bluuebunny/crossref_metadata_2025 huggingface dataset:
FLAER Revealed Normally Expected Non‐PNH FLAER‐Dim Immature Myeloid Cells (CD117+/CD34‐) In Bone Marrow Aspirates and Could Be Utilized as a Marker of Hierarchical Hematopoiesis
Authors: Karela Christina , Tsagarakis Nikolaos J. , Oudatzis Georgios , Xanthopoulos Vasileios , Milaiou Maroula , Nikolaou Sofia , Zina Vassiliki , Vasileiou Paraskevi , Karianakis Georgios , Marinakis Theodoros , Griva Elpiniki , Paterakis Georgios
Published: October 2024

Introduction

Fluorescently labeled aerolysin (FLAER) is widely used for the identification of paroxysmal nocturnal hemoglobinuria (PNH) clones in peripheral blood (PB) samples. However, there are only a few reports on the differential fluorescent intensity of FLAER in normal bone marrow (BM) cell subpopulations. The purpose of this study was to evaluate FLAER expression during normal and pathological hematopoiesis, to map the critical existence of non‐PNH FLAER‐dim cells.

Methods

A total of 54 BM aspirates were prospectively analyzed with FLAER‐based flow cytometric (FC) protocols, during their routine work‐up. These were obtained from patients with the following diagnoses: PNH (3), infections/reactive (5), myelodysplastic syndromes (MDS) (7), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (4), chronic myelogenous leukemia (CML) (3), acute myelogenous leukemia (AML) at diagnosis (20), AML in measurable residual disease (MRD) assessment (7), and B‐cell acute lymphoblastic leukemia (B‐ALL) in MRD assessment (5). The applied protocols consisted of FLAER, HLA‐DR, CD14, CD33, CD34, CD66b, CD38, CD117, CD64, CD45, and FLAER, CD66c, CD14, CD33, CD34, CD66b, CD123, CD16, CD64, and CD45, respectively. FLAER expression was assessed in CD34++/CD38‐ and CD34+/CD38+ stem cells, CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors, and CD64+/CD14‐/HLA‐DR+ monocyte precursors but also in mature myeloid cells.

Results

All patients revealed an intermediate FLAER intensity in CD34++/CD38‐ stem cells, with a discrete FLAER‐negative subpopulation observed only in maturing CD34+/CD38+ stem cells of patients with PNH. The lowest FLAER intensity was noticed in CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors, not only in patients with PNH but also in PNH‐negative BM aspirates. An ascending FLAER intensity was further observed during monocytic and granulocytic maturation, with a discrete FLAER‐negative population in CD64+/CD14‐/HLA‐DR+ monocyte precursors and maturing neutrophils and monocytes of patients with PNH only. The maturation pattern of FLAER expression was further confirmed in a patient with acute promyelocytic leukemia treated with all‐trans retinoic acid (ATRA), where FLAER was concurrently upregulated with CD66b in a consecutive series of PB samples tested over a 20‐day‐period after diagnosis.

Conclusion

The application of FLAER in PNH‐positive and PNH‐negative reactive or malignant BM aspirates identified normally expected non‐PNH FLAER‐dim CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors in all samples. A specific FLAER‐associated maturation pattern was observed, which is proposed for further study within MRD and diagnostic protocols.
Improvement of RBD‐FC Immunogenicity by Using Alum–Sodium Alginate Adjuvant Against SARS‐COV‐2
Authors: Dehghan Mahboobeh , Askari Hossein , Tohidfar Masoud , Siadat Seyed Omid Ranaei , Fatemi Fataneh
Published: October 2024

Background

Adjuvants use several mechanisms to boost immunogenicity and to modulate immune response. The strength of adsorption of antigen by adjuvants can be a determinant factor for significant improvement of immunopotentiation.

Methods

We expressed recombinant RBD‐FC in PichiaPink Strain 4 and examined the vaccination of mice by vaccine formulation with different adjuvants (sodium alginate and aluminum hydroxide, alone and together).

Results

Sodium alginate significantly increased the immunogenicity and stability of RBD‐FC antigen, so RBD‐FC formulated with combined alginate and alum (AlSa) and sodium alginate alone showed higher antibody titer and stability. Immunogenicity of RBD‐FC:AlSa was determined by serological assays including direct enzyme‐linked immunosorbent assay (ELISA) and surrogate virus neutralization test (sVNT). High levels of IgGs and neutralizing antibodies were measured in serum of mice immunized with the RBD‐FC:AlSa formulation. On the other hand, cytokines IL‐10 and INF‐γ were severely accumulated in response to RBD‐FC:AlSa, and after 10 days, their accumulation was significantly declined, whereas IL‐4 showed the highest and the lowest accumulation in response to alum and alginate, respectively.

