bluuebunny/crossref_metadata_2025 huggingface dataset:
Phage single-stranded DNA-binding protein or host DNA damage triggers the activation of the AbpAB phage defense system
Authors: Sasaki Takaomi , Takita Saya , Fujishiro Takashi , Shintani Yunosuke , Nojiri Satoki , Yasui Ryota , Yonesaki Tetsuro , Otsuka Yuichi
Published: October 2023

Bacteria have developed various defense mechanisms against phages. Abortive infection (Abi), a bacterial defense mechanism, can be achieved through various means, including toxin-antitoxin systems, cyclic oligonucleotide-based antiphage signaling systems, and retrons. AbpA and AbpB (AbpAB) defend against many lytic phages harboring double-stranded DNA genomes in
Escherichia coli
; however, how AbpAB senses phage infection and inhibits its propagation remains unclear. Here, we demonstrated that AbpAB inhibited the growth of the φX174 lytic phage with single-stranded DNA (ssDNA) as well as the lysogenization and induction of the Sakai prophage 5 lysogenic phage. The AbpAB defense system limits T4 and φX174 phage propagation via Abi. AbpA contains a nuclease domain at its N-terminus, and AbpB has an ATP-dependent RNA helicase domain; both domains are required for phage defense. This system is activated by phage Gp32 binding to ssDNA and inhibits
E. coli
growth. Without phage infection, DNA replication inhibitors or defects in the DNA repair factors RecB and RecC activate this system. Therefore, the
E. coli
AbpAB defense system may sense DNA-protein complexes, including the phage-encoded ssDNA-binding protein or those formed by interrupting host DNA replication or repair.

IMPORTANCE

Although numerous phage defense systems have recently been discovered in bacteria, how these systems defend against phage propagation or sense phage infections remains unclear. The
Escherichia coli
AbpAB defense system targets several lytic and lysogenic phages harboring DNA genomes. A phage-encoded single-stranded DNA-binding protein, Gp32, activates this system similar to other phage defense systems such as Retron-Eco8, Hachiman, ShosTA, Nhi, and Hna. DNA replication inhibitors or defects in DNA repair factors activate the AbpAB system, even without phage infection. This is one of the few examples of activating phage defense systems without phage infection or proteins. The AbpAB defense system may be activated by sensing specific DNA-protein complexes.
Landscape of gut microbiota and metabolites and their interaction in comorbid heart failure and depressive symptoms: a random forest analysis study
Authors: Huang Kai , Duan Jiahao , Wang Ruting , Ying Hangfeng , Feng Qinwen , Zhu Bin , Yang Chun , Yang Ling
Published: October 2023

Depression is an individual risk factor for poor prognosis in patients with heart failure (HF). Recent studies show that gut microbiota and metabolites play a critical role in comorbid HF and depressive symptoms. We recruited 95 subjects including 35 HF patients with depressive symptoms (HF-DS), 36 HF patients without depressive symptoms (HF-NDS), and 24 healthy controls (HC). The 16S rRNA, metagenome sequencing, and untargeted metabolomic analysis were employed to test fecal samples. Our analysis found a significant difference in composition of gut microbiota in HF-DS, HF-NDS, and HC populations. At the genus level,
Mediterranea
,
Tolumona
, and
Parabacteroides
were significantly increased in HF-DS patients compared with HF-NDS patients, while
Pedobacter
,
Azospirillum
, and
Ruminiclostridium
were significantly decreased. Furthermore, anti-inflammatory mediators (abietic acid, quinic acid, linoleic acid, etc.) and neurotransmitters (catechin, serotonin, tryptamine, phenylethylamine, etc.) were reduced in HF-DS. The enrichment analysis revealed that the gut microbiota highly conformed to the functional pathways of metabolites, and amino acid-related metabolism, fatty acid-related metabolism, and cAMP signaling pathways may be crucial biological mechanisms involved in the development of comorbid depression and HF. Finally,
Cloacibacillus
and alpha-tocopherol were determined as diagnostic markers for HF-DS patients.

IMPORTANCE

There is increasing evidence that alterations in gut microbial composition and function are associated with cardiovascular or psychiatric disease. Therefore, it is meaningful to investigate the taxonomic and functional characterization of the microbiota in HF patients who also have depressive symptoms. In this cross-sectional study,
Cloacibacillus
and alpha-tocopherol were determined as new diagnostic markers. Furthermore, intestinal microecosystem disorders are closely linked to depressive symptoms in HF patients, providing a new reference viewpoint for understanding the gut-heart/brain axis.
Oral lactoferrin administration does not impact the diversity or composition of the infant gut microbiota in a Peruvian cohort
Authors: González Luis , Paredes Sosa Jose Luis , Mosquito Susan , Filio Yesenia , Romero Pedro E. , Ochoa Theresa J. , Tsukayama Pablo
Published: October 2023

Lactoferrin is a protein from breast milk involved in early-life microbiome assembly. It is believed to promote the growth of lactic acid-producing bacteria and inhibit pathogens by limiting iron availability and enabling an acidic environment in the gut. Previous reports suggest that oral administration of lactoferrin in neonates promotes the increase of gut microbiota diversity and the enrichment of beneficial microbes. However, its effect on infant gut microbiota over time has yet to be thoroughly studied to fully understand its potential as a prebiotic. Using 16s rRNA gene amplicon sequencing, we analyzed the gut microbiota composition of 60 toddlers at 12–18 months of age from Lima, Peru, who received daily oral administration of lactoferrin or placebo for 6 months since enrollment. Samples were analyzed at 0, 2, and 4 months after beginning treatment. Our results show that lactoferrin treatment does not increase gut microbiota diversity over time nor affect its bacterial composition compared to the placebo group.

