bluuebunny/crossref_metadata_2025 huggingface dataset:
Spliceosomal protein U2B″ delays leaf senescence by enhancing splicing variant JAZ9β expression to attenuate jasmonate signaling in Arabidopsis
Authors: Yang Qi , Tan Shuya , Wang Hou‐Ling , Wang Ting , Cao Jie , Liu Hairong , Sha Yueqi , Zhao Yaning , Xia Xinli , Guo Hongwei , Li Zhonghai
Published: August 2023

The regulatory framework of leaf senescence is gradually becoming clearer; however, the fine regulation of this process remains largely unknown.

Here, genetic analysis revealed that U2 small nuclear ribonucleoprotein B (U2B″), a component of the spliceosome, is a negative regulator of leaf senescence. Mutation of U2B″ led to precocious leaf senescence, whereas overexpression of U2B″ extended leaf longevity. Transcriptome analysis revealed that the jasmonic acid (JA) signaling pathway was activated in the u2b″ mutant. U2B″ enhances the generation of splicing variant JASMONATE ZIM‐DOMAIN 9β (JAZ9β) with an intron retention in the Jas motif, which compromises its interaction with CORONATINE INSENSITIVE1 and thus enhances the stability of JAZ9β protein. Moreover, JAZ9β could interact with MYC2 and obstruct its activity, thereby attenuating JA signaling. Correspondingly, overexpression of JAZ9β rescued the early senescence phenotype of the u2b″ mutant.

Furthermore, JA treatment promoted expression of U2B″ that was found to be a direct target of MYC2. Overexpression of MYC2 in the u2b″ mutant resulted in a more pronounced premature senescence than that in wild‐type plants.

Collectively, our findings reveal that the spliceosomal protein U2B″ fine‐tunes leaf senescence by enhancing the expression of JAZ9β and thereby attenuating JA signaling.
CRISPR/Cas9‐mediated seamless gene replacement in protoplasts expands the resistance spectrum to TMV‐U1 strain in regenerated Nicotiana tabacum
Authors: Li Yanli , Huang Changjun , Liu Yong , Zeng Jianmin , Yu Haiqin , Tong Zhijun , Yuan Xinjie , Sui Xueyi , Fang Dunhuang , Xiao Bingguang , Zhao Shancen , Yuan Cheng
Published: August 2023

CRISPR/Cas‐based genome editing is now extensively used in plant breeding and continues to evolve. Most CRISPR/Cas current applications in plants focus on gene knock‐outs; however, there is a pressing need for new methods to achieve more efficient delivery of CRISPR components and gene knock‐ins to improve agronomic traits of crop cultivars. We report here a genome editing system that combines the advantages of protoplast technologies with recent CRISPR/Cas advances to achieve seamless large fragment insertions in the model Solanaceae plant Nicotiana tabacum. With this system, two resistance‐related regions of the N′ gene were replaced with homologous fragments from the N′alata gene to confer TMV‐U1 resistance in the T0 generation of GMO‐free plants. Our study establishes a reliable genome‐editing tool for efficient gene modifications and provides a detailed description of the optimization process to assist other researchers adapt this system for their needs.
Polyhydroxybutyrate synthesis in Camelina: Towards coproduction of renewable feedstocks for bioplastics and fuels
Authors: Malik Meghna R. , Patterson Nii , Sharma Nirmala , Tang Jihong , Burkitt Claire , Ji Yuanyuan , Martino Matthew , Hertig Andrew , Schweitzer Dirk , Peoples Oliver , Snell Kristi D.
Published: August 2023

Plant‐based co‐production of polyhydroxyalkanoates (PHAs) and seed oil has the potential to create a viable domestic source of feedstocks for renewable fuels and plastics. PHAs, a class of biodegradable polyesters, can replace conventional plastics in many applications while providing full degradation in all biologically active environments. Here we report the production of the PHA poly[(R)‐3‐hydroxybutyrate] (PHB) in the seed cytosol of the emerging bioenergy crop Camelina sativa engineered with a bacterial PHB biosynthetic pathway. Two approaches were used: cytosolic localization of all three enzymes of the PHB pathway in the seed, or localization of the first two enzymes of the pathway in the cytosol and anchoring of the third enzyme required for polymerization to the cytosolic face of the endoplasmic reticulum (ER). The ER‐targeted approach was found to provide more stable polymer production with PHB levels up to 10.2% of the mature seed weight achieved in seeds with good viability. These results mark a significant step forward towards engineering lines for commercial use. Plant‐based PHA production would enable a direct link between low‐cost large‐scale agricultural production of biodegradable polymers and seed oil with the global plastics and renewable fuels markets.
Optimized bone grafting
Authors: Miron Richard J.
Published: August 2023