Conclusions

Our data may suggest that combination of alum and sodium alginate has a better compatibility with RBD‐FC in vaccine formulation.
Time: Friend or Foe
Authors: Charlotte Moulis
Published: October 2024

Using many years of experience in the UK's state primary schools, I consider that a limited understanding of time has damaging implications for both pupils and adults within the education system. The sector neglects the fact that time has much potential, many definitions and is a powerful influence on man. I share how education took clock‐time and manipulated it to an extreme, leading to the rule clock‐time now has over our schools. We are being held to account by time, and it has become our foe; however, I believe that it can become our friend. I explain why education should accept time's many facets and use them to help reshape its structure and practice. Time, in educational spaces, could be understood and experienced differently, taking in to account the human and all manner of other relevant things, for the greater good. This article began as a combined work of spoken word, poetry recital and research paper.
Serum metabolomics signature of maternally inherited diabetes and deafness by gas chromatography–time of flight mass spectrometry
Authors: Cao Baige , Lu Huijuan , Liu Peng , Zhang Yinan , Wang Congrong
Published: October 2024

Aims/Introduction

The aim of this study was to identify a metabolic signature of MIDD as compared to healthy controls and other types of diabetes.

Methods

We performed a comprehensive serum metabolomic analysis using gas chromatography‐time of flight mass spectrometry (GC‐TOFMS) in participants diagnosed with MIDD (n = 14), latent autoimmune diabetes in adults (LADA) (n = 14), type 2 diabetes mellitus (n = 14), and healthy controls (n = 14). Each group was matched for gender and age.

Results

There were significant metabolic differences among MIDD and other diabetic and control groups. Compared with control, MIDD patients had high levels of carbohydrates (glucose, galactose, mannose, sorbose, and maltose), fatty acids (2‐Hydroxybutyric acid, eicosapentaenoic acid, and octadecanoic acid), and other metabolites (alanine, threonic acid, cholesterol, lactic acid, and gluconic acid), but low level of threonine. Compared with LADA, MIDD patients had high levels of threonic acid and some amino acids (alanine, tryptophan, histidine, proline, glutamine, and creatine) but low levels of serine. Compared with type 2 diabetes mellitus, MIDD patients had high levels of citrulline, creatine, 3‐Amino‐2‐piperidone, but low levels of ornithine, fatty acids (arachidonic acid and octadecanoic acid), and intermediates of the tricarboxylic acid cycle (malic acid and succinic acid).

Conclusions

Our study identified a specific metabolic profile related to glycolysis and the tricarboxylic acid cycle in MIDD that differs from healthy controls and other types of diabetes. This unique metabolic signature provides new perspectives for understanding the pathophysiology and underlying mechanisms of MIDD.
Causal association between insulin sensitivity index and Alzheimer's disease
Authors: Xu Fang , Wu Shiyang , Gao Shan , Li Xuan , Huang Chen , Chen Yan , Zhu Ping , Liu Guiyou
Published: October 2024

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD.

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Costs and economic impact of student‐led clinics—A systematic review
Authors: Mitchell Debra , Maloney Stephen , Robinson Luke , Haines Terry , Foo Jonathan
Published: October 2024

Purpose

Student‐led clinics generate a range of benefits to multiple stakeholder groups. Students receive important educational opportunities to advance in their training. Patients with limited access to care may access effective care or a higher amount of effective care and so reduce burden on the health care system. The financial viability of student‐led clinics run by universities is uncertain, and establishing this is complicated by the range of stakeholder costs and benefits that may be involved. This systematic review aimed to synthesise evidence related to the costs and benefits of student‐led clinics and report the methods that have been used to measure these costs and benefits.

Method

We conducted a systematic search of MEDLINE All, PsychInfo, CINAHL, A+ Education (Informit), ERIC (ProQuest) and ProQuest Education databases for studies that reported the costs and/or economic benefits of student‐led clinics from inception through August 2023. Studies were screened for eligibility, and data were extracted including study characteristics, student‐led clinic description and economic outcomes. A narrative synthesis was undertaken due to the heterogeneity of studies.

Results

Of 349 potentially eligible studies, 24 were included. Nine studies (38%) used an outcome description‐monetised approach; four used partial economic evaluation (17%); four employed cost description (17%); two used cost approximation (8%); two used cost analyses (8%); and one was a full economic analysis (4%). Studies examined costs or benefits, from the perspective of a range of stakeholders, but few examined both. Only six studies (25%) had established the clinical effectiveness of their service. Student clinics generate costs for universities in supplying supervision, capital and consumables. Benefits are shared by patients, students, universities and the broader health system, however, economic evaluations to date have largely ignored or not monetised/valued these benefits.

Conclusions

Student‐led clinics involve many different stakeholders, each of whom may incur costs and reap benefits. This complicates how we can go about trying to establish the economic efficiency and viability of student‐led clinics. Measurement of both costs and benefits is needed to understand the efficiency of student‐led clinics in comparison to alternatives. Without the full picture, decision‐makers may make decisions that are ill‐informed and lead to a loss of benefit for society.
The social significance of slang
Authors: Damirjian Alice
Published: October 2024

It is well‐established within linguistics that slang serves a group‐identifying function. In this paper, a new understanding of the notion of lexical metadata is developed to provide a philosophical treatment of said function. The proposed account explains the group‐identifying function of slang in terms of certain inferences about a speaker's group affiliations that people competent with a slang word will be disposed to make given the lexical metadata related to the word in question. The resulting view is theoretically simple and may extend to a whole range of linguistic phenomena that speakers utilize to position themselves in social space.
Methyl jasmonate mitigates Fusarium graminearum infection in wheat by inhibiting deoxynivalenol synthesis
Authors: Gao Jing , Sun Yidan , Jin Weiguo , Zhang Feng , Zhou Mingguo , Song Xiushi
Published: October 2024