IMPORTANCE

Previous studies have suggested that oral lactoferrin enhances diversity in the gut microbiota in infants while inhibiting the growth of opportunistic pathogens. However, the effect of lactoferrin on infant gut microbiota over time has yet to be thoroughly studied. Our study suggests that lactoferrin oral treatment in infants aged 12–18 months does not affect gut microbiome diversity and composition over time. To our knowledge, this is the first study to report the effect of lactoferrin on infant gut microbiome composition over time and helps elucidate its impact on infant health and its therapeutic potential.
L-glutamine sensitizes Gram-positive-resistant bacteria to gentamicin killing
Authors: Fan Lvyuan , Pan Zhiyu , Zhong Yilin , Guo Juan , Liao Xu , Pang Rui , Xu Qingqiang , Ye Guozhu , Su Yubin
Published: October 2023

Because of the stubborn resistance to antibiotics, treating clinically resistant bacteria is a tricky business. Although considerable attention has been devoted to preventing and treating infections from drug-resistant bacteria, few studies are available on combining metabolites and antibiotics to combat methicillin-resistant
Staphylococcus aureus
(MRSA). This study found that exogenous L-glutamine potentiated aminoglycoside (gentamicin)-mediated killing efficacy in a dose- and time-dependent manner in MRSA (USA300 cell line) and other Gram-positive-resistant bacteria including MRSA 252,
Listeria monocytogenes
, and
Corynebacterium diphtheriae
. L-glutamine promoted the uptake of gentamicin through increasing the membrane permeability and was correlated with disrupted pH gradient. Furthermore, L-glutamine decreased intracellular reactive oxygen species by glutathione, which also increased USA300 sensitivity to gentamicin. We also demonstrated that combined treatment with gentamicin and L-glutamine enhanced the survival of MRSA-infected mice. In conclusion, we developed a promising therapeutic strategy for treating Gram-positive-resistant bacterial infections.

IMPORTANCE

Methicillin-resistant
Staphylococcus aureus
(MRSA) infection severely threatens human health due to high morbidity and mortality; it is urgent to develop novel strategies to tackle this problem. Metabolites belong to antibiotic adjuvants which improve the effect of antibiotics. Despite reports of L-glutamine being applied in antibiotic adjuvant for Gram-negative bacteria, how L-glutamine affects antibiotics against Gram-positive-resistant bacteria is still unclear. In this study, L-glutamine increases the antibacterial effect of gentamicin on MRSA, and it links to membrane permeability and pH gradient (ΔpH), resulting in uptake of more gentamicin. Of great interest, reduced reactive oxygen species (ROS) by glutathione was found under L-glutamine treatment; USA300 becomes sensitive again to gentamicin. This study not only offers deep understanding on ΔpH and ROS on bacterial resistance but also provides potential treatment solutions for targeting MRSA infection.
Self-assembling a 1,4-dioxane-degrading consortium and identifying the key role of
Shinella
sp. through dilution-to-extinction and reculturing
Authors: Tian Kun , Zhang Yue , Chen Ruihuan , Tan Ding , Zhong Ming , Yao Dandan , Dong Yuanhua , Liu Yun
Published: October 2023

Assembling a functional consortium and identifying novel degraders from contaminated environments are still challenging due to the large diversity of microorganisms and the difficulty in isolating pure cultures. Here, we constructed a relatively simple functional consortium by enriching 1,4-dioxane-degrading-consortia using a culture-dependent dilution-to-extinction (DTE) method and reported a new key dioxane-degrader
Shinella
sp. Our results showed that serial dilution and reculture led to a divergence in the degradation ability of each consortium. Next-generation sequencing data revealed that the divergence in degradation performance was due to the reassembly of microbiota in the DTE process, which occurred most notably in 10
−8
and 10
−9
dilutions. The shift in community structure at 10
−9
prevented the recovery of 1,4-dioxane degradation capacity, and the newly dominant taxa,
Xanthobacter
and
Acinetobacter
, struggled to replace the original dominant genus
Shinella
for 1,4-dioxane biodegradation. Combining differential analysis of community structure and metabolic function, we confirmed that
Shinella
species have a stronger 1,4-dioxane degradation ability than
Xanthobacter
species in the enriched consortium. In addition, we verified our findings using our isolated dioxane-degrading bacteria,
Shinella yambaruensis
, resulting in the rapid recovery of degradation performance of a 10
−9
dilution consortium with
Xanthobacter
and
Acinetobacter
as the dominant microbiota. Taken together, this study provides a strategy for self-assembling functional consortiums and identifying the key degraders to explore the underlying biological mechanisms of enriched contaminant-degrading consortia.