Bone grafting is routinely performed in periodontology and oral surgery to fill bone voids. While autogenous bone is considered the gold standard because of its regenerative properties, allografts and xenografts have more commonly been utilized owing to their availability as well as their differential regenerative/biomechanical properties. In particular, xenografts are sintered at high temperatures, which allows for their slower degradation and resorption rates and/or nonresorbable features. As a result, clinicians have combined xenografts with other classes of bone grafts (most notably allografts and autografts in various ratios) for procedures requiring better long‐term stability, such as contour grafting, sinus elevation procedures, and vertical bone augmentations. This review addresses the regenerative properties of each class of bone grafts and then highlights the importance of understanding each of their biomechanical and regenerative properties for clinical applications, including extraction site management, contour augmentation, sinus grafting, and horizontal and vertical augmentation procedures. Thereafter, an introduction toward the novel production of nonresorbable bone allografts (NRBAs) via high‐temperature sintering is presented. These NRBAs not only pose the advantage of being more biocompatible than xenografts owing to their origin (human vs. animal bone) but also display nonresorbable properties similar to those of xenografts. Thus, while packaging allografts with xenografts in premixtures specific to various clinical indications has never been permitted owing to cross‐species contamination and FDA/CE requirements, the discovery and production of NRBAs allows premixing with standard allografts in various ratios without regulatory restrictions. Therefore, premixtures of allografts with NRBAs can be produced in various ratios for specific indications (e.g., a 1:1 ratio similar to an allograft/xenograft mixture for sinus grafting) without the need for purchasing separate classes of bone grafts. This optimized form of bone grafting could theoretically provide clinicians more precise ratios without the need to purchase separate bone grafts. This review highlights the future potential for simplified and optimized bone grafting in periodontology and implant dentistry.
The use of platelet‐rich plasma in wound healing and vitiligo: A systematic review and meta‐analysis
Authors: Wang Zhi , Feng Cheng , Chang Guojing , Liu Hao , Li Shuo
Published: August 2023

Objective

To critically assess the effect and safety of platelet‐rich plasma (PRP) in chronic wounds and vitiligo.

Methods

A systematic literature searching was performed. Results were expressed as weight mean difference (WMD) or risk ratio (RR) with 95% confidence intervals (CIs). Pooled estimates were performed using a fixed‐effects model or random‐effects model, depending on the heterogeneity among studies.

Results

A total of 27 studies were included in this meta‐analysis. In patients with chronic diabetic ulcers, PRP significantly increased proportion of complete wound healing, percentage of wound area healed, and shortened the complete wound healing. In venous ulcers, PRP improved the epithelialized area and percentage of wound area healed. In vitiligo, PRP had better results in degree of improvement and mean repigmentation than controls. Regarding the safety profile, PRP did not increase the risk of infection in patients with chronic diabetic ulcers. Meta‐regression revealed that source of PRP and preparation method of PRP significantly affected the proportion of complete wound healing, whereas age, gender, country, duration of wound, and wound size had no impact on this outcome.

Conclusion

PRP is effective and safe, and can be used as a potential therapeutic adjunct or alternative treatment in chronic wounds of multiple etiologies and vitiligo.
Strigolactones repress nodule development and senescence in pea
Authors: Van Dingenen Judith , De Keyser Annick , Desmet Sandrien , Clarysse Alexander , Beullens Serge , Michiels Jan , Planque Mélanie , Goormachtig Sofie
Published: August 2023

Strigolactones are a class of phytohormones that are involved in many different plant developmental processes, including the rhizobium–legume nodule symbiosis. Although both positive and negative effects of strigolactones on the number of nodules have been reported, the influence of strigolactones on nodule development is still unknown. Here, by means of the ramosus (rms) mutants of Pisum sativum (pea) cv Terese, we investigated the impact of strigolactone biosynthesis (rms1 and rms5) and signaling (rms3 and rms4) mutants on nodule growth. The rms mutants had more red, that is, functional, and larger nodules than the wild‐type plants. Additionally, the increased nitrogen fixation and senescence zones with consequently reduced meristematic and infection zones indicated that the rms nodules developed faster than the wild‐type nodules. An enhanced expression of the nodule zone‐specific molecular markers for meristem activity and senescence supported the enlarged, fast maturing nodules. Interestingly, the master nodulation regulator, NODULE INCEPTION, NIN, was strongly induced in nodules of all rms mutants but not prior to inoculation. Determination of sugar levels with both bulk and spatial metabolomics in roots and nodules, respectively, hints at slightly increased malic acid levels early during nodule primordia formation and reduced sugar levels at later stages, possibly the consequence of an increased carbon usage of the enlarged nodules, contributing to the enhanced senescence. Taken together, these results suggest that strigolactones regulate the development of nodules, which is probably mediated through NIN, and available plant sugars.
Recuperación de la memoria histórica cultural del municipio de Agua de Dios, Cundinamarca
Authors: Niño Bernal Saudy Giovanna , Serrano Galán Silvana
Published: August 2023