Methyl jasmonate (MeJA), a plant growth regulator, coordinates a diverse array of physiological responses, including the inhibition of seed germination, modulation of secondary metabolite biosynthesis, and activation of defence responses. The external application of MeJA has been demonstrated to effectively diminish the severity of fungal diseases. Here, we unveil a novel mechanism through which exogenous MeJA alleviates Fusarium head blight (FHB) by inhibiting the synthesis of deoxynivalenol (DON) in Fusarium graminearum, rather than by enhancing the wheat resistance response. MeJA treatment reduced the infection by wild‐type F. graminearum in wheat coleoptiles, but exhibited no significant influence on that of the DON‐deficient mutant strain (∆Tri5). The production of DON in F. graminearum was significantly inhibited both in vitro and in planta. MeJA affected the expression of genes related to DON biosynthesis, without influencing the formation of toxisomes as observed under microscopic analysis. Exogenous MeJA demonstrated a limited impact on the early genes of plant jasmonic acid signalling pathway, in contrast to the wild‐type pathogen strain, which induced the upregulation of these genes. The expression levels of defence marker genes induced by MeJA were notably lower compared to those induced by the pathogen. This study elucidates the molecular mechanisms of MeJA in modulating the wheat‐F. graminearum interaction, providing new insights into the development of environmentally friendly strategies against fungi.
PbRVE6 Promotes Anthocyanins Accumulation in Pear Fruit Peel by Regulating Key Biosynthetic Genes
Authors: Li Xieyu , Du Wei , Cheng Yinsheng , Yang Li , Dong Xiujuan , Hussain Syed Bilal , Xu Lingfei , Liu Zheng , Wu Tao
Published: October 2024

Red peel color, a desirable trait in pears, is determined by anthocyanin accumulation. While REVEILLE (RVEs) transcription factors regulate anthocyanin biosynthesis in some plant species, their role in pear peel has not been well‐studied. This study investigates the function of RVEs in anthocyanin biosynthesis in ‘Zaosu’ (low anthocyanin content) and its red bud mutant, ‘Red Zaosu’ (high anthocyanin content) fruit peel. Consistent with higher anthocyanin content, ‘Red Zaosu’ pears exhibited increased PbRVE6 expression compared to ‘Zaosu’, while PbRVE3a and PbRVE3b levels remained unchanged. Additionally, PbRVE6 was localized to the nucleus. Overexpression of PbRVE6 in ‘Zaosu’ pear pericarp significantly increased anthocyanin content and upregulated key anthocyanin pathway genes PbANS and PbUFGT. Conversely, VIGS silencing of PbRVE6 in ‘Red Palacer’ pears led to decreased expression of PbANS and PbUFGT and a slight reduction in anthocyanin content. Yeast one‐hybrid and dual‐luciferase assays confirmed that PbRVE6 can bind and activate the promoters of PbANS and PbUFGT. These findings demonstrate that PbRVE6 promotes anthocyanin accumulation in pear peel by directly regulating PbANS and PbUFGT expression. This study provides a valuable foundation for understanding the regulatory network of anthocyanins in pear peels, and offers potential genetic resources for the production of new pear germplasm.
Measuring fisheries outcomes from coastal wetland restoration: a review and meta‐analysis
Authors: Bugnot Ana B. , Gorman Daniel , Steven Andrew D. L. , Vanderklift Mathew A.
Published: October 2024

Coastal wetlands, including saltmarshes, mangrove forests, and seagrass meadows, can support fisheries by providing habitat and exporting food and nutrients to adjacent or distant ecosystems. However, there is insufficient understanding about the extent to which wetland restoration can benefit fishery species. Here, we report qualitative and quantitative reviews of literature to evaluate the approaches used to measure or estimate fisheries outcomes of coastal wetland restoration and test for the effects of restoration on fisheries outcomes. Most studies focused on saltmarshes and mangroves, with fewer studies focussing on seagrasses. We found that effects of wetland restoration on fish populations have mainly been assessed for species that reside in coastal wetlands for at least part of their life cycle, while few studies have tested effects on fish populations via trophic subsidies. Moreover, few studies have directly assessed the effects of restoration on fisheries production. Instead, most studies have measured abundances of individual species at restored sites and compared those to undisturbed and/or disturbed areas. Restored areas contained similar fish densities to undisturbed or disturbed areas; but few studies compared restored areas to both undisturbed and disturbed areas at the same time. Overall, we did not find consistent and robust evidence for fisheries outcomes from wetland restoration projects because (1) there were not many studies, (2) the studies reported substantial variability in outcomes, and (3) the density of fish measured at a restoration site is not an accurate measure of the total fisheries benefit as adult fishes do not always reside in the restored habitat.
A cytoplasmic osmosensing mechanism mediated by molecular crowding–sensitive DCP5
Authors: Wang Zhenyu , Yang Qiuhua , Zhang Dan , Lu Yuanyi , Wang Yichuan , Pan Yajie , Qiu Yuping , Men Yongfan , Yan Wei , Xiao Zhina , Sun Ruixue , Li Wenyang , Huang Hongda , Guo Hongwei
Published: October 2024