IMPORTANCE

Assembling a functional microbial consortium and identifying key degraders involved in the degradation of 1,4-dioxane are crucial for the design of synergistic consortia used in enhancing the bioremediation of 1,4-dioxane-contaminated sites. However, due to the vast diversity of microbes, assembling a functional consortium and identifying novel degraders through a simple method remain a challenge. In this study, we reassembled 1,4-dioxane-degrading microbial consortia using a simple and easy-to-operate method by combining dilution-to-extinction and reculture techniques. We combined differential analysis of community structure and metabolic function and confirmed that Shinella species have a stronger 1,4-dioxane degradation ability than Xanthobacter species in the enriched consortium. In addition, a new dioxane-degrading bacterium was isolated,
Shinella yambaruensis
, which verified our findings. These results demonstrate that DTE and reculture techniques can be used beyond diversity reduction to assemble functional microbial communities, particularly to identify key degraders in contaminant-degrading consortia.
A novel
TRIM22
gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B
Authors: Wang Long , Lin Ni , Zhang Yanfang , Guo Shaoying , Liu Can , Lin Caorui , Zeng Yongbin , Wu Wennan , Guo Jianhui , Zhu Chenggong , Zhan Fuguo , Ou Qishui , Xun Zhen
Published: October 2023

Objectives: Pegylated interferon alfa (PegIFNα) has limited efficacy in patients with chronic hepatitis B (CHB). Because single-nucleotide polymorphisms (SNPs) are known to confer disease susceptibility and influence treatment response, we aimed to identify novel tripartite motif-containing 22 (TRIM22) SNPs that were associated with therapeutic efficacy in patients with CHB after PegIFNα treatment. Samples from 107 patients with CHB were genotyped using Asian Screening Array gene chips. The related mechanisms of SNPs screened were explored through both cell experiments and RNA sequence methods.
TRIM22
was the most upregulated upon stimulation with PegIFNα. Specifically, the SNP rs10838543 CC genotype in
TRIM22
was found to be associated with the positive response to PegIFNα treatment. The SNP rs10838543 CC genotype in
TRIM22
was more stable and more robustly inhibited hepatitis B virus (HBV) replication in HepAD38 cells compared to the TT genotype. Mechanistically, we showed that the cytokine-cytokine receptor interaction signaling pathway was significantly upregulated in HepAD38 cells stably expressing the SNP rs10838543 CC genotype of
TRIM22
compared to the TT genotype after PegIFNα treatment and that the SNP rs10838543 CC genotype in
TRIM22
enhanced PegIFNα-induced anti-HBV activity by inducing the secretion of IFNL1, CCL3, and CCL5. The SNP rs10838543 CC genotype in
TRIM22
increased the secretion of the cytokines IFNL1, CCL3, and CCL5 from hepatocytes by regulating the cytokine-cytokine receptor interaction signaling pathway and was positively correlated with the PegIFNα-induced treatment response in patients with CHB. Our findings suggest that genotyping patients with CHB for the SNP rs10838543 in
TRIM22
may be a useful biomarker to help physicians identify patients who are most likely to benefit from PegIFNα treatment.

IMPORTANCE

Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.
Resistance mechanisms for Gram-negative bacteria-specific lipopeptides, turnercyclamycins, differ from that of colistin
Authors: Lim Albebson L. , Miller Bailey W. , Lin Zhenjian , Fisher Mark A. , Barrows Louis R. , Haygood Margo G. , Schmidt Eric W.
Published: October 2023

Turnercyclamycin A and B lipopeptides exhibit Gram-negative bacteria-specific toxicity. This includes CDC urgent threat organisms such as multidrug-resistant
Acinetobacter baumannii
. Like the last-line agent colistin, turnercyclamycins interact with the lipopolysaccharide (LPS) pathway, but they remain active against clinical isolates that are colistin resistant. Here, we aimed to determine why turnercyclamycins A and B show little cross-resistance with colistin despite some potential mechanistic and structural similarities. The outer membrane was important in the actions of all three agents, since the deletion of
lpxC
that synthesizes LPS and the addition of exogenous LPS led to resistance to turnercyclamycins and colistin. Even so, it was much more difficult to generate resistance to turnercyclamycin A than turnercyclamycin B. In
Escherichia coli
, disruption of the
mlaA
gene, which is involved in outer membrane homeostasis, resulted in resistance to turnercyclamycin B. However,
mlaA
disruption blocked neither turnercyclamycin A nor colistin activity. This activity was recapitulated in
A. baumannii
, where transposon mutants were more resistant to turnercyclamycin B. Moreover, the common
A. baumannii
colistin resistance gene
mcr-1
blocked colistin activity in
E. coli
but did not affect turnercyclamycins. These results demonstrate a unique resistance profile for turnercyclamycins A and B, in addition to suggesting differences in the mechanism of action. Further, turnercyclamycin A was effective in a mouse model of
A. baumannii
infection, indicating that this compound class may have potential promise in treating drug-resistant infections.