El municipio de Agua de Dios posee un valor histórico y cultural alrededor de la enfermedad de la lepra; sin embargo, no se ha aprovechado su potencial turístico, desde el conocimiento de las experiencias y memorias de las comunidades locales de este territorio. Por ello, a partir del turismo cultural es posible afianzar los elementos identitarios de una comunidad, puesto que históricamente estos territorios ya cuentan con una serie de acontecimientos que se deben conservar y recrear para mantener vivas las culturas a través del tiempo. El presente estudio presenta un análisis exhaustivo y coyuntural de las memorias, experiencias, relatos, y del estado actual de los atractivos culturales declarados patrimonio en el territor
Cellular Mechanics of Finger-Like Structures of Collective Cell Migration
Authors: Xu Xiangyu , Xu Jiayi , Liu Jie , Jiang Chaohui , Tian Liangfei , Xu Yingke , Li Dechang , Ji Baohua
Published: August 2023

Finger-like structures emerging from groups of cells at the forefront of cell layer take crucial roles in the migration of collective cell assemblies. However, the mechanics of the finger-like structure has not been fully understood. Here, we constructed a two-dimensional collective cell migration model and quantitatively analyzed the cellular mechanics of finger-like structures during the collective cell migration through experimental study and numerical simulation. We found that substrate stiffness, cell density, cell prestress, and mechanical loading significantly influence the generation and behaviors of the finger-like structures by regulating the lamellipodia spreading area, cellular traction force, and collectivity of cell motion. We showed that the regions with higher maximum principal stress tend to produce larger finger-like structures. Increasing the spreading area of lamellipodia and the velocity of leader cells could promote the generation of higher finger-like structures. For a quantitative understanding of the mechanisms of the effects of these mechanical factors, we adopted a coarse-grained cell model based on the traction-distance law. Our numerical simulation recapitulated the cell velocity distribution, cell motility integrity, cell polarization, and stress distribution in the cell layer observed in the experiment. These analyses revealed the cellular mechanics of the finger-like structure and its roles in collective cell migration. This study provides valuable insights into the collective cell behaviors in tissue engineering and regenerative medicine for biomedical applications.
Digital Twinning and Optimization of Manufacturing Process Flows
Authors: Lee Hankang , Yang Hui
Published: August 2023

The new wave of Industry 4.0 is transforming manufacturing factories into data-rich environments. This provides an unprecedented opportunity to feed large amounts of sensing data collected from the physical factory into the construction of digital twin (DT) in cyberspace. However, little has been done to fully utilize the DT technology to improve the smartness and autonomous levels of small and medium-sized manufacturing factories. Indeed, only a small fraction of small and medium-sized manufacturers (SMMs) has considered implementing DT technology. There is an urgent need to exploit the full potential of data analytics and simulation-enabled DTs for advanced manufacturing. Hence, this paper presents the design and development of DT models for simulation optimization of manufacturing process flows. First, we develop a multi-agent simulation model that describes nonlinear and stochastic dynamics among a network of interactive manufacturing things, including customers, machines, automated guided vehicles (AGVs), queues, and jobs. Second, we propose a statistical metamodeling approach to design sequential computer experiments to optimize the utilization of AGV under uncertainty. Third, we construct two new graph models—job flow graph and AGV traveling graph—to track and monitor the real-time performance of manufacturing jobshops. The proposed simulation-enabled DT approach is evaluated and validated with experimental studies for the representation of a real-world manufacturing factory. Experimental results show that the proposed methodology effectively transforms a manufacturing jobshop into a new generation of DT-enabled smart factories. The sequential design of experiments effectively reduces the computation overhead of expensive simulations while optimally scheduling the AGV to achieve production throughput cost-effectively. This research is strongly promised to help SMMs fully utilize big data and DT technology for gaining competitive advantages in the global marketplace.
Implementing a course-based authentic learning experience with upper- and lower-division physics classes
Authors: Jensen Mikkel Herholdt , Morris Eliza J. , Ray M. W.
Published: August 2023

We describe a dual-class authentic learning experience (ALE) in which undergraduate upper-division physics students develop low-cost instruments, which are then used by students in a lower-division course to monitor water quality in rivers. The ALE bridges the experiences of lower- and upper-division physics majors by involving students across different stages of their college careers in a collaborative project. Lower-division physics students characterize, calibrate, and troubleshoot the instrument prototypes developed by their upper-division peers, and their work informs instrument modifications in future upper-division physics classes. This paper describes the first iteration of this project along with student perceptions. We find that lower-division students report an increase in their awareness of possible upper-division projects, an increased sense that their coursework has real-world applications, and a heightened understanding of how physicists can play a role in research on environmental issues.
The use of lexical semantics for processing face-masked speech in monolinguals and bilinguals
Authors: Ghanim Iyad , Perovic Aida
Published: August 2023

