (patient assessment of upper gastrointestinal symptoms; PAGI‐SYM) and for ARFID (nine‐item ARFID screen; NIAS).

Key Results

One hundred and seven patients (age 45.4 ± 17.2 yrs, 84.1% female, BMI 26.4 ± 7.3) with Gp (4‐h gastric retention 33.5 ± 21.8%) were included. Eighty‐two of the 107 Gp patients (77%) screened positive for ARFID. Positive ARFID screen was most often on the NIAS appetite subscale (84%) and fear subscale (76%), with a lower positive screen rate on the picky subscale (45%). Of the Gp who screened positive for ARFID, 38% reported that eating difficulties came after their Gp diagnosis, whereas 17% reported that eating difficulties preceded their Gp diagnosis, and 15% reported that both began at the same time.

Conclusions

Many (77%) patients with Gp screened positive for ARFID. In Gp patients with ARFID, the Gp diagnosis was more likely to precede the development of eating difficulties. Thus, a subset of patients with Gp may be at risk for developing ARFID. Further longitudinal research is needed to confirm findings and identify risk factors.
Ectomycorrhizal fungi enhance pine growth by stimulating iron‐dependent mechanisms with trade‐offs in symbiotic performance
Authors: Zhang Kaile , Wang Haihua , Tappero Ryan , Bhatnagar Jennifer M. , Vilgalys Rytas , Barry Kerrie , Keymanesh Keykhosrow , Tejomurthula Sravanthi , Grigoriev Igor V. , Kew William R. , Eder Elizabeth K. , Nicora Carrie D. , Liao Hui‐Ling
Published: December 2023

Iron (Fe) is crucial for metabolic functions of living organisms. Plants access occluded Fe through interactions with rhizosphere microorganisms and symbionts. Yet, the interplay between Fe addition and plant–mycorrhizal interactions, especially the molecular mechanisms underlying mycorrhiza‐assisted Fe processing in plants, remains largely unexplored.

We conducted mesocosms in Pinus plants inoculated with different ectomycorrhizal fungi (EMF) Suillus species under conditions with and without Fe coatings. Meta‐transcriptomic, biogeochemical, and X‐ray fluorescence imaging analyses were applied to investigate early‐stage mycorrhizal roots.

While Fe addition promoted Pinus growth, it concurrently reduced mycorrhiza formation rate, symbiosis‐related metabolites in plant roots, and aboveground plant carbon and macronutrient content. This suggested potential trade‐offs between Fe‐enhanced plant growth and symbiotic performance. However, the extent of this trade‐off may depend on interactions between host plants and EMF species. Interestingly, dual EMF species were more effective at facilitating plant Fe uptake by inducing diverse Fe‐related functions than single‐EMF species. This subsequently triggered various Fe‐dependent physiological and biochemical processes in Pinus roots, significantly contributing to Pinus growth. However, this resulted in a greater carbon allocation to roots, relatively reducing the aboveground plant carbon content.

Our study offers critical insights into how EMF communities rebalance benefits of Fe‐induced effects on symbiotic partners.
The role ovariectomies and/or the administration of artificial female sex hormones play in orthodontic tooth movement: A systematic review
Authors: Berry Stefani , Emile Rossouw Paul , Barmak Abdul Basir , Malik Shaima
Published: December 2023

The objective was to assess how ovariectomy or the administration of artificial female sex hormones affects orthodontic tooth movement (OTM) with fixed appliances. An electronic search of indexed databases was completed without language or time restrictions up to June 2022. The following eligibility criteria were utilized: (i) prospective original controlled clinical studies; (ii) experimental studies on animal models; (iii) subjects undergoing orthodontic therapy with fixed appliances; (iv) clearly defined control groups not undergoing ovariectomy or administration of artificial female sex hormone; and (v) studies with experimental groups receiving the intervention of interest (ovariectomy or artificial female sex hormone administration). Review articles, letters to the editor, case reports, case series, commentaries, cross‐sectional studies, retrospective studies, and studies with no well‐defined control group were excluded. The quality of the available evidence and the risk of bias within the studies were assessed. All disagreements were resolved via discussion. Seven animal studies were included in the systematic review. Five studies reported that ovariectomy increased the rate of orthodontic tooth movement. Two studies reported that the administration of artificial female sex hormones decreased the rate of orthodontic tooth movement. There is an association between ovariectomies and OTM and between the administration of artificial female sex hormones and OTM. The full extent of the association remains unclear due to the biases that are present and the length of time of orthodontic therapy.
Altering maternal calcium and phosphorus dietary intake induces persistent sex‐specific changes in the dentition of the offspring
Authors: Hassan Mohamed G. , Hassan Reham , Hassan Dina G. , Abdelrahman Hams H. , Cox Timothy C. , Jheon Andrew H.
Published: December 2023

Background

The maternal diet is essential to offspring development, but the specific effects on tooth morphology are still unknown. The aim of this study was to evaluate the effects of altering maternal calcium (Ca) and phosphorus (P) supplementation during gestation and lactation on offspring dentition.