IMPORTANCE

Bacterial resistance to antibiotics is a crisis.
Acinetobacter baumannii
is among the CDC urgent threat pathogens in part for this reason. Lipopeptides known as turnercyclamycins are produced by symbiotic bacteria that normally live in marine mollusks, where they may be involved in shaping their symbiotic niche. Turnercyclamycins killed Gram-negative pathogens including drug-resistant
Acinetobacter
, but how do the mechanisms of resistance compare to other lipopeptide drugs? Here, we define resistance from a truncation of MlaA, a protein involved in regulating bacterial membrane phospholipids. Intriguingly, this resistance mechanism only affected one turnercyclamycin variant, which differed only in two atoms in the lipid tail of the compounds. We could not obtain significant resistance to the second turnercyclamycin variant, which was also effective in an infection model. This study reveals an unexpected subtlety in resistance to lipopeptide antibiotics, which may be useful in the design and development of antibiotics to combat drug resistance.
Broad-range capsule-dependent lytic
Sugarlandvirus
against
Klebsiella
sp.
Authors: Concha-Eloko Robby , Barberán-Martínez Pilar , Sanjuán Rafael , Domingo-Calap Pilar
Published: October 2023

The emergence of antibiotic-resistant bacteria has become a serious global health threat requiring the development of novel treatments.
Klebsiella pneumoniae
is an encapsulated bacterium considered a major concern due to its high resistance, prevalence, and mortality rates. Phage therapy has been proposed as a very promising alternative to combat infections by
Klebsiella
sp. infections. However, most of the
Klebsiella
phages described so far present a high specificity, infecting one or a few capsular types due to the presence of depolymerases in their genomes, which limits their therapeutic potential. Here, we present three new
Klebsiella
phages isolated from the environment, vB_Kpn_K7PH164C4, vB_Kpn_K30λ2.2, and vB_Kpl_K32PH164C1, belonging to the family
Demerecviridae
and the genus
Sugarlandvirus
. The most important feature of these new
Klebsiella
phages is their broad host range, especially vB_Kpn_K7PH164C4 and vB_Kpn_K30λ2.2, which infects strains of more than 20 different capsular types, representing the broadest infection range observed for
Klebsiella
phages. Genomic analysis revealed the presence of three receptor-binding proteins lacking depolymerase domains. Nevertheless, capsule expression is suggested to be a determining factor in phage infectivity, despite the absence of depolymerase activity against capsular components. Our findings hold potential for the development of promising phage-based therapeutics directed against
K. pneumoniae
.

IMPORTANCE

The emergence of multi-drug resistant bacteria is a global health problem. Among them,
Klebsiella pneumoniae
is considered a high-priority pathogen, making it necessary to develop new therapeutic tools to reduce the bacterial burden in an effective and sustainable manner. Phages, bacterial viruses, are very promising tools. However, phages are highy specific, rendering large-scale therapeutics costly to implement. This is especially certain in
Klebsiella
, a capsular bacterium in which phages have been shown to be capsular type dependent, infecting one or a few capsular types through specific enzymes called depolymerases. In this study, we have isolated and characterized novel phages with lytic ability against bacteria from a wide variety of capsular types, representing the
Klebsiella
phages with the widest range of infection described. Remarkably, these broad-range phages showed capsule dependency, despite the absence of depolymerases in their genomes, implying that infectivity could be governed by alternative mechanisms yet to be uncovered.
No evidence for a volcanic trigger for late Cambrian carbon-cycle perturbations
Authors: Frieling J. , Mather T.A. , Fendley I.M. , Jenkyns H.C. , Zhao Z. , Dahl T.W. , Bergquist B.A. , Cheng K. , Nielsen A.T. , Dickson A.J.
Published: October 2023

The early Paleozoic was marked by several carbon-cycle perturbations and associated carbon-isotope excursions (CIEs). Whether these CIEs are connected to significant (external) triggers, as is commonly considered to be the case for CIEs in the Mesozoic and Cenozoic, or result from small carbon-cycle imbalances that became amplified through lack of efficient silicate weathering or other feedbacks remains unclear. We present concentration and isotope data for sedimentary mercury (Hg) and osmium (Os) to assess the impact of subaerial and submarine volcanism and weathering during the late Cambrian and early Ordovician. Data from the Alum Shale Formation (Sweden) cover the Steptoean positive carbon-isotope excursion (SPICE; ca. 497–494 Ma), a period marked by marine anoxia and biotic overturning, and several smaller CIEs extending into the early Ordovician. Our Hg and Os data offer no strong evidence that the CIEs present in our record were driven by (globally) elevated volcanism or continental weathering. Organic-carbon and Hg concentrations covary cyclically, providing further evidence of an unperturbed Hg cycle. Mesozoic and Cenozoic CIEs are commonly linked to enhanced volcanic activity and weathering, but similar late Cambrian–early Ordovician events cannot easily be connected to such external triggers. Our results are more consistent with reduced early Paleozoic carbon-cycle resilience that allowed small imbalances to develop into large CIEs.
Clumped isotope evidence for microbial alteration of thermogenic methane in terrestrial mud volcanoes
Authors: Liu Jiarui , Treude Tina , Abbasov Orhan R. , Baloglanov Elnur E. , Aliyev Adil A. , Harris Carolynn M. , Leavitt William D. , Young Edward D.
Published: October 2023