Plants are frequently challenged by osmotic stresses. How plant cells sense environmental osmolarity changes is not fully understood. We report that
Arabidopsis
Decapping 5 (DCP5) functions as a multifunctional cytoplasmic osmosensor that senses and responds to extracellular hyperosmolarity. DCP5 harbors a plant-specific intramolecular crowding sensor (ICS) that undergoes conformational change and drives phase separation in response to osmotically intensified molecular crowding. Upon hyperosmolarity exposure, DCP5 rapidly and reversibly assembles to DCP5-enriched osmotic stress granules (DOSGs), which sequestrate plenty of mRNA and regulatory proteins, and thus adaptively reprograms both the translatome and transcriptome to facilitate plant osmotic stress adaptation. Our findings uncover a cytoplasmic osmosensing mechanism mediated by DCP5 with plant-specific molecular crowding sensitivity and suggest a stress sensory function for hyperosmotically induced stress granules.
A molecular mechanism for bright color variation in parrots
Authors: Arbore Roberto , Barbosa Soraia , Brejcha Jindich , Ogawa Yohey , Liu Yu , Nicolaï Michaël P. J. , Pereira Paulo , Sabatino Stephen J. , Cloutier Alison , Poon Emily Shui Kei , Marques Cristiana I. , Andrade Pedro , Debruyn Gerben , Afonso Sandra , Afonso Rita , Roy Shatadru Ghosh , Abdu Uri , Lopes Ricardo J. , Mojzeš Peter , Marík Petr , Sin Simon Yung Wa , White Michael A. , Araújo Pedro M. , Corbo Joseph C. , Carneiro Miguel
Published: October 2024

Parrots produce stunning plumage colors through unique pigments called psittacofulvins. However, the mechanism underlying their ability to generate a spectrum of vibrant yellows, reds, and greens remains enigmatic. We uncover a unifying chemical basis for a wide range of parrot plumage colors, which result from the selective deposition of red aldehyde- and yellow carboxyl-containing psittacofulvin molecules in developing feathers. Through genetic mapping, biochemical assays, and single-cell genomics, we identified a critical player in this process, the aldehyde dehydrogenase
ALDH3A2
, which oxidizes aldehyde psittacofulvins into carboxyl forms in late-differentiating keratinocytes during feather development. The simplicity of the underlying molecular mechanism, in which a single enzyme influences the balance of red and yellow pigments, offers an explanation for the exceptional evolutionary lability of parrot coloration.
A self-regenerative heat pump based on a dual-functional relaxor ferroelectric polymer
Authors: Wu Hanxiang , Zhu Yuan , Yan Wenzhong , Zhang Siyu , Budiman William , Liu Kede , Wu Jianghan , Meng Yuan , Zhao Xun , Mehta Ankur , Kaur Sumanjeet , Pei Qibing
Published: October 2024

Electrocaloric (EC) cooling presents a promising approach to efficient and compact solid-state heat pumps. However, reported EC coolers have complex architectures and limited cooling temperature lift. In this work, we introduce a self-regenerative heat pump (SRHP) using a cascade of EC polymer film stacks, which have electrostrictive actuations in response to an electric field that are directed to realize efficient heat transfer, eliminating the need for additional transportive or regenerative mechanisms. The SRHP demonstrates a cooling of 8.8 kelvin below ambient temperature in 30 seconds and delivers a maximum specific cooling power of 1.52 watts per gram. The temperature lift of the SRHP is 14.2 kelvin. These results underscore the potential of the compact solid-state cooling mechanism to address the increasing need for localized thermal management.
You won’t believe this
Authors: Kupferschmidt Kai
Published: October 2024

Researchers are trying to “inoculate” people against misinformation by giving them small doses
In Other Journals
Authors: Jiang Di , Ross Sarah H. , Lopez Bianca , Jin Sumin , Lavine Marc S. , Uzogara Ekeoma , Yeston Jake S.
Published: October 2024

Editors’ selections from the current scientific literature
Alzheimer’s drug approvals create prescribing dilemmas
Authors: Couzin-Frankel Jennifer
Published: October 2024

Clinicians and patients weigh modest benefits of the antibodies against sometimes-serious side effects
Targeted delivery of flagellin by nebulization offers optimized respiratory immunity and defense against pneumococcal pneumonia
Authors: Baldry Mara , Costa Charlotte , Zeroual Yasmine , Cayet Delphine , Pardessus Jeoffrey , Soulard Daphnée , Wallet Frédéric , Beury Delphine , Hot David , MacLoughlin Ronan , Heuzé-Vourc’h Nathalie , Sirard Jean-Claude , Carnoy Christophe
Published: October 2024