Face masks impede visual and acoustic cues that help make speech processing and language comprehension more efficient. Many studies report this phenomenon, but few examined how listeners utilize semantic information to overcome the challenges posed by face masks. Fewer still investigated this impact on bilinguals' processing of face-masked speech [Smiljanic, Keerstock, Meemann, and Ransom, S. M. (2021). J. Acoust. Soc. Am. 149(6), 4013–4023; Truong, Beck, and Weber (2021). J. Acoust. Soc. Am. 149(1), 142–144]. Therefore, this study aims to determine how monolingual and bilingual listeners use semantic information to compensate for the loss of visual and acoustic information when the speaker is wearing a mask. A lexical priming experiment tested how monolingual listeners and early-acquiring simultaneous bilingual listeners responded to video of English word pairs. The prime-target pairs were either strongly related, weakly related, or unrelated and were both either masked or unmasked. Analyses of reaction time results showed an overall effect of masking in both groups and an effect of semantic association strength on processing masked and unmasked speech. However, speaker groups were not different; subsequent analyses of difference values showed no effect of semantic context. These results illustrate the limited role of word-level semantic information on processing in adverse listening conditions. Results are discussed in light of semantic processing at the sentence level.
A simulation study on the sensitivity of transcranial ray-tracing ultrasound modeling to skull properties
Authors: Drainville Robert Andrew , Chatillon Sylvain , Moore David , Snell John , Padilla Frederic , Lafon Cyril
Published: August 2023

In transcranial focused ultrasound therapies, such as treating essential tremor via thermal ablation in the thalamus, acoustic energy is focused through the skull using a phased-array transducer. Ray tracing is a computationally efficient method that can correct skull-induced phase aberrations via per-element phase delay calculations using patient-specific computed tomography (CT) data. However, recent studies show that variations in CT-derived Hounsfield unit may account for only 50% of the speed of sound variability in human skull specimens, potentially limiting clinical transcranial ultrasound applications. Therefore, understanding the sensitivity of treatment planning methods to material parameter variations is essential. The present work uses a ray-tracing simulation model to explore how imprecision in model inputs, arising from clinically significant uncertainties in skull properties or considerations of acoustic phenomena, affects acoustic focusing quality through the skull. We propose and validate new methods to optimize ray-tracing skull simulations for clinical treatment planning, relevant for predicting intracranial target's thermal rise, using experimental data from ex-vivo human skulls.
Biodegradable electrospinning superhydrophilic nanofiber membranes for ultrafast oil-water separation
Authors: Cheng Xiquan , Li Tongyu , Yan Linlin , Jiao Yang , Zhang Yingjie , Wang Kai , Cheng Zhongjun , Ma Jun , Shao Lu
Published: August 2023

Although membrane technology has attracted considerable attention for oily wastewater treatment, the plastic waste generated from discarded membranes presents an immediate challenge for achieving eco-friendly separation. We designed on-demand biodegradable superhydrophilic membranes composed of polylactic acid nanofibers in conjunction with polyethylene oxide hydrogels using electrospinning technology for ultrafast purification of oily water. Our results showed that the use of the polyethylene oxide hydrogels increased the number of hydrogen bonds formed between the membrane surface and water molecules by 357.6%. This converted hydrophobic membranes into superhydrophilic ones, which prevented membrane fouling and accelerated emulsion penetration through the membranes. The oil-in-water emulsion permeance of our newly designed nanofiber membranes increased by 61.9 times (2.1 × 10
4
liters per square meter per hour per bar) with separation efficiency >99.6%, which was superior to state-of-the-art membranes. Moreover, the formation of hydrogen bonds was found to accelerate polylactic acid biodegradation into lactic acid by over 30%, offering a promising approach for waste membrane treatment.
FcγRIIB expressed on CD8+T cells limits responsiveness to PD-1 checkpoint inhibition in cancer
Authors: Bennion Kelsey B. , Tariq Marvi , Wyatt Megan M. , Duneton Charlotte , Baecher Kirsten M. , Paulos Chrystal M. , Kudchadkar Ragini R. , Lowe Michael C. , Ford Mandy L.
Published: August 2023