Methods

Pregnant mice were fed an experimental diet containing a threefold increase in Ca and a threefold decrease in P compared to the standard mouse chow diet at embryonic Day 0.5 (E0.5). Offspring mice were maintained on standard or experimental diets from post‐natal Day 0 to weaning, then fed control diets until 6 weeks of age. Six‐week‐old offspring heads were collected and scanned using micro‐computed tomography. Dental morphometrics of offspring maxillary and mandibular first and third molars (n = 5–6 per diet/per sex) were determined. A two‐way ANOVA test was employed to verify the existence of any significant differences between groups. The significance level was set at P < .05.

Results

A two‐way ANOVA revealed a statistically significant interaction between the effects of diet and sex on the upper and lower dentition. Moreover, experimental diet‐fed female offspring exhibited smaller molars with shorter mesiodistal width and larger pulp chambers relative to controls, while experimental diet‐fed male offspring possessed larger molars with wider mesiodistal width and smaller pulp chambers.

Conclusion

Our findings reveal that altering the maternal and offspring dietary Ca:P ratio during gestation, lactation and weaning led to significant, sex‐specific changes in the offspring dentition. The differences in dentition appeared to be correlated with the sex‐specific changes in the craniofacial skeleton.
Single‐cell RNA sequencing reveals diverse B cell phenotypes in patients with anti‐NMDAR encephalitis
Authors: Li Sisi , Hu Xiang , Wang Minjin , Yu Luoting , Zhang Qi , Xiao Jing , Hong Zhen , Zhou Dong , Li Jinmei
Published: December 2023

Backgrounds

Anti‐N‐methyl‐D‐aspartate receptor encephalitis (NMDAR‐E) is a severe autoimmune disorder characterized by prominent psychiatric symptoms. Although the role of NMDAR antibodies in the disease has been extensively studied, the phenotype of B cell subsets is still not fully understood.

Methods

We utilized single‐cell RNA sequencing, single‐cell B cell receptor sequencing (scBCR‐seq), bulk BCR sequencing, flow cytometry, and enzyme‐linked immunosorbent assay to analyze samples from both NMDAR‐E patients and control individuals.

Results

The cerebrospinal fluid (CSF) of NMDAR‐E patients showed significantly increased B cell counts, predominantly memory B (Bm) cells. CSF Bm cells in NMDAR‐E patients exhibited upregulated expression of differential expression genes (DEGs) associated with immune regulatory function (TNFRSF13B and ITGB1), whereas peripheral B cells upregulated DEGs related to antigen presentation. Additionally, NMDAR‐E patients displayed higher levels of IgD−CD27− double negative (DN) cells and DN3 cells in peripheral blood (PB). In vitro, DN1 cell subsets from NMDAR‐E patients differentiated into DN2 and DN3 cells, while CD27+ and/or IgD+B cells (non‐DN) differentiated into antibody‐secreting cells (ASCs) and DN cells. NR1‐IgG antibodies were found in B cell culture supernatants from patients. Differential expression of B cell IGHV genes in CSF and PB of NMDAR‐E patients suggests potential antigen class switching.

Conclusion

B cell subpopulations in the CSF and PB of NMDAR‐E patients exhibit distinct compositions and transcriptomic features. In vitro, non‐DN cells from NMDAR‐E can differentiate into DN cells and ASCs, potentially producing NR1‐IgG antibodies. Further research is necessary to investigate the potential contribution of DN cell subpopulations to NR1‐IgG antibody production.
Exploring testicular miRNA profiles during developmental stages in Dezhou donkeys: A preliminary insight
Authors: Ahmed Zulfiqar , Liu Wei , Yu Jie , Dong Hong , Naseer Zahid , Ahmad Imtiaz , Ahmed Imran , Wang Xijun
Published: December 2023