Novel therapeutic strategies are urgently needed to combat pneumonia caused by
Streptococcus pneumoniae
strains resistant to standard-of-care antibiotics. Previous studies have shown that targeted stimulation of lung innate immune defenses through intranasal administration of the Toll-like receptor 5 agonist flagellin improves the treatment of pneumonia when combined with antibiotics. To promote translation to the clinic application, this study assessed the direct delivery of flagellin to the airways through nebulization using a vibrating mesh nebulizer in mice. Intranasal delivery achieved approximately 40% lung deposition of the administered flagellin dose, whereas nebulization yielded less than 1%. Despite these differences, nebulized flagellin induced transient activation of lung innate immunity characterized by cytokine/chemokine production and neutrophil infiltration into airways analogous to intranasal administration. Furthermore, inhalation by nebulization resulted in an accelerated resolution of systemic pro-inflammatory responses. Lastly, adjunct therapy combining nebulized flagellin and amoxicillin proved effective against antibiotic-resistant pneumococcal pneumonia in mice. We posit that flagellin aerosol therapy represents a safe and promising approach to address bacterial pneumonia within the context of antimicrobial resistance.
Development of a
Limosilactobacillus reuteri
therapeutic delivery platform with reduced colonization potential
Authors: Alexander Laura M. , Khalid Saima , Gallego-Lopez Gina M. , Astmann Theresa J. , Oh Jee-Hwan , Heggen Mark , Huss Phil , Fisher Renee , Mukherjee Amitava , Raman Srivatsan , Choi In Young , Smith Morgan N. , Rogers Claude J. , Epperly Michael W. , Knoll Laura J. , Greenberger Joel S. , van Pijkeren Jan-Peter
Published: October 2024

Bacterial biotherapeutic delivery vehicles have the potential to treat a variety of diseases. This approach obviates the need to purify the recombinant effector molecule, allows delivery of therapeutics
in situ
via oral or intranasal administration, and protects the effector molecule during gastrointestinal transit. Lactic acid bacteria have been broadly developed as therapeutic delivery vehicles though risks associated with the colonization of a genetically modified microorganism have so-far not been addressed. Here, we present an engineered
Limosilactobacillus reuteri
strain with reduced colonization potential. We applied a dual-recombineering scheme for efficient barcoding and generated mutants in genes encoding five previously characterized and four uncharacterized putative adhesins. Compared with the wild type, none of the mutants were reduced in their ability to survive gastrointestinal transit in mice. CmbA was identified as a key protein in
L. reuteri
adhesion to HT-29 and enteroid cells. The nonuple mutant, a single strain with all nine genes encoding adhesins inactivated, had reduced capacity to adhere to enteroid monolayers. The nonuple mutant producing murine IFN-β was equally effective as its wild-type counterpart in mitigating radiation toxicity in mice. Thus, this work established a novel therapeutic delivery platform that lays a foundation for its application in other microbial therapeutic delivery candidates and furthers the progress of the
L. reuteri
delivery system towards human use.

IMPORTANCE

One major advantage to leverage gut microbes that have co-evolved with the vertebrate host is that evolution already has taken care of the difficult task to optimize survival within a complex ecosystem. The availability of the ecological niche will support colonization. However, long-term colonization of a recombinant microbe may not be desirable. Therefore, strategies need to be developed to overcome this potential safety concern. In this work, we developed a single strain in which we inactivated the encoding sortase, and eight genes encoding characterized/putative adhesins. Each individual mutant was characterized for growth and adhesion to epithelial cells. On enteroid cells, the nonuple mutant has a reduced adhesion potential compared with the wild-type strain. In a model of total-body irradiation, the nonuple strain engineered to release murine interferon-β performed comparable to a derivative of the wild-type strain that releases interferon-β. This work is an important step toward the application of recombinant
L. reuteri
in humans.
Corynebacterial membrane vesicles disrupt cariogenic interkingdom assemblages
Authors: Treerat Puthayalai , Rozendal Tanner , de Mattos Camilla , Davis Anli , Helliwell Emily , Merritt Justin , Kreth Jens
Published: October 2024

Polymicrobial diseases such as periodontal disease and caries pose significant treatment challenges due to their resistance to common approaches like antibiotic therapy. These infections exhibit increased resilience, due to microbial interactions that also disrupt host immune responses. Current research focuses on virulence and disease-promoting interactions, but less is known about interactions that could inhibit or prevent disease development. Normally human-associated microbiomes maintain homeostasis, preventing pathobionts from becoming dominant. In conditions like chronic disseminated candidiasis or severe early childhood caries (s-ECC), an overgrowth of microbes such as
Candida albicans
disrupts this balance. Typically,
C. albicans
coexists benignly within the microbial community but can become pathogenic, forming biofilms and interacting with other microbes such as cariogenic
Streptococcus mutans
. This interaction is particularly significant in s-ECC, where it exacerbates the disease’s progression and severity. Here, we present that
Corynebacterium durum
, itself and through its extracellular membrane vesicles disrupts interkingdom assemblages between
C. albicans
and
S. mutans
. Mechanistically the interaction interference occurs at the genetic level with downregulated HWP1 expression, a surface protein specifically induced in the presence of
S. mutans
promoting the interkingdom interaction. Additionally, we show that
C. durum
can impede
C. albican
s systemic virulence in the
Galleria mellonella
infection model. This suggests that oral corynebacteria may act as a beneficial commensal species, exerting antifungal effects within polymicrobial communities and opening new avenues for managing polymicrobial diseases.