Methane in oil reservoirs originates mostly from thermogenic sources, yet secondary microbial methane production from petroleum biodegradation is known to be pervasive. The conventional approach for identifying this secondary microbial methane commonly relies on geochemical characteristics of other gas molecules such as the carbon isotopic composition of carbon dioxide and propane. This information is sometimes obscured by isotopic variations in source material and may not be available in certain geological reservoirs. To better constrain the presence of secondary microbial methane, we studied the clumped isotopologue compositions of methane in terrestrial Azerbaijanian mud volcanoes, which support the occurrence of secondary microbial gas. Here, a deficit in Δ12CH2D2 of thermogenic methane occurs due to different δD of hydrogen sources that contribute to the formation of methane molecules (i.e., combinatorial effect). The Δ12CH2D2 is expected to move toward equilibrium as thermal maturity increases. More importantly, both Δ13CH3D and Δ12CH2D2 values of methane approach low-temperature thermodynamic equilibrium in most gases, suggesting that the original thermogenic methane has been altered by newly formed microbial methane in addition to isotope exchange among methane molecules catalyzed by the methyl-coenzyme M reductase enzyme. We conclude that methane clumped isotopes provide a unique proxy for identifying secondary microbial methane and understanding the exact evolution stages for natural gases.
Healthcare professionals’ perspectives of the provision of, and challenges for, eating, drinking and psychological support post stroke: findings from semistructured interviews across India
Authors: Jones Stephanie P , Injety Ranjit J , Pandian Jeyaraj D , Ratra Sanjali , Sylaja PN , Babu Veena , Srivastava MV Padma , Sharma Sakshi , Sharma Sudhir , Webster Jemin , Koirala Amrit , Kaushal Pawna , Kulkarni Girish Baburao , Dixit Anand , Sharma Arvind , Prajapati Jagruti , Weldon Jo Catherine , Kuroski Jennifer A , Watkins Caroline Leigh , Lightbody Catherine Elizabeth
Published: October 2023

Aim

This qualitative study explores with health professionals the provision of, and challenges for, postdischarge stroke care, focussing on eating, drinking and psychological support across India.

Design

Qualitative semistructured interviews.

Setting

Seven geographically diverse hospitals taking part in a Global Health Research Programme on Improving Stroke Care in India.

Participants

A purposive sample of healthcare professionals with current experience of working with patients who had a stroke.

Results

Interviews with 66 healthcare professionals (23 nurses (14 staff nurses; 7 senior nurse officers; 1 intensive care unit nurse; 1 palliative care nurse)); 16 doctors (10 neurologists; 6 physicians); 10 physiotherapists; 5 speech and language therapists; 4 occupational therapists; 4 dieticians; 2 psychiatrists; and 2 social workers resulted in three main themes: integrated inpatient discharge care planning processes; postdischarge patient and caregiver role and challenges; patient and caregiver engagement post discharge.

Conclusions

Discharge planning was integrated and customised, although resources were limited in some sites. Task shifting compensated for a lack of specialists but was limited by staff education and training. Caregivers faced challenges in accessing and providing postdischarge care. Postdischarge care was mainly hospital based, supported by teleservices, especially for rural populations. Further research is needed to understand postdischarge care provision and the needs of stroke survivors and their caregivers.
MCT4 blockade increases the efficacy of immune checkpoint blockade
Authors: Babl Nathalie , Decking Sonja-Maria , Voll Florian , Althammer Michael , Sala-Hojman Ada , Ferretti Roberta , Korf Clarissa , Schmidl Christian , Schmidleithner Lisa , Nerb Benedikt , Matos Carina , Koehl Gudrun E , Siska Peter , Bruss Christina , Kellermeier Fabian , Dettmer Katja , Oefner Peter J , Wichland Marvin , Ugele Ines , Bohr Christopher , Herr Wolfgang , Ramaswamy Shivapriya , Heinrich Timo , Herhaus Christian , Kreutz Marina , Renner Kathrin
Published: October 2023

Background & Aims

Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.

Methods

To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).

Results

Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.

Conclusions

These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.
Using qualitative free-text data to investigate the lived experience of the COVID-19 pandemic for a large cohort of Australians with different multiple sclerosis related disability levels
Authors: Campbell Julie A , van der Mei Ingrid , Taylor Bruce V , Palmer Andrew J , Henson Glen J , Laslett Laura Louise , Simpson-Yap Steve , Claflin Suzi B
Published: October 2023

Background

No large-scale qualitative studies have investigated the lived experience of people living with multiple sclerosis (PwMS) during the pandemic according to their disability level. We used qualitative research methods to investigate the lived experience of a large cohort of Australians living with differing multiple sclerosis (MS)-related disability levels during the COVID-19 pandemic. We also provided useful contextualisation to existing quantitative work.

Methods

This was a retrospective survey-based mixed-methods cohort study. A quality-of-life study was conducted within the Australian MS Longitudinal Study during the pandemic. Disability severity was calculated using the Patient Determined Disease Steps. Qualitative free-text data regarding COVID-19 impacts was collected/analysed for word frequency and also thematically (inductively/deductively using sophisticated grounded theory) using NVivo software. We also triangulated word frequency with emerging themes.