Testicular development and spermatogenesis are complex phenomena controlled by various genetic factors, including miRNA‐based post‐transcriptional gene expression regulation. Exploring the miRNA expression patterns during testicular development in Dezhou donkeys would enhance our understanding of equine fertility and spermatogenesis. In this investigation, we examined the testicular miRNA profiles at various stages of development. The experimental animals were divided into three groups based on their developmental stages: 2 months old (juvenile: n = 3), 12 months old (adolescent; n = 3) and 24 months old (adult; n = 3) donkeys. Total RNA was extracted from dissected testicles for miRNA sequencing and analysis. In total, 586 miRNAs, including 451 known miRNAs and 135 novel miRNAs, were identified. Among identified miRNAs, 315 displayed age‐dependent expression differences. The levels of miRNA expression in the juvenile group were significantly higher than in the adolescent or adult groups. The MiR‐483 exhibited the maximum fold change between juvenile and adolescent groups. Several screened genes, including SLC45A4 and TFCP2L1, have been linked to male reproductive pathways in donkeys. In addition, miR‐744 was predicted to regulate SPIN2B, a gene implicated in spermatocyte cell cycle progression and genomic integrity of spermatozoa. These results contribute to our comprehension of microRNA regulation during testicular development and spermatogenesis in Dezhou donkeys. The identified microRNAs and their target genes have the potential to serve as biomarkers for evaluating the reproductive capacity of stud donkeys.
Insecurity on the Labor Market
Authors: Clark Andrew E.
Published: December 2023

There is a common feeling that life has become more insecure over time. I here consider this proposition with respect to the labor market. I first discuss how labor‐market insecurity might be measured, and then its potential consequences for individuals. To answer the question of “What Happened,” I then review a number of pieces of evidence regarding developments in the labor market, and perhaps surprisingly find no consistent support for the proposition that the labor market has become significantly more insecure.
Cinema of Rupture: Urbicide, Eastern European Rubble Films, and the Documentary Impulse
Authors: Mandušić Zdenko
Published: December 2023

Currently in Ukraine, and previously in conflicts such as the Bosnian War (1992–96), local film collectives have expanded the mediation of wars to include the perspectives of those close to their subjects, foregrounding the participation of filmmakers in the wartime urban setting. In the 1990s, during the four‐year‐long siege of Bosnia’s capital, the collective Sarajevo Group of Artists (SAGA) produced sixty films of varying lengths, many of which included footage of destroyed buildings. Since 2014, several Ukrainian video projects and collectives, including Babylon’13, Freefilmers, War Against War, and Thickets (Khashchi), have made films documenting various aspects of the Russian invasion of Ukraine. Although there is no evidence of direct influence, structural and contextual similarities make SAGA an important earlier model for Ukrainian collectives of local filmmakers determined to define the consequences and experiences of war from the perspective of those with personal stakes in the conflict. This essay comparatively examines the creative wartime documentaries of Bosnian and Ukrainian film collectives specifically to consider how filmmakers with close personal connections to conflicts produce documentary representations of wartime destruction
Effectiveness of an educational intervention to increase professional nurses' person‐centred care competence in long‐term care of older people—Quasi‐experimental study
Authors: Pakkonen Mari , Stolt Minna , Edvardsson David , Charalambous Andreas , Pasanen Miko , Suhonen Riitta
Published: December 2023

Background

Based on previous evidence person‐centred care (PCC) as a quality indicator is important in long‐term care (LTC) settings for older people. Effective ways to increase nurses' person‐centred care competence are missing.

Aim

To evaluate the effectiveness of a continuing education (CE) intervention named ‘Person First—Please’ (PFP) for improving nurses' PPC competence and its connection to PPC climate.

Methods

Quasi‐experimental cluster design with intervention and control groups was carried out in LTC settings for older people. The intervention group (n = 77) received a 10‐week CE intervention, with control group (n = 123) working as usual. The primary outcome was professional nurses' PCC competence. Secondary outcome was the PCC climate as perceived by nurses and, residents with their next of kin. Measurements were conducted pre−/post‐intervention and after 6 weeks using the validated, Person‐centred Care Competence scale and the Person‐centred Care Climate questionnaire, staff and patient versions. Data was analysed with descriptive and inferential statistics.

Results

PCC competence was significantly increased in the intervention group and remained after 6 weeks of follow‐up. PCC climate increased in the intervention group in total score and also in all sub‐scales, across residents with their next of kin. The control group did not show any significant change. Comparisons of PCC competence and PCC climate in time between intervention and control groups confirmed that changes seen between groups were statistically significant in intervention group.

Limitations

Measurements were self‐assessments, which may have been affected by bias, especially in context of competence assessment.