IMPORTANCE

Polymicrobial diseases such as severe early childhood caries (s-ECC) lack effective treatment options. Prevention, requiring a deeper understanding of ecological processes before the onset of disease symptoms, could be a potential strategy. In this context, we investigated how relatively abundant oral biofilm
Corynebacterium
species, which are associated with oral health, can interfere with the interkingdom partnership of
Streptococcus mutans
and
Candida albicans
. This partnership is a significant driver of tooth decay in s-ECC due to synergistic activities that increase cariogenicity. Our study reveals that oral corynebacteria, through the production of extracellular membrane vesicles, can disrupt the
S. mutans
and
C. albicans
partnership by inhibiting fungal hyphae formation. Additionally, the fatty acid cargo within these vesicles exhibits antifungal properties, suggesting that corynebacteria play a role in shaping microbial dynamics within the oral biofilm.
Cyclophilin A facilitates HIV-1 integration
Authors: Padron Adrian , Dwivedi Richa , Chakraborty Rajasree , Prakash Prem , Kim Kyusik , Shi Jiong , Ahn Jinwoo , Pandhare Jui , Luban Jeremy , Aiken Christopher , Balasubramaniam Muthukumar , Dash Chandravanu
Published: October 2024

Cyclophilin A (CypA) binds to the HIV-1 capsid to facilitate reverse transcription and nuclear entry and counter the antiviral activity of TRIM5α. Interestingly, recent studies suggest that the capsid enters the nucleus of an infected cell and uncoats prior to integration. We have previously reported that the capsid protein regulates HIV-1 integration. Therefore, we probed whether CypA-capsid interaction also regulates this post-nuclear entry step. First, we challenged CypA-expressing (CypA
+/+
) and CypA-depleted (CypA
-/-
) cells with HIV-1 and quantified the levels of provirus. CypA-depletion significantly reduced integration, an effect that was independent of CypA’s effect on reverse transcription, nuclear entry, and the presence or absence of TRIM5α. In addition, cyclosporin A, an inhibitor that disrupts CypA-capsid binding, inhibited proviral integration in CypA
+/+
cells but not in CypA
-/-
cells. HIV-1 capsid mutants (G89V and P90A) deficient in CypA binding were also blocked at the integration step in CypA
+/+
cells but not in CypA
-/-
cells. Then, to understand the mechanism, we assessed the integration activity of the HIV-1 preintegration complexes (PICs) extracted from acutely infected cells. PICs from CypA
-/-
cells retained lower integration activity
in vitro
compared to those from CypA
+/+
cells. PICs from cells depleted of both CypA and TRIM5α also had lower activity, suggesting that CypA’s effect on PIC was independent of TRIM5α. Finally, CypA protein specifically stimulated PIC activity, as this effect was significantly blocked by CsA. Collectively, these results provide strong evidence that CypA directly promotes HIV-1 integration, a previously unknown role of this host factor in the nucleus of an infected cell.

IMPORTANCE

Interaction between the HIV-1 capsid and host cellular factors is essential for infection. However, the molecular details and functional consequences of viral-host factor interactions during HIV-1 infection are not fully understood. Over 30 years ago, Cyclophilin A (CypA) was identified as the first host protein to bind to the HIV-1 capsid. Now it is established that CypA-capsid interaction promotes reverse transcription and nuclear entry of HIV-1. In addition, CypA blocks TRIM5α-mediated restriction of HIV-1. In this report, we show that CypA promotes the post-nuclear entry step of HIV-1 integration by binding to the viral capsid. Notably, we show that CypA stimulates the viral DNA integration activity of the HIV-1 preintegration complex. Collectively, our studies identify a novel role of CypA during the early steps of HIV-1 infection. This new knowledge is important because recent reports suggest that an operationally intact HIV-1 capsid enters the nucleus of an infected cell.
Identification of critical residues for RNA binding of nairovirus nucleoprotein
Authors: Ohta Keisuke , Saka Naoki , Nishio Machiko
Published: October 2024

Orthonairovirus haemorrhagiae (CCHFV) is a tick-borne virus of the
Orthonairovirus
genus. CCHFV nucleoprotein binds to the viral genomic RNA, which is essential for transcription and replication. Based on structural analyses, several residues located in positively-charged regions of CCHFV nucleoprotein have been indicated to be important for RNA binding. We investigated the effects of each residue on RNA binding using Orthonairovirus hazaraense (HAZV), a surrogate model for CCHFV, to address the lack of detailed investigations. RNA immunoprecipitation assay revealed that the four basic amino acid residues (R59, R178, K414, and K465) are critical for RNA binding. All of these residues are located within the same positively-charged region. Basicity of these residues was also found to be necessary for RNA binding. Recombinant HAZVs carrying RNA binding-defective mutants of nucleoprotein could not be rescued. We identified the critical residues for RNA binding of nairovirus nucleoprotein. This study provides new insights into a detailed binding model between nairovirus nucleoprotein and its genomic RNA.

