bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of the transcription factor MexT to quorum sensing and virulence in
Pseudomonas aeruginosa
Authors: Kostylev Maxim , Smalley Nicole E. , Chao Man Hou , Greenberg E. Peter
Published: November 2023

Quorum sensing (QS) regulates expression of many virulence genes in the opportunistic human pathogen
Pseudomonas aeruginosa
. There are two acyl-homoserine lactone (AHL) QS circuits, LasI-R and RhlI-R, which together activate expression of hundreds of genes in a cell density-dependent manner. There is also an inter-related non-AHL QS circuit, the
Pseudomonas
Quinolone Signal (PQS) circuit. Studies of the model strain PAO1 show that AHL QS is hierarchical, with the LasI-R system required for full activity of RhlI-R. We show that the LysR-type transcription factor MexT is an important modulator of the RhlI-R and PQS circuits. MexT delays the expression of genes activated by PQS and by the RhlI-R circuits but not genes regulated by the LasI-R circuit. In PAO1, MexT is constitutively active because of a mutation in
mexS
, a gene involved in maintaining redox homeostasis. Consistent with other reports, we show that in another model strain, PA14, MexT is quiescent but is activated by disulfide stress, and we show that this is true for all clinical isolates we tested. Compared with strain PA14, strain PAO1 has a virulence defect in a
Caenorhabditis elegans
infection model. We show that PAO1 mutants with inactive MexT are more virulent than their parent during
C. elegans
infection. Conversely, a PA14 mutant with a constitutively active MexT is attenuated for virulence. Our findings point to an important role for MexT as a governor of
P. aeruginosa
virulence and show that MexT limits virulence though its inhibition of the RhlI-R system.

IMPORTANCE

Pseudomonas aeruginosa
is an opportunistic bacterial pathogen. Many of its virulence genes are regulated by quorum sensing (QS), a form of cell-to-cell communication.
P. aeruginosa
QS consists of three interlinked circuits, LasI-R, Rhl-R, and
Pseudomonas
quinolone signal (PQS). Additionally, its QS system is interconnected with other regulatory networks, which help optimize gene expression under variable conditions. The numbers of genes regulated by QS differ substantially among
P. aeruginosa
strains. We show that a regulatory factor MexT, which is activated in response to certain antibiotics, downregulates the RhlI-R circuit and in turn measurably lowers virulence in a nematode worm infection model. Our findings help understand how existing and future therapeutic interventions for
P. aeruginosa
infections may impact this bacterium’s gene regulation and physiology.
Cross-regulation in a three-component cell envelope stress signaling system of
Brucella
Authors: Chen Xingru , Alakavuklar Melene A. , Fiebig Aretha , Crosson Sean
Published: November 2023

A multi-layered structure known as the cell envelope separates the controlled interior of bacterial cells from a fluctuating physical and chemical environment. The transcription of genes that determine cell envelope structure and function is commonly regulated by two-component signaling (TCS) systems, comprising a sensor histidine kinase and a cognate response regulator. To identify TCS genes that contribute to cell envelope function in the intracellular mammalian pathogen,
Brucella ovis
, we subjected a collection of non-essential TCS deletion mutants to compounds that disrupt cell membranes and the peptidoglycan cell wall. Our screen led to the discovery of three TCS proteins that coordinately function to confer resistance to cell envelope stressors and to support
B. ovis
replication in the intracellular niche. This tripartite regulatory system includes the known cell envelope regulator, CenR, and a previously uncharacterized TCS, EssR-EssS, which is widely conserved in Alphaproteobacteria. The CenR and EssR response regulators bind a shared set of sites on the
B. ovis
chromosomes to control transcription of an overlapping set of genes with cell envelope functions. CenR directly interacts with EssR and functions to stimulate phosphoryl transfer from the EssS kinase to EssR, while CenR and EssR control the cellular levels of each other via a post-transcriptional mechanism. Our data provide evidence for a new mode of TCS cross-regulation in which a non-cognate response regulator affects both the activity and protein levels of a cognate TCS protein pair.

IMPORTANCE

As intracellular pathogens,
Brucella
must contend with a variety of host-derived stressors when infecting a host cell. The inner membrane, cell wall, and outer membrane, i.e. the cell envelope, of
Brucella
provide a critical barrier to host assault. A conserved regulatory mechanism known as two-component signaling (TCS) commonly controls transcription of genes that determine the structure and biochemical composition of the cell envelope during stress. We report the identification of previously uncharacterized TCS genes that determine
Brucella ovis
fitness in the presence of cell envelope disruptors and within infected mammalian host cells. Our study reveals a new molecular mechanism of TCS-dependent gene regulation, and thereby advances fundamental understanding of transcriptional regulatory processes in bacteria.
Genome sequence of the
Klebsiella quasipneumoniae
bacteriophage EKq1 with activity against
Klebsiella pneumoniae
Authors: Bird Jordan T. , Burke Kevin A. , Urick Caitlin D. , Braverman Jamie L. , Mzhavia Nino , Ellison Damon W. , Nikolich Mikeljon P. , Filippov Andrey A.
Published: November 2023

We describe the genome of a lytic phage EKq1 isolated on
Klebsiella quasipneumoniae
, with activity against
Klebsiella pneumoniae
. EKq1 is an unclassified representative of the class Caudoviricetes, similar to
Klebsiella
phages VLCpiS8c, phiKp_7-2, and vB_KleS-HSE3. The 48,244-bp genome has a GC content of 56.43% and 63 predicted protein-coding genes.
The
Candida albicans
ζ-crystallin homolog Zta1 promotes resistance to oxidative stress
Authors: Gandra Rafael M. , Johnson Chad J. , Nett Jeniel E. , Konopka James B.
Published: November 2023

The fungal pathogen
Candida albicans
is capable of causing lethal infections in humans. Its pathogenic potential is due in part to the ability to resist various stress conditions in the host, including oxidative stress. Recent studies showed that a family of four flavodoxin-like proteins (Pst1, Pst2, Pst3, Ycp4) that function as quinone reductases promotes resistance to oxidation and is needed for virulence. Therefore, in this study, Zta1 was examined because it belongs to a structurally distinct family of quinone reductases that are highly conserved in eukaryotes and have been called the ζ-crystallins. The levels of Zta1 in
C. albicans
rapidly increased after exposure to oxidants, consistent with a role in resisting oxidative stress. Accumulation of reactive oxygen species (ROS) was significantly higher in cells lacking
ZTA1
upon exposure to quinones and other oxidants. Furthermore, the deletion of
ZTA1
in a mutant lacking the four flavodoxin-like proteins, resulted in further increased susceptibility to quinones, indicating that these distinct quinone reductases work in combination. These results demonstrate that Zta1 contributes to
C. albicans
survival after exposure to oxidative conditions, which increases the understanding of how
C. albicans
resist stressful conditions in the host.

IMPORTANCE

Candida albicans
is an important human pathogen that can cause lethal systemic infections