Results

N=509 PwMS participated providing n=22 530 words of COVID-19-specific data. Disability severity could be calculated for n=501 PwMS. The word ‘working’ was important for PwMS with no disability, and ‘support’ and ‘isolation’ for higher disability levels. For PwMS with milder disability, thematic analysis established that multitasking increased stress levels, particularly if working from home (WFH) and home-schooling children. If not multitasking, WFH was beneficial for managing fatigue. PwMS with severe disability raised increased social isolation as a concern including prepandemic isolation.

Conclusions

We found negative impacts of multitasking and social isolation for PwMS during the pandemic. WFH was identified as beneficial for some. We recommend targeted resourcing decisions for PwMS in future pandemics including child-care relief and interventions to reduce social isolation and suggest that these could be incorporated into some form of advanced care planning. As the nature of work changes postpandemic, we also recommend a detailed investigation of WFH for PwMS including providing tailored employment assistance.
Pavement freezing depth estimation using hybrid deep-learning models
Authors: Roh Seunghyun , Yami Yonathan Alemu , Hwang Hyunsik , Cho Yoonho
Published: October 2023

Predicting pavement temperature by depth is crucial for road design, analysis, and maintenance. However, current methods predominantly utilize regression and/or open-form solutions focusing on highways. Additionally, most machine-learning models focus on asphalt layers and do not extend to deeper pavement layers. Therefore, this study provides deep-learning models using weather parameters to predict pavement temperature from surface to sublayers and estimate pavement freezing depth for developing massive apartment complexes. Temperature-by-depth data collected from thin pavements from three locations in South Korea were used. Comparative analyses of long short-term memory (LSTM), convolutional neural network-LSTM (CNN-LSTM), and convolutional LSTM were performed. Results showed that CNN-LSTM model performed better with coefficients of determination ( R2) of 0.965, 0.987, and 0.981. Additionally, the CNN-LSTM predicted freezing depth with 0.3%–13.1% error margins outperforming the LSTM, Aldrich’s, and Korean Ministry of Transport approaches. The proposed approach shows that deep-learning models better estimate the freezing depth of pavements than existing approaches.
Boosting new physics searches in $$t{\bar{t}}Z$$ and tZj production with angular moments
Authors: Abraham Roshan Mammen , Gonçalves Dorival
Published: October 2023

The angular moments of the Z boson can be used as analyzers for the underlying production dynamics for the $$t{{\bar{t}}} Z$$

t

t

¯

Z

and tZj processes. In this manuscript, we derive these angular moments at leading and next-to-leading order in QCD at the LHC. We show that these observables work as efficient probes to beyond the Standard Model effects, considering the Standard Model Effective Field theory framework. Remarkably, we observe that these probes unveil blind directions to CP-odd operators, providing sizable new physics sensitivity at the 14 TeV LHC with 3 ab$$^{-1}$$

-
1

of data.
Constrained Off-policy Learning over Heterogeneous Information for Fairness-aware Recommendation
Authors: Wang Xiangmeng , Li Qian , Yu Dianer , Li Qing , Xu Guandong
Published: October 2023

Fairness-aware recommendation eliminates discrimination issues to build trustworthy recommendation systems. Existing fairness-aware approaches ignore accounting for rich user and item attributes and thus cannot capture the impact of attributes on affecting recommendation fairness. These real-world attributes severely cause unfair recommendations by favoring items with popular attributes, leading to item exposure unfairness in recommendations. Moreover, existing approaches mostly mitigate unfairness for static recommendation models, e.g., collaborative filtering. Static models can not handle dynamic user interactions with the system that reflect users’ preferences shift through time. Thus, static models are limited in their ability to adapt to user behavior shifts to gain long-run user satisfaction. As user and item attributes are largely involved in modern recommenders and user interactions are naturally dynamic, it is essential to develop a novel method that eliminates unfairness caused by attributes meanwhile embrace the dynamic modeling of user behavior shifts. In this article, we propose
Constrained Off-policy Learning over Heterogeneous Information for Fairness-aware Recommendation (Fair-HINpolicy)
, which uses recent advances in context-aware off-policy learning to produce fairness-aware recommendations with rich attributes from a Heterogeneous Information Network. In particular, we formulate the off-policy learning as a Constrained Markov Decision Process (CMDP) by dynamically constraining the fairness of item exposure at each iteration. We also design an attentive action sampling to reduce the search space for off-policy learning. Our solution adaptively receives HIN-augmented corrections for counterfactual risk minimization, and ultimately yields an effective policy that maximizes long-term user satisfaction. We extensively evaluate our method through simulations on large-scale real-world datasets, obtaining favorable results compared with state-of-the-art methods.
BOOM-Explorer: RISC-V BOOM Microarchitecture Design Space Exploration
Authors: Bai Chen , Sun Qi , Zhai Jianwang , Ma Yuzhe , Yu Bei , Wong Martin D. F.
Published: October 2023