IMPORTANCE

We sought to identify the important residues for RNA binding of nairovirus nucleoprotein using Orthonairovirus hazaraense, a surrogate model for Orthonairovirus haemorrhagiae. The four basic amino acid residues of Orthonairovirus hazaraense nucleoprotein were critical for RNA binding. Sufficient RNA-binding capacity of nucleoprotein was essential for successful virus replication. This study provides new insights into a detailed binding model between nairovirus nucleoprotein and its genomic RNA.
Supplemental Material: Multi-stage tectonic record of the Central Sakarya Terrane Basement (NW Turkey): Implications for the Paleozoic evolution of Rheic Ocean and northern Gondwanan margin
Authors: Yasar I. Dogancan , al. et
Published: October 2024

Analytical methods, supplemental figures, and chemical and isotopic data. 
Effect of a microencapsulated complex of biofactors and antioxidants on the growth performance, plasma biochemistry, intestinal health, and immune and antioxidant status of broiler chickens challenged with cold stress
Authors: Oretomiloye Fisayo , Lahaye Ludovic , Adewole Deborah
Published: October 2024

The study examined the effects of a microencapsulated complex of biofactors and antioxidants (P(BF + AOx)) on growth and health status of broiler chickens challenged with cold stress. Day-old broilers were allotted to four treatments in a 2 × 2 factorial design with two dietary treatments: (1) Control (CON; corn–wheat–soybean-based) and (2) CON + 0.015% P(BF + AOx), and two thermal treatments: (1) Thermoneutral (TN; 29 °C ± 1 on days 8–10, 54 h) and (2) Cold stress (CS; 20 °C on days 8–10, 54 h). Treatments were allocated to six replicates, with eight chicks/replicate. Growth performance was measured weekly from days 0–21. On day 14, two birds/cage were euthanized. Cold stress reduced ( P < 0.05) total antioxidant capacity (TAC), serum IgM, jejunal villus height (VH), villus width (VW), and VH:crypt depth (VH:CD). Irrespective of CS, P(BF + AOx) improved ( P < 0.05) feed intake (631 vs. 592 g/bird), body weight (BW) (383 vs. 349 g/bird), BW gain (337 vs. 301 g/bird) up to day 14, and plasma TAC. Regardless of the challenge model, P(BF + AOx) increased ( P < 0.05) duodenal VW, VH:CD, jejunal, and ileal VH:CD, and the relative abundance of cecal Intestinimonas and Colidextribacteria, compared to the CON. In conclusion, CS altered broiler blood parameters and gut morphology, but 0.015% P(BF + AOx) improved early life growth performance, TAC, and gut health, irrespective of CS, suggesting that it could be an effective strategy to support overall health and performance.
Diet Changes and Colorectal Cancer Risk in the UK Biobank
Authors: Hoang Tung , Cho Sooyoung , Shin Aesun
Published: October 2024

Background:

Modifying dietary behaviors into healthier habits may attenuate the risk of colorectal cancer. This study aimed to investigate the association between dietary changes and the risk of colorectal cancer.

Methods:

Following dietary recommendations for red and processed meat, fruit and vegetables, and alcohol consumption, we classified 50,640 participants into poor and good adherence groups in the UK Biobank. Changes in dietary habits were defined as stable poor, poor to good, good to poor, and stable to good adherences. A Cox proportional hazard model was used to examine the association between dietary changes and colorectal cancer risk.

Results:

Women were more likely to follow dietary recommendations than men. After a median of 3.3 years from the latest follow-up, 8,328 (16.4%) participants followed an improved dietary habit and 5,808 (11.5%) participants had a worsened diet. Compared with men who stably consumed fruit and vegetables <5 servings/day, those who increased their consumption to ≥5 servings/day were related to colorectal cancer risk reduction [HR: 0.24 (0.09–0.63)]. However, the beneficial associations of increased fruit and vegetable consumption were not statistically significant in women [HR: 0.41 (0.11–1.56)].

Conclusions:

Our findings support the evidence that increasing fruit and vegetable intake could serve as a beneficial strategy to mitigate colorectal cancer risk in men.

Impact:

Participants from the UK Biobank significantly changed their adherence to dietary recommendations during the follow-up. Increasing fruit and vegetable consumption was inversely associated with colorectal cancer risk among men.
Supplementary Table S7 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

Table S7. Variable Importance for predicting BCLM CD4+PD1+ using primary tumor clusters.
Supplementary Table S5 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

Table S5. Variable Importance for predicting BCLM CD206+ using primary tumor clusters.
Supplementary Table S12 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

Table S12. Variable Importance for predicting BCLM CD8a+PD1- using primary tumor clusters.
Supplementary Figure S11 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

Table S11. Variable importance for prediction of BCLM MMP9+, PD-L1+, pERK+, and αSMA+ using ML models.
Figure 5 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

AUROC curves of ML models using primary IMC tumor cluster densities as input features to predict BCLM IMC cluster densities as being either above or below median values. One ML model was created per BCLM cluster.
Figure 4 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