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8+T cells in the tumors of mice and humans, raising the possibility that CD8+T cell responses may be directly modulated by checkpoint inhibitor binding to T cell–expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIBposCD8+T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBnegCD8+T cells in vitro. Moreover, frequencies of FcγRIIBposCD8+T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8+T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIBposCD8+T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti–PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIBposCD8+T cells, without altering the response of FcγRIIBnegCD8+T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.
Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and
in vivo
efficacy
Authors: Eke Ifeanyichukwu E. , Williams John T. , Haiderer Elizabeth R. , Albrecht Veronica J. , Murdoch Heather M. , Abdalla Bassel J. , Abramovitch Robert B.
Published: August 2023

Nitro-containing compounds have emerged as important agents in the control of tuberculosis (TB). From a whole-cell high-throughput screen for
Mycobacterium tuberculosis
(Mtb) growth inhibitors, 10 nitro-containing compounds were prioritized for characterization and mechanism of action studies. HC2209, HC2210, and HC2211 are nitrofuran-based prodrugs that need the cofactor F
420
machinery for activation. Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F
420
-dependent reductase for activation. These nitrofurans also differ from pretomanid in their potent activity against
Mycobacterium abscessus
. Four dinitrobenzamides (HC2217, HC2226, HC2238, and HC2239) and a nitrofuran (HC2250) are proposed to be inhibitors of decaprenyl-phosphoryl-ribose 2′-epimerase 1 (DprE1), based on isolation of resistant mutations in
dprE1
. Unlike other DprE1 inhibitors, HC2250 was found to be potent against non-replicating persistent bacteria, suggesting additional targets. Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb
in vitro
, but a proposed mechanism of action could not be defined. In a pilot
in vivo
efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.
Profiling of the β-glucosidases identified in the genome of
Penicillium funiculosum
: insights from genomics, transcriptomics, proteomics, and homology-modeling studies
Authors: Okereke Omoaruemike Ebele , Gupta Mayank , Ogunyewo Olusola A. , Sharma Kanika , Kapoor Sonal , Sinha Tulika , Yazdani Syed Shams
Published: August 2023

The enzymatic conversion of lignocellulosic biomass to bioethanol depends on efficient enzyme systems with β-glucosidase as one of the key components. In this study, we performed in-depth profiling of the various β-glucosidases present in the genome of the hypercellulolytic fungus
Penicillium funiculosum
using genomics, transcriptomics, proteomics, and molecular dynamics simulation approaches. Of the eight β-glucosidase genes identified in the
P. funiculosum
genome, three were predicted to be extracellular based on signal peptide prediction and abundance in the secretome. Among the three secreted β-glucosidases, two belonged to the GH3 family and one belonged to the GH1 family. Homology models of these proteins predicted a deep and narrow active site for the GH3 β-glucosidases (
Pf
Bgl3A and
Pf
Bgl3B) and a shallow open active site for the GH1 β-glucosidase (
Pf
Bgl1A). The enzymatic assays indicated that
P. funiculosum
-secreted proteins showed high β-glucosidase activities with prominent bands on the 4‐methylumbelliferyl β‐D‐glucopyranoside zymogram. To understand the contributory effects of each of the three secreted β-glucosidases (
Pf
Bgls), the corresponding gene was deleted separately, and the effect of the deletion on the β-glucosidase activity of the secretome was examined. Although not the most abundant,
Pf
Bgl3A was found to be one of the most important β-glucosidases, as evidenced by a 42% reduction in β-glucosidase activity in the Δ
Pf
Bgl3A strain. Our results advance the understanding of the genetic and biochemical nature of all β-glucosidases produced by
P. funiculosum
and pave the way to design a superior biocatalyst for the hydrolysis of lignocellulosic biomass.

IMPORTANCE

Commercially available cellulases are primarily produced from
Trichoderma reesei
. However, external supplementation of the cellulase cocktail from this host with exogenous β-glucosidase is often required to achieve the desired optimal saccharification of cellulosic feedstocks. This challenge has led to the exploration of other cellulase-producing strains. The nonmodel hypercellulolytic fungus
Penicillium funiculosum
has been studied in recent times and identified as a promising source of industrial cellulases mainly due to its ability to produce a balanced concoction of cellulolytic enzymes, including β-glucosidases. Various genetic interventions targeted at strain improvement for cellulase production have been performed; however, the β-glucosidases of this strain have remained largely understudied. This study, therefore, reports profiling of all eight β-glucosidases of
P. funiculosum
via molecular and computational approaches. The results of this study provide useful insights that will establish the background for future engineering strategies to transform this fungus into an industrial workhorse.
Draft genome sequence of yeast
Vanrija
sp. strain TS01, isolated from leukemia patient’s urine
Authors: Meng Lingning , Liu Chang , Zhu Liguo , Wang Xinlei , Li Chuchu
Published: August 2023