Microarchitecture parameters tuning is critical in the microprocessor design cycle. It is a non-trivial design space exploration (DSE) problem due to the large solution space, cycle-accurate simulators’ modeling inaccuracy, and high simulation runtime for performance evaluations. Previous methods require massive expert efforts to construct interpretable equations or high computing resource demands to train black-box prediction models. This article follows the black-box methods due to better solution qualities than analytical methods in general. We summarize two learned lessons and propose BOOM-Explorer accordingly. First, embedding microarchitecture domain knowledge in the DSE improves the solution quality. Second, BOOM-Explorer makes the microarchitecture DSE for register-transfer-level designs within the limited time budget feasible. We enhance BOOM-Explorer with the diversity-guidance, further improving the algorithm performance. Experimental results with RISC-V Berkeley-Out-of-Order Machine under 7-nm technology show that our proposed methodology achieves an average of 18.75% higher Pareto hypervolume, 35.47% less average distance to reference set, and 65.38% less overall running time compared to previous approaches.
On Detecting and Measuring Exploitable JavaScript Functions in Real-world Applications
Authors: Kluban Maryna , Mannan Mohammad , Youssef Amr
Published: October 2023

JavaScript is often rated as the most popular programming language for the development of both client-side and server-side applications. Because of its popularity, JavaScript has become a frequent target for attackers who exploit vulnerabilities in the source code to take control over the application. To address these JavaScript security issues, such vulnerabilities must be identified first. Existing studies in vulnerable code detection in JavaScript mostly consider package-level vulnerability tracking and measurements. However, such package-level analysis is largely imprecise, as real-world services that include a vulnerable package may not use the vulnerable functions in the package. Moreover, even the inclusion of a vulnerable function may not lead to a security problem if the function cannot be triggered with exploitable inputs. In this article, we develop a vulnerability detection framework that uses vulnerable pattern recognition and textual similarity methods to detect vulnerable functions in real-world JavaScript projects, combined with a static multi-file taint analysis mechanism to further assess the impact of the vulnerabilities on the whole project (i.e., whether the vulnerability can be exploited in a given project). We compose a comprehensive dataset of 1,360 verified vulnerable JavaScript functions using the Snyk vulnerability database and the VulnCode-DB project. From this ground-truth dataset, we build our vulnerable patterns for two common vulnerability types: prototype pollution and Regular Expression Denial of Service (ReDoS). With our framework, we analyze 9,205,654 functions (from 3,000 NPM packages, 1,892 websites and 557 Chrome Web extensions), and detect 117,601 prototype pollution and 7,333 ReDoS vulnerabilities. By further processing all 5,839 findings from NPM packages with our taint analyzer, we verify the exploitability of 290 zero-day cases across 134 NPM packages. In addition, we conduct an in-depth contextual analysis of the findings in 17 popular/critical projects and study the practical security exposure of 20 functions. With our semi-automated vulnerability reporting functionality, we disclosed all verified findings to project owners. We also obtained 25 published CVEs for our findings, 19 of them rated as “Critical” severity and six rated as “High” severity. Additionally, we obtained 169 CVEs that are currently “Reserved” (as of Apr. 2023). As evident from the results, our approach can shift JavaScript vulnerability detection from the coarse package/library level to the function level and thus improve the accuracy of detection and aid timely patching.
Modeling Dynamic Evolution of Oxygen Vacancies in Solid Oxide Materials
Authors: Gaikwad Prashik S. , Pawar Gorakh , Shin Yun Kyung , Hossain Md. Jamil , van Duin Adri
Published: October 2023

SOEC is a promising H2 generation technology for mitigating climate change. Novel material design and optimization strategies, such as oxygen vacancy chemistries, can enhance SOEC efficiency. In this study, Monte Carlo-ReaxFF and eReaxFF simulations were used to study oxygen vacancies (Ov) and electron migration in BZY20 solid oxide material. Our results shows that Ov migrate towards the surface, increasing surface Ov concentration by 10%. Yttrium restricts electron mobility and functions as an electron trapping site, while Zr accelerates electron mobility and migration. These insights could improve solid-state electrolytes’ electrochemical performance in renewable energy applications.
Effect of Na2SiO3 and TEA Electrolyte Additives on the Corrosion Inhibition of Zinc Electrodes and Electrochemical Performance of Rechargeable Alkaline Manganese Batteries
Authors: Zhang Youwei , Zhang Zhenzhong , Zhao Fangxia , Gu Chengyang , Liu Yana , Sun Quan
Published: October 2023