Conclusion

The intervention was effective in increasing professional nurses' PCC competence and on person‐centred care climate in long‐term care settings for older people.
Gut bacteria at 6 months of age are associated with immune cell status in 1‐year‐old children
Authors: Nilsen Morten , Nygaard Unni Cecilie , Brodin Petter , Carlsen Karin Cecilie Lødrup , Fredheim Cecilie , Haugen Guttorm , Hedlin Gunilla , Jonassen Christine Monceyron , Jonsmoen Unni Lise Albertsdottir , Lakshmikanth Tadepally , Nordlund Björn , Olin Axel , Rehbinder Eva Maria , Skjerven Håvard O. , Snipen Lars , Staff Anne Cathrine , Söderhäll Cilla , Vettukattil Riyas , Rudi Knut
Published: December 2023

Age‐related gut bacterial changes during infancy have been widely studied, but it remains still unknown how these changes are associated with immune cell composition. This study's aim was to explore if the temporal development of gut bacteria during infancy prospectively affects immune cell composition. Faecal bacteria and short‐chain fatty acids were analysed from 67 PreventADALL study participants at four timepoints (birth to 12 months) using reduced metagenome sequencing and gas chromatography. Immune cell frequencies were assessed using mass cytometry in whole blood samples at 12 months. The infants clustered into four groups based on immune cell composition: clusters 1 and 2 showed a high relative abundance of naïve cells, cluster 3 exhibited increased abundance of classical‐ and non‐classical monocytes and clusters 3 and 4 had elevated neutrophil levels. At all age groups, we did observe significant associations between the gut microbiota and immune cell clusters; however, these were generally from low abundant species. Only at 6 months of age we observed significant associations between abundant (>8%) species and immune cell clusters. Bifidobacterium adolescentis and Porphyromonadaceae are associated with cluster 1, while Bacteroides fragilis and Bifidobacterium longum are associated with clusters 3 and 4 respectively. These species have been linked to T‐cell polarization and maturation. No significant correlations were found between short‐chain fatty acids and immune cell composition. Our findings suggest that abundant gut bacteria at 6 months may influence immune cell frequencies at 12 months, highlighting the potential role of gut microbiota in shaping later immune cell composition.
Sacred serpents and the discourse on conservation: Interrogating interspecies dynamics in rural Bardhaman
Authors: Saha Salini
Published: December 2023

Built on extensive ethnographic fieldwork in rural Bardhaman, West Bengal, India, the article argues for the centrality of animals’ non‐human agency as sacred beings involved in interactive experiences with humans, amidst changing climatic conditions. For the people of Musharu, the sacredness of their village deity is embedded in their practical ways of living and inhabiting with special varieties of cobras as exemplars of sacred nature. The article also draws attention to how the survival of these local cobras is adversely affected due to monsoonal vulnerability. The article addresses three critical concerns. It situates the human–snake interaction within wider discourse of post‐humanist debates, highlighting the elusive nature of the ‘wild’ and the animalist agency it enables. It captures alternative versions of conservation that the human–animal–divine nexus in Musharu creates. The third concerns the reproduction of rural community consciousness and indigeneity that this interaction brings about. It concludes with the understanding that Musharu's human–animal inhabitation reveals the contextual nature of ‘wilderness’ reframes the Indigenous status emerging out of human–non‐human associations and rethinks the role of local cultures in global wildlife conservation discourses.
Participant Self‐Reference, Under‐Determination, Generalisation, Vagueness, and Ambiguity in Political Discourse: A Contrastive Analysis of Parliamentary Debate and Twitter Usages*
Authors: Nogué‐Serrano Neus
Published: December 2023

The main aim of this chapter is to analyse under‐determination, generalisation, vagueness, and ambiguity in the speaker's self‐reference strategies used in Catalan parliamentary debate and Twitter. Parliaments are one of the main arenas where politicians develop their activity. On the other hand, Twitter allows politicians to build their own public image and to be in touch with voters, and citizens in general, in a more direct way. The theoretical background of the analysis includes the classical studies on deixis and on person deixis in Catalan; Goffman (1981)'s participation frameworks; functional linguistics and the ethnography of communication, and Twitter communication analysis.

In this corpus‐driven analysis, parliamentary discourses and tweets of two members of the Parliament of Catalonia are analysed. The corpus has been drawn from their speeches in the 2020 general politics debate and from the Twitter messages they published in the same period, in autumn 2020.
The differential sensitivity of the hypothalamic–hypophysial–ovarian axis to 5‐hydroxytryptophan alters the secretion of estradiol
Authors: Monroy Juana , Cortés Omar D. , Domínguez Roberto , Mendoza‐Garrido María Eugenia , Gallegos Eloir , Cárdenas Mario , Aragón Andrés , Ayala María E.
Published: December 2023