Vanrija
sp. strain TS01 was isolated from urine sample from a leukemia patient in Nanjing, China. The closest known relative strain is
Vanrija humicol
a with average nucleotide identity value of 93.1. The draft genome comprises 22.0 Mb in 52 contigs, with G + C content of 62.57%.
Mode of action of antimicrobial agents albofungins in eradicating penicillin- and cephalosporin-resistant
Vibrio parahaemolyticus
biofilm
Authors: She Weiyi , Cheng Aifang , Ye Wenkang , Zeng Ping , Wang Hao , Qian Pei-Yuan
Published: August 2023

Albofungin is a promising broad-spectrum antimicrobial compound against multidrug-resistant bacteria. In the present study, we further investigated albofungin’s biofilm eradication activity and its potential mode of action against drug-resistant
Vibrio parahaemolyticus
. Among all derivatives, albofungin exhibited the best antibiofilm and antibacterial activity with rapid killing effects at 0.12 µg mL
−1
. Confocal microscopy observation exhibited that albofungin disrupted
V. parahaemolyticus
biofilms by killing or dispersing biofilm cells. Meanwhile, scanning electron microscope and fluorescent staining experiments demonstrated that albofungin rapidly destroyed the integrity and permeability of the bacterial cell membrane. Moreover, this study revealed an antibiofilm mechanism of albofungin involving inhibition of peptidoglycan biosynthesis, flagella assembly pathways, and secretion system proteins in
V. parahaemolyticus
by quantitative proteomics and validation experiments. Our results highlighted albofungin’s mechanism of action in planktonic cells and biofilms and suggested further development and potential applications of albofungin for treating infections caused by penicillins-and-cephalosporins-resistant
V. parahaemolyticus
.

IMPORTANCE

Infections caused by multidrug-resistant bacteria, as well as a scarcity of new antibiotics, have become a major health threat worldwide. To tackle the demand for new and effective treatments, we investigated the mechanism of action of albofungin, a natural product derived from
Streptomyces
, which exhibits potent antimicrobial activity against multidrug-resistant bacteria. Albofungin showed potent biofilm eradication activity against penicillins-and-cephalosporins-resistant
Vibrio parahaemolyticus
, which expresses a novel metallo-β-lactamase and, thus, reduces their sensitivity to various antibiotics. We observed membrane disruption and permeation mechanisms in planktonic cells and biofilms after albofungin treatment, while albofungin had a weak interaction with bacterial DNA. Moreover, the antibiofilm mechanism of albofungin included inhibition of peptidoglycan biosynthesis, flagellar assembly pathways, and secretion system proteins. Our finding suggested potential applications of albofungin as an antibacterial and antibiofilm therapeutic agent.
Constraining the elemental stoichiometry of early marine life
Authors: Fakhraee Mojtaba , Tarhan Lidya G. , Reinhard Christopher T. , Planavsky Noah J.
Published: August 2023

The relative proportions of carbon, nitrogen, and phosphorus, commonly referred to as the Redfield ratio (106:16:1), have likely varied dramatically through Earth’s history in response to changes in oceanic redox state and nutrient availability. However, there have been few attempts to track long-term secular patterns in the elemental stoichiometry of marine life. We use a sediment reactive-transport (diagenetic) modeling approach to provide new constraints on the elemental stoichiometry of marine ecosystems during Earth’s early history, by simulating environmental conditions associated with the formation and deposition of suites of Archean sedimentary iron and phosphorus-bearing minerals. Our results suggest that siderite formation in porewaters linked to dissimilatory iron reduction but limited formation of authigenic P phases can only be reproduced when C to P ratios in marine biomass are at least 500 (mol/mol), approximately five times higher than the values that characterize the modern ocean. This constraint indicates that Archean oceans were strongly nutrient-limited.
History information management strategy for minimising biases and noise for improved medical diagnosis
Authors: Shimizu Taro , Dror Itiel E
Published: August 2023

Despite measures for physicians’ excellence in diagnosis, the need for improvement of medical history techniques has been pointed out as one of the critical elements for improving diagnosis. Specific and proactive frameworks related to methods of effective history acquisition are needed to minimise bias and optimise decision-making. Therefore, this paper uses Linear Sequential Unmasking- Expanded to develop and propose a structured medical history acquisition strategy. The strength of this lies in its reliance on cognitive psychological processes. Breaking information gatherings and decisions into smaller tasks and ordering them correctly reduces cognitive load as well as minimises noise and bias cascade. Additionally, this approach can help physicians develop diagnostic expertise regardless of specialty.
Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration
Authors: Bertels Xander , Edris Ahmed , Garcia-Aymerich Judith , Faner Rosa , Meteran Howraman , Sigsgaard Torben , Alter Peter , Vogelmeier Claus , Olvera Nuria , Kermani Nazanin Zounemat , Agusti Alvar , Donaldson Gavin C , Wedzicha Jadwiga A , Brusselle Guy G , Backman Helena , Rönmark Eva , Lindberg Anne , Vonk Judith M , Chung Kian Fan , Adcock Ian M , van den Berge Maarten , Lahousse Lies
Published: August 2023

Background

The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts.