To inhibit hydrogen evolution corrosion, passivation, and zinc dendrite growth during the charging and discharging of the zinc negative electrode of rechargeable alkaline manganese battery containing ultra-fine zinc powders, the effects of the single addition amounts of inorganic corrosion inhibitor Na2SiO3 and organic corrosion inhibitor TEA and their compounding ratio on the corrosion inhibition effect and the charging and discharging performance of alkaline manganese battery were systematically investigated in this paper. SEM and XPS were used to observe the microscopic morphology of the zinc anode, and the inhibition mechanisms of the relevant inhibitors were explored. The results show that, the addition of Na2SiO3 and TEA can synergistically improve the coverage of the protective film, thereby inhibiting hydrogen evolution corrosion, passivation and dendrites of zinc electrodes. Compared to blank electrolyte, when the composite concentration of Na2SiO3 and TEA is 1 g l−1 Na2SiO3+56.25 mg l−1 TEA, the hydrogen evolution corrosion inhibition efficiency can reach 70.56%, the initial specific capacity and the specific capacity after 50 cycles can increase from 160.7 mAh g−1, 58 mAh g−1 to 198.4 mAh g−1, 74 mAh g−1, respectively. This study has great theoretical and engineering value for guiding the design of electrolytes for rechargeable alkaline manganese batteries.
Recent Developments in Sensor Technologies for Enabling the Hydrogen Economy
Authors: Ramaiyan Kannan , Tsui Lok-kun , Brosha Eric L. , Kreller Cortney , Stetter Joseph R. , Russ Tamara , Du Winncy , Peaslee David , Hunter Gary , Xu Jennifer , Makel Darby , Garzon Fernando , Mukundan Rangachary
Published: October 2023

Efforts to create a sustainable hydrogen economy are gaining momentum as governments all over the world are investing in hydrogen production, storage, distribution, and delivery technologies to develop a hydrogen infrastructure. This involves transporting hydrogen in gaseous or liquid form or using carrier gases such as methane, ammonia, or mixtures of methane and hydrogen. Hydrogen is a colorless, odorless gas and can easily leak into the atmosphere leading to economic loss and safety concerns. Therefore, deployment of robust low-cost sensors for various scenarios involving hydrogen is of paramount importance. Here, we review some recent developments in hydrogen sensors for applications such as leak detection, safety, process monitoring in production, transport and use scenarios. The status of methane and ammonia sensors is covered due to their important role in hydrogen production and transportation using existing natural gas and ammonia infrastructure. This review further provides an overview of existing commercial hydrogen sensors and also addresses the potential for hydrogen as an interferent gas for currently used sensors. This review can help developers and users make informed decisions about how to drive hydrogen sensor technology forward and to incorporate hydrogen sensors into the various hydrogen deployment projects in the coming decade.
A novel method for automated crystal visualization and quantification in murine folic acid-induced acute kidney injury
Authors: Hamid Ahmad Kamal , Pastor Arroyo Eva Maria , Lee Sung Sik , Wagner Carsten Alexander , Egli-Spichtig Daniela
Published: October 2023

Here, we describe a novel method for the visualization and quantification of renal folic acid (FA) crystals in the rodent FA-induced acute kidney injury (FA-AKI) model. The protocol involves a straightforward histological approach followed by fully automated imaging and quantification steps. Applicability was confirmed by showing that the FA-AKI model is sex-dependent. The method can serve as a tool to aid in characterizing FA-AKI and to control for studies investigating prophylactic therapeutic avenues using FA-AKI.
Static respiratory mechanics are unaltered in males and females with obesity
Authors: Stickford Jonathon L. , Bhammar Dharini M. , Balmain Bryce N. , Babb Tony G.
Published: October 2023

The potential influence of obesity on the interrelationships between maximal expiratory flow, lung volume, and static lung elastic recoil pressure is unclear. These data show that the presence of obesity does not alter the relationship of flow and pressure across the mid-expiratory range in males and females. In addition, independent of obesity, females have smaller lungs and greater upstream flow resistance, which contributes to reduced maximal flow, when compared with males.
CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease
Authors: Glatz Jan F. C. , Heather Lisa C. , Luiken Joost J. F. P.
Published: October 2023

The multifunctional membrane glycoprotein CD36 is expressed in different types of cells and plays a key regulatory role in cellular lipid metabolism, especially in cardiac muscle. CD36 facilitates the cellular uptake of long-chain fatty acids, mediates lipid signaling, and regulates storage and oxidation of lipids in various tissues with active lipid metabolism. CD36 deficiency leads to marked impairments in peripheral lipid metabolism, which consequently impact on the cellular utilization of multiple different fuels because of the integrated nature of metabolism. The functional presence of CD36 at the plasma membrane is regulated by its reversible subcellular recycling from and to endosomes and is under the control of mechanical, hormonal, and nutritional factors. Aberrations in this dynamic role of CD36 are causally associated with various metabolic diseases, in particular insulin resistance, diabetic cardiomyopathy, and cardiac hypertrophy. Recent research in cardiac muscle has disclosed the endosomal proton pump vacuolar-type H+-ATPase (v-ATPase) as a key enzyme regulating subcellular CD36 recycling and being the site of interaction between various substrates to determine cellular substrate preference. In addition, evidence is accumulating that interventions targeting CD36 directly or modulating its subcellular recycling are effective for the treatment of metabolic diseases. In conclusion, subcellular CD36 localization is the major adaptive regulator of cellular uptake and metabolism of long-chain fatty acids and appears a suitable target for metabolic modulation therapy to mend failing hearts.
Cannabinoid treatments in epilepsy and seizure disorders
Authors: Devinsky Orrin , Jones Nicholas A. , Cunningham Mark O. , Jayasekera B. Ashan P. , Devore Sasha , Whalley Benjamin J.
Published: October 2023

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.