Serotonin [5‐hydroxytryptamine (5‐HT)] modulates ovarian function. The precursor of 5‐HT, 5‐hydroxytryptophan (5‐HTP), has been used to treat depression. However, the effects of 5‐HTP on ovarian and reproductive physiology remain unknown. In this research, we analysed the impact of 5‐HTP on the monoaminergic system and its interactions with the reproductive axis and ovarian estradiol secretion when administered by distinct routes. Female rats 30 days of age were injected with 5‐HTP i.p. (100 mg/kg), into the ovarian bursa (1.5 µg/40 µL) or into the median raphe nucleus (20 µg/2.5 µL) and were killed 60 or 120 min after injection. As controls, we used rats of the same age injected with vehicle (0.9% NaCl). Monoamine, gonadotrophin and steroid ovarian hormone concentrations were measured. The injection of 5‐HTP either i.p. or directly into the ovarian bursa increased the concentrations of 5‐HT and the metabolite 5‐hydroxyindole‐3‐acetic acid in the ovary. For both routes of administration, the serum concentration of estradiol increased. After i.p. injection of 5‐HTP, the concentrations of luteinizing hormone were decreased and follicle‐stimulating hormone increased after 120 min. Micro‐injection of 5‐HTP into the median raphe nucleus increased the concentrations of 5‐HT in the anterior hypothalamus and dopamine in the medial hypothalamus after 120 min. Our results suggest that the administration of 5‐HTP either i.p. or directly into the ovarian bursa enhances ovarian estradiol secretion.
Adsorption behavior of serum proteins on anodized titanium is driven by surface nanomorphology
Authors: Akdoğan Ebru , Tolga Şirin Hasret , Öztatlı Hayriye , Kılıçarslan Boğaç , Bayram Cem , Garipcan Bora
Published: December 2023

Protein adsorption behavior can play a critical role in defining the outcome of a material by affecting the subsequent in vivo response to it. To date, the effect of surface properties on protein adsorption behavior has been mainly focused on surface chemistry, but research on the effect of nanoscale surface topography remains limited. In this study, the adsorption behavior of human serum albumin, immunoglobulin G, and fibrinogen in terms of the adsorbed amount and conformational changes were investigated on bare and anodized titanium (Ti) samples (40 and 60 V applied voltages). While the surface chemistry, RMS surface roughness, and arithmetic surface roughness of the anodized samples were similar, they had distinctly different nanomorphologies identified by atomic force microscopy and scanning electron microscopy, and the surface statistical parameters, surface skewness Ssk and kurtosis Sku. The Feret pore size distribution was more uniform on the 60 V sample, and surface nanostructures were more symmetrical with higher peaks and deeper pores. On the other hand, the 40 V sample surface presented a nonuniform pore size distribution and asymmetrical surface nanostructures with lower peaks and shallower pores. The amount of surface-adsorbed protein increased on the sample surfaces in the order of Ti < 40 V < 60 V with the predominant factor affecting the amount of surface-adsorbed protein being the increased surface area attained by pore formation. The secondary structure of all adsorbed proteins deviated from that of their native counterparts. While comparing the secondary structure components of proteins on anodized surfaces, it was observed that all three proteins retained more of their secondary structure composition on the surface with more uniform and symmetrical nanofeatures than the surface having asymmetrical nanostructures. Our results suggest that the nanomorphology of the peaks and outer walls of the nanotubes can significantly influence the conformation of adsorbed serum proteins, even for surfaces having similar roughness values.
Bifidobacterium infantis
associates with T cell immunity in human infants and is sufficient to enhance antigen-specific T cells in mice
Authors: Nyangahu Donald D. , Happel Anna-Ursula , Wendoh Jerome , Kiravu Agano , Wang Yuli , Feng Colin , Plumlee Courtney , Cohen Sara , Brown Bryan P. , Djukovic Danijel , Ganief Tariq , Gasper Melanie , Raftery Daniel , Blackburn Jonathan M. , Allbritton Nancy L. , Gray Clive M. , Paik Jisun , Urdahl Kevin B. , Jaspan Heather B.
Published: December 2023

Bacille Calmette-Guerin (BCG) vaccine can elicit good T
H
1 responses in neonates. We hypothesized that the pioneer gut microbiota affects vaccine T cell responses. Infants who are HIV exposed but uninfected (iHEU) display an altered immunity to vaccination. BCG-specific immune responses were analyzed at 7 weeks of age in iHEU, and responses were categorized as high or low.
Bifidobacterium longum
subsp.
infantis
was enriched in the stools of high responders, while
Bacteroides thetaiotaomicron
was enriched in low responders at time of BCG vaccination. Neonatal germ-free or SPF mice orally gavaged with live
B. infantis
exhibited significantly higher BCG-specific T cells compared with pups gavaged with
B. thetaiotaomicron. B. infantis
and
B. thetaiotaomicron
differentially affected stool metabolome and colonic transcriptome. Human colonic epithelial cells stimulated with
B. infantis
induced a unique gene expression profile versus
B. thetaiotaomicron
. We thus identified a causal role of
B. infantis
in early-life antigen-specific immunity.
Evidence for the role of selection for reproductively advantageous alleles in human aging
Authors: Long Erping , Zhang Jianzhi
Published: December 2023