Methods

This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model.

Results

The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI.

Conclusions

AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.
Abstracts from international emergency medicine journals
Authors: Production EMJ
Published: August 2023

Editor’s note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication.
hMENA isoforms regulate cancer intrinsic type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade in NSCLC
Authors: Trono Paola , Tocci Annalisa , Palermo Belinda , Di Carlo Anna , D'Ambrosio Lorenzo , D'Andrea Daniel , Di Modugno Francesca , De Nicola Francesca , Goeman Frauke , Corleone Giacomo , Warren Sarah , Paolini Francesca , Panetta Mariangela , Sperduti Isabella , Baldari Silvia , Visca Paolo , Carpano Silvia , Cappuzzo Federico , Russo Vincenzo , Tripodo Claudio , Zucali Paolo , Gregorc Vanesa , Marchesi Federica , Nistico Paola
Published: August 2023

Background

Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA11aisoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA11adownregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA11adownregulation.

Methods

Effects of hMENA11adownregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort.

Results

Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA11ainduces IFN pathway activation, the production of different inflammatory mediators including IFNβviaRIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA11a, high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy.

Conclusions

Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA11ain modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC.
Saponin-based adjuvants enhance antigen cross-presentation in human CD11c+CD1c+CD5−CD163+conventional type 2 dendritic cells
Authors: Ho Nataschja I , Huis in 't Veld Lisa G M , van Eck van der Sluijs Jesper , Heuts Branco M H , Looman Maaike W G , Kers-Rebel Esther D , van den Dries Koen , Dolstra Harry , Martens Joost H A , Hobo Willemijn , Adema Gosse J
Published: August 2023

Background

Adjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition to antibody responses. Recent preclinical studies revealed that SBAs induced cross-presentation and lipid bodies in otherwise poorly cross-presenting CD11b+murine dendritic cells (DCs).

Method

Here, we investigated the response of human DC subsets to SBAs with RNA sequencing and pathway analyses, lipid body induction visualized by laser scanning microscopy, antigen translocation to the cytosol, and antigen cross-presentation to CD8+T cells.

Results

RNA sequencing of SBA-treated conventional type 1 DC (cDC1) and type 2 DC (cDC2) subsets uncovered that SBAs upregulated lipid-related pathways in CD11c+CD1c+cDC2s, especially in the CD5−CD163+CD14+cDC2 subset. Moreover, SBAs induced lipid bodies and enhanced endosomal antigen translocation into the cytosol in this particular cDC2 subset. Finally, SBAs enhanced cross-presentation only in cDC2s, which requires the CD163+CD14+cDC2 subset.

Conclusions

These data thus identify the CD163+CD14+cDC2 subset as the main SBA-responsive DC subset in humans and imply new strategies to optimize the application of saponin-based adjuvants in a potent cancer vaccine.
Does industry funding and study location impact findings from randomized controlled trials of spinal cord stimulation? A systematic review and meta-analysis
Authors: Eldabe Sam , Nevitt Sarah , Copley Sue , Maden Michelle , Goudman Lisa , Hayek Salim , Mekhail Nagy , Moens Maarten , Rigoard Phillipe , Duarte Rui
Published: August 2023

Background/importance

Concerns have been raised that effects observed in studies of spinal cord stimulation (SCS) funded by industry have not been replicated in non-industry-funded studies and that findings may differ based on geographical location where the study was conducted.

Objective

To investigate the impact of industry funding and geographical location on pain intensity, function, health-related quality of life and adverse events reported in randomized controlled trials (RCTs) of SCS.

Evidence review

Systematic review conducted using MEDLINE, CENTRAL, EMBASE and WikiStim databases until September 2022. Parallel-group RCTs evaluating SCS for patients with neuropathic pain were included. Results of studies were combined in random-effects meta-analysis using the generic-inverse variance method. Subgroup meta-analyses were conducted according to funding source and study location. Risk of bias was assessed using Cochrane RoB 2.0 tool.