IMC cluster correlations. A, Correlations between primary tumor (breast) and BCLM (liver) marker clusters. B, Pairs of strongly correlated clusters (|ρ| ≥ 0.75).
Figure 1 from Characterization of the Breast Cancer Liver Metastasis Microenvironment via Machine Learning Analysis of the Primary Tumor Microenvironment
Authors: Goodin Dylan A. , Chau Eric , Zheng Junjun , O’Connell Cailin , Tiwari Anjana , Xu Yitian , Niravath Polly , Chen Shu-Hsia , Godin Biana , Frieboes Hermann B.
Published: October 2024

Workflow of study design. A, Study profile. Primary breast cancer samples were taken from 15 patients. After subsequent diagnosis of BCLM, a core needle biopsy was also obtained. B, Summary of analysis. ROIs from primary tumor and BCLM were identified using H&E staining for tumor tissue and TME. Multiple marker clusters were quantified by IMC, producing 20 common clusters between two analytical batches. IMC ROI missing multiple tumor markers (Ki-67, E-cad+, or αSMA) were excluded. Multiple ML models were trained to classify BCLM cluster expression into low (< median) or high (≥ median) groups using primary tumor cluster data. Forward feature selection was performed on preprocessed data using varImp to identify primary TME markers associated with BCLM classification. C, Diagram of model training and validation. Primary tumor data were randomly sorted and split into k folds (subsets; here, k = 5). Each model was trained with k-1 folds and validated with the kth fold. This process was repeated until all folds were used once as the validation set. Twenty permutations were performed in total, repeating the validation process for each fold within each permutation. Final results of each model are the averages of the validations across all folds and all iterations (n = 100). H&E, hematoxylin and eosin.
Primary Small Cell Carcinoma of Left Maxillary Sinus: A Case Report of Rare Tumor on Rare Location
Authors: Jamil Anique Ahmad , Rehman Abdur , Arshad Sarah , Rafique Anam , Khan Muhammad Shuaib , Ihtesham Arham , Shafiq Usama , Maqbool Shahzaib , Iqbal Javed
Published: October 2024

Introduction: Primary extrapulmonary small cell carcinoma (EPSCC) is a rare and aggressive tumor with diverse clinical manifestations. In the realm of head and neck pathology, EPSCC most commonly presents in the larynx or oral cavity. Sinonasal small cell neuroendocrine carcinoma represents a particularly infrequent and aggressive neoplasm affecting the nasal cavity and paranasal sinuses. Case Presentation: Here in, we are presenting a case of a 40-year-old nonsmoking male with left maxillary sinus EPSCC, demonstrating extensive local invasion and regional lymphadenopathy. The patient presented with nasal obstruction, ocular swelling, visual loss, and multiple neck swellings. Diagnosis was challenging, requiring a multidisciplinary approach and histopathological confirmation. Immunohistochemistry revealed positive cytokeratin AE1/AE3 and synaptophysin markers validating the diagnosis of small cell carcinoma. Conclusion: This case underscores the diagnostic complexities and highlights the importance of swift intervention and a multidisciplinary treatment approach for optimizing patient outcomes in rare and aggressive tumors like EPSCC. Early detection and prompt management are crucial in resource-limited settings to mitigate morbidity and mortality.
A Multidimensional Approach to the Management of Patients in Prolonged Weaning from Mechanical Ventilation: The Concept of Treatable Traits – A Narrative Review
Authors: Trudzinski Franziska C. , Neetz Benjamin , Dahlhoff Jana C. , Wilkens Finn Moritz , Katzenschlager Stephan , Fähndrich Sebastian , Kempa Axel , Neurohr Claus , Schneider Armin , Joves Biljana , Sommerwerck Urte , Eberhardt Ralf , Bornitz Florian , Herth Felix J.F. , Michels-Zetsche Julia D.
Published: October 2024

Background: Established structured weaning approaches, which are effective for patients in simple and difficult weaning, are often not appropriate for patients undergoing prolonged weaning. Addressing the complexity of weaning failure requires personalized precision medicine. The therapeutic concept of treatable traits (TTs) has been proposed as a new paradigm for the management of chronic respiratory diseases. It is based on a multidimensional assessment of specific characteristics, which can be addressed by specific interventions that go beyond traditional diagnostic criteria. The concept is increasingly adopted for other complex diseases. Summary: This is a narrative review and an expert opinion on the development of a concept of TTs for patients undergoing prolonged weaning. The proposed TTs are based on a systematic review of risk factors for prolonged weaning, an analysis of claims data to assess risk factors within 96 h of IMV onset and data from the WEAN SAFE study. A multidisciplinary team identified clinically important TTs and determined appropriate interventions. The following TTs have been identified: airway disorders and complications associated with tracheostomy or intubation, such as airway obstruction, strictures or tracheomalacia, infectious aspects, anxiety, depression, delirium, post-traumatic stress disorder, anemia, pulmonary and cardio-renal disease. The multidimensional holistic approach also includes tailored sedation and pain management, nutritional therapy, early mobilization, and physiotherapy. Key Message: We propose a framework of relevant considerations for a multidimensional approach to the management of patients undergoing prolonged weaning that supports the regain of respiratory capacity, reduces the respiratory load, and thus could resolve the respiratory workload imbalance.