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here, we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 U.K. Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and life span. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), andPGSRincreased over birth cohorts from 1940 to 1969. Similar trends are seen from individual genetic variants examined. The antagonistically pleiotropic variants are often associated with cis-regulatory effects across multiple tissues or on multiple target genes. These and other findings support the antagonistic pleiotropy hypothesis of aging in humans and point to potential molecular mechanisms of the reproduction–life-span antagonistic pleiotropy.
Antigiardial and antiamebic activities of fexinidazole and its metabolites: new drug leads for giardiasis and amebiasis
Authors: Escrig Jose Ignacio , Miyamoto Yukiko , Aznar Alejandro Delgado , Eckmann Lars , Debnath Anjan
Published: December 2023

The intestinal parasites
Giardia lamblia
and
Entamoeba histolytica
are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%–40% of cases. Potential resistance of
E. histolytica
to metronidazole is an increasing concern. Therefore, it is critical to search for more effective drugs to treat giardiasis and amebiasis. We identified antigiardial and antiamebic activities of the rediscovered nitroimidazole compound, fexinidazole, and its sulfone and sulfoxide metabolites. Fexinidazole is equally active against
E. histolytica
and
G. lamblia
trophozoites, and both metabolites were 3- to 18-fold more active than the parent drug. Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of
G. lamblia
.
G. lamblia
and
E. histolytica
cell extracts exhibited decreased residual nitroreductase activity when metabolites were used as substrates, indicating nitroreductase may be central to the mechanism of action of fexinidazole. In a cell invasion model, fexinidazole and its metabolites significantly reduced the invasiveness of
E. histolytica
trophozoites through basement membrane matrix. A q.d. oral dose of fexinidazole and its metabolites at 10 mg/kg for 3 days reduced
G. lamblia
infection significantly in mice compared to control. The newly discovered antigiardial and antiamebic activities of fexinidazole, combined with its FDA-approval and inclusion in the WHO Model List of Essential Medicines for the treatment of human African trypanosomiasis, offer decreased risk and a shortened development timeline toward clinical use of fexinidazole for treatment of giardiasis or amebiasis.
The emergence of cefiderocol resistance in
Pseudomonas aeruginosa
from a heteroresistant isolate during prolonged therapy
Authors: Teran Nicholas , Egge Stephanie L. , Phe Kady , Baptista Rodrigo P. , Tam Vincent H. , Miller William R.
Published: December 2023

Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant
P. aeruginosa
that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.
Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study
Authors: Novy Emmanuel , Abdul-Aziz Mohd H. , Cheng Vesa , Burrows Fay , Buscher Hergen , Corley Amanda , Diehl Arne , Gilder Eileen , Levkovich Bianca J. , McGuinness Shay , Ordonez Jenny , Parke Rachael , Parker Suzanne , Pellegrino Vincent , Reynolds Claire , Rudham Sam , Wallis Steven C. , Welch Susan A. , Fraser John F. , Shekar Kiran , Roberts Jason A.
Published: December 2023

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC
0-24
/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.
Recombinant
Pseudomonas
growing on non-natural fluorinated substrates shows stress but overall tolerance to cytoplasmically released fluoride anion
Authors: Dodge Anthony G. , Thoma Calvin J. , O’Connor Madeline R. , Wackett Lawrence P.
Published: December 2023

Microbial response to toxic fluoride anion has traditionally been studied by adding inorganic fluoride salts to growth media. Fluoride is known to spontaneously transit the membrane as hydrogen fluoride (HF) and manifests significant toxicity in the cytoplasm. The present study investigated how microbes respond to high levels of HF generated directly in the cytoplasm to better understand potential limits of microbial defluorination of organofluorine compounds. For that purpose,
Pseudomonas putida
ATCC 12633 was engineered to express a defluorinase enzyme from
Delftia acidovorans
strain B that had high activity in producing growth-supporting alcohols from organofluorinated compounds of xenobiotic origin. Genome annotation predicted the growth of
P. putida
ATCC 12633 on all possible chiral products from 2-fluoropropionic acid and α-fluorophenylacetic acid when defluroinases are expressed. The defluorinase was shown to have complete enantioselectivity for (
S
)-fluoro substrates via experimental and computational modeling methods. The bacterium grew to a high turbidity with stoichiometric release of fluoride from the (
S
)-enantiomers into the medium. The highest yield of fluoride obtained was 50 mM with 2-fluoropropionic acid as the growth substrate. The growth yield was significantly lowered by 41% with α-fluorophenylacetic acid or 2-fluoropropionic acid compared to (
S
)-mandelic acid or D-lactic acid, respectively. Fluoride stress was also indicated by longer lag phases, slower growth, and cell morphology changes on fluorinated substrates or the cognate alcohols with NaF in the medium. In total, these studies show the potential for engineering bacterial defluorination of non-natural substrates within limits posed by fluoride stress.