Findings

Twenty-nine reports of 17 RCTs (1823 participants) were included. For the comparison of SCS with usual care, test for subgroup differences indicate no significant differences (p=0.48, moderate certainty evidence) in pain intensity score at 6 months for studies with no funding or funding not disclosed (pooled mean difference (MD) −1.96 (95% CI −3.23 to −0.69; 95% prediction interval (PI) not estimable, I2=0%, τ2=0)), industry funding (pooled MD −2.70 (95% CI −4.29 to −1.11; 95% PI −8.75 to 3.35, I2=97%, τ2=2.96) or non-industry funding (MD −3.09 (95% CI −4.47 to −1.72); 95% PI, I2and τ2not applicable). Studies with industry funding for the comparison of high-frequency SCS (HF-SCS) with low-frequency SCS (LF-SCS) showed statistically significant advantages for HF-SCS compared to LF-SCS while studies with no funding showed no differences between HF-SCS and LF-SCS (low certainty evidence).

Conclusion

All outcomes of SCS versus usual care were not significantly different between studies funded by industry and those independent from industry. Pain intensity score and change in pain intensity from baseline for comparisons of HF-SCS to LF-SCS seem to be impacted by industry funding.
Cerebral venous sinus thrombosis: changing trends in the incidence, age and gender (findings from the CMC Vellore CVT registry)
Authors: Miraclin T Angel , Prasad John Davis , Ninan George Abraham , Gowri Mahasampath , Bal Deepti , Shaikh Atif Iqbal Ahmed , Benjamin Rohit N , Prabhakar Appaswamy Thirumal , Sivadasan Ajith , Mathew Vivek , Aaron Sanjith
Published: August 2023

Background

Multiple cerebral venous sinus thrombosis (CVT) registries from various geographical regions indicate that female gender, the use of contraceptive pills, pregnancy and puerperium are important risk factors. In this study, we report the changes in the epidemiology of patients with CVT managed over the past 26 years.

Methods

The CMC Vellore CVT registry is a prospectively maintained database at the Christian Medical College, Vellore since January 1995. Stata software was used to analyse the data and assess the changes in the incidence, age and gender distribution over the previous 26 years.

Results

Among 1701 patients treated during the study period, 908 (53%) were women and 793 (47%) were men. The mean incidence of CVT was 49 per 100 000 admissions before 2010, which increased to 96 per 100 000 after 2010. Male gender had a higher odds of developing CVT (OR – 2.07 (CI 1.68 to 2.55, p<.001). This could be attributed to the declining incidence of postpartum CVT after 2010 compared with the decade before 2010 (50% vs 20%). The mean age at presentation had increased from 24.5 to 33.2 years in the last decade.

Conclusions

There was a clear change in the gender pattern from being a condition with female preponderance, to one where equal or more men are being affected. Lower incidence of postpartum CVT cases could be the driving factor. An increase in the overall incidence of CVT cases was noted, probably due to a higher index of clinical suspicion and better diagnostic imaging modalities.
The ideals of the monoid of all orientation-preserving extensive full transformations
Authors: Zhao Ping , Hu Huabi
Published: August 2023

Let [Formula: see text] be the monoid of all orientation-preserving and extensive full transformations on [Formula: see text]. In this paper, we compute the rank and the idempotent rank of the ideals of the monoid [Formula: see text]. Moreover, we determine the maximal subsemigroups as well as the maximal subsemibands of the ideals of the monoid [Formula: see text]. Our work extends previous results found in the literature.
Heads-Up Computing Moving Beyond the Device-Centered Paradigm
Authors: Zhao Shengdong , Tan Felicia , Fennedy Katherine
Published: August 2023

Developing tools that better complement natural human capabilities to support a more human-centered vision.
Distilling What We Know
Authors: Greengard Samuel
Published: August 2023

Researchers look to cut large GPT models down to size.
How Many Ways Can You Teach a Robot?
Authors: Hoffmann Leah
Published: August 2023

ACM Prize recipient Pieter Abbeel is working to help robots learn, and learn to improve.
Closing Our Digital Divides
Authors: Narechania Tejas N.
Published: August 2023

Seeking a more efficient path to improved broadband Internet access.
Coming of Age
Authors: Zanero Stefano
Published: August 2023

Stressing the importance of threat models.
Fairness in Machine Learning: A Survey
Authors: Caton Simon , Haas Christian
Published: August 2023

When Machine Learning technologies are used in contexts that affect citizens, companies as well as researchers need to be confident that there will not be any unexpected social implications, such as bias towards gender, ethnicity, and/or people with disabilities. There is significant literature on approaches to mitigate bias and promote fairness, yet the area is complex and hard to penetrate for newcomers to the domain. This article seeks to provide an overview of the different schools of thought and approaches that aim to increase the fairness of Machine Learning. It organizes approaches into the widely accepted framework of pre-processing, in-processing, and post-processing methods, subcategorizing into a further 11 method areas. Although much of the literature emphasizes binary classification, a discussion of fairness in regression, recommender systems, and unsupervised learning is also provided along with a selection of currently available open source libraries. The article concludes by summarizing open challenges articulated as five dilemmas for fairness research.