IMPORTANCE

Society uses thousands of organofluorine compounds, sometimes denoted per- and polyfluoroalkyl substances (PFAS), in hundreds of products, but recent studies have shown some to manifest human and environmental health effects. As a class, they are recalcitrant to biodegradation, partly due to the paucity of fluorinated natural products to which microbes have been exposed. Another limit to PFAS biodegradation is the intracellular toxicity of fluoride anion generated from C-F bond cleavage. The present study identified a broader substrate specificity in an enzyme originally studied for its activity on the natural product fluoroacetate. A recombinant
Pseudomonas
expressing this enzyme was used here as a model system to better understand the limits and effects of a high level of intracellular fluoride generation. A fluoride stress response has evolved in bacteria and has been described in
Pseudomonas
spp. The present study is highly relevant to organofluorine compound degradation or engineered biosynthesis in which fluoride anion is a substrate.
Bile acid fitness determinants of a
Bacteroides fragilis
isolate from a human pouchitis patient
Authors: Fiebig Aretha , Schnizlein Matthew K. , Pena-Rivera Selymar , Trigodet Florian , Dubey Abhishek Anil , Hennessy Miette K. , Basu Anindita , Pott Sebastian , Dalal Sushila , Rubin David , Sogin Mitchell L. , Eren A. Murat , Chang Eugene B. , Crosson Sean
Published: December 2023

Bacteroides fragilis
comprises 1%–5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated a
B. fragilis
strain from a UC patient with pouch inflammation (i.e., pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impact
B. fragilis
fitness in DC and crude bile. Treatment of
B. fragilis
with a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems, and down-regulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further defined
B. fragilis
genes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of a
B. fragilis
bile response and genetic determinants of its fitness in DC and crude bile.

IMPORTANCE

The Gram-negative bacterium
Bacteroides fragilis
is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enable
B. fragilis
to grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for a
B. fragilis
strain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, where
B. fragilis
often blooms. Using this resource, we uncovered pathways and processes that impact
B. fragilis
fitness in bile and that may contribute to population expansions during bouts of gut inflammation.
Can antimicrobial blue light contribute to resistance development? Genome-wide analysis revealed aBL-protective genes in
Escherichia coli
Authors: Kruszewska-Naczk Beata , Grinholc Mariusz , Waleron Krzysztof , Bandow Julia Elisabeth , Rapacka-Zdończyk Aleksandra
Published: December 2023

Antimicrobial blue light (aBL) is a promising non-antibiotic approach to fighting multidrug-resistant bacteria. However, the complete mechanism of aBL action is not fully understood yet. This study contributes to a better understanding that the response to aBL depends on many factors and that it is hardly possible to identify a predominant mechanism underlying microbial sensitivity to photoinactivation. The results of this study provide insights into genetic changes that may lead to bacterial survival at higher aBL doses, giving rise to aBL-resistant strains. To our best knowledge, this is the first study concerning genome-wide mutant testing of aBL. We managed to identify 64 single-gene mutants that lacked certain protective genes expressing aBL-increased sensitivity.

IMPORTANCE

Increasing antibiotic resistance and the lack of new antibiotic-like compounds to combat bacterial resistance are significant problems of modern medicine. The development of new alternative therapeutic strategies is extremely important. Antimicrobial blue light (aBL) is an innovative approach to combat multidrug-resistant microorganisms. aBL has a multitarget mode of action; however, the full mechanism of aBL antibacterial action requires further investigation. In addition, the potential risk of resistance development to this treatment should be considered.
Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an
in vitro
hollow fiber infection model against multidrug-resistant
Escherichia coli
Authors: Kroemer Niklas , Amann Lisa F. , Farooq Aneeq , Pfaffendorf Christoph , Martens Miklas , Decousser Jean-Winoc , Grégoire Nicolas , Nordmann Patrice , Wicha Sebastian G.
Published: December 2023

Rational combination therapy offers a valuable option to increase efficacy and prevent emergence of resistance. Therefore, this study provides a translational pharmacokinetic/pharmacodynamic analysis of the synergy of /avibactam and fosfomycin in a clinical
Escherichia coli
strain expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Detailed static time-kill experiments primed dynamic hollow fiber studies mimicking mono- and combination therapies with doses of ceftazidime/avibactam ranging from 0.06/0.015 to 2/0.5 g every 8 h (q8h) and doses of fosfomycin ranging from 0.125 to 6 g q8h. The drug effects and interactions were quantitatively evaluated by pharmacokinetic/pharmacodynamic modeling using semi-mechanistic and subpopulation synergy. A pharmacokinetic/pharmacodynamic model describing the effects of ceftazidime, avibactam, and fosfomycin and their synergy was developed from the static time-kill experiments and hollow fiber studies. Simulations revealed that combined doses as low as 0.5-g q8h fosfomycin and 0.25-/0.06-g q8h ceftazidime/avibactam lead to suppression of the bacterial count. Conversely, in monotherapy, substantially higher doses by a factor of 12 for fosfomycin (6 g q8h) or by a factor of 6 for ceftazidime/avibactam (1.5/0.375 g q8h) were needed to achieve a comparable killing over 72 h. The combination of ceftazidime/avibactam and fosfomycin was therefore shown to be highly synergistic and suppressed the emergence of resistances. Clinical evaluations of potential dose reductions or the possibility to treat strains with high-level resistance with this combination are warranted.

IMPORTANCE

Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical
Escherichia coli
isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.
Supplemental Material: Fault activity in the San Gabriel Mountains, Southern California, USA: Insights from landscape morphometrics, erosion rates, and fault-slip rates
Authors: Mere Andre M. , McPhillips Devin
Published: December 2023

Supplemental Text S1: Critical area estimation. Supplemental Text S2: Topographic smoothing. Supplemental Text S3: Bare-rock exposure. Supplemental Text S4: Potential waterfall bias to θopt. Supplemental Text S5: Potential wildfire bias to detrital 10Be concentrations. Supplemental Text S6. Orographic precipitation effects on ksn. Supplemental Text S7. Bedrock hillslope and stream power residual analysis. Supplemental Text S8. Landscape adjustment timescales. Supplemental Text S9. Range-wide ksn.
Supplemental Material: Formation of a dome-and-basin fold interference pattern by granite intrusions
Authors: Rosenbaum Gideon , et al.
Published: December 2023

Table S1: LA-ICP-MS data for felsic intrusive rocks from the Montgomery Range igneous complex.
The Role of the Grass Snake Natrix natrix (Reptilia, Colubridae) in the Transfer of Polyunsaturated Fatty Acids from Aquatic to Terrestrial Ecosystems to Land
Authors: Dgebuadze Yu. Yu. , Neymark L. A. , Bashinskiy I. V. , Sushchik N. N. , Rudchenko A. E. , Gladyshev M. I.
Published: December 2023

As a result of analyses of fatty acid (FA) composition in the grass snake Natrix natrix and its food objects, tadpoles and metamorphs of two amphibian species: the moor frog Rana arvalis and the Pallas spadefoot toad Pelobates vespertinus, it was shown for the first time that the high total content of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in the biomass of the snakes indicates its important role in the transfer of these essential substances from aquatic ecosystems to land. It was found that, since food sources of DHA in terrestrial ecosystems are absent, its high level in R. arvalis metamorps and grass snakes may be provided only by synthesis from biochemical precursors contained in food of aquatic origin.
Auricular leishmaniasis mimicking squamous cell carcinoma of the pinna
Authors: Unar Ambreen Abdullah , Awan Muhammad Ozair , Akhtar Shabbir , Akram Saba
Published: December 2023

Cutaneous leishmaniasis can occur on any exposed area of the body; however, the pinna is an exceptionally rare site for the disease. Caused by the parasiteLeishmania, cutaneous leishmaniasis has a wide range of presentations and thus is very easy to misdiagnose or mistake for a neoplastic lesion. Here, we report the case of a middle-aged male patient presenting with a painful, ulcerated lesion on the left auricle initially suspected to be a malignancy with histopathology eventually revealing a diagnosis of auricular leishmaniasis. The patient received appropriate therapy and was found to be disease free at follow-up. These isolated lesions of the pinna often resemble neoplastic lesions and thus may escape diagnosis for months at a time, increasing patient stress as well as expenditure. In addition, prompt recognition may also help mitigate recurrence of the disease, making it worthwhile to include cutaneous leishmaniasis as part of the differential, especially in endemic areas.
Multimodal treatment of oligometastatic non-small cell lung cancer
Authors: Graça Luís Lourenço , Pego Alice , Lareiro Susana , Pancas Rita
Published: December 2023

The management of patients with oligometastatic non-small cell lung cancer has undergone significant improvement in recent years. The combination of increase in sensitivity of diagnostic tests, development in systemic therapies, surgical techniques and radiotherapy allowing radical ablative treatment of metastases have significantly influenced the treatment of advanced lung cancer, mainly in the patients in which these treatment modalities converge.

We report a rare case of a young patient with an oligometastatic lung adenocarcinoma with a single synchronous brain metastasis, who underwent aggressive locoregional and systemic therapies and is still in annual follow-up with excellent quality of life and progression-free survival of 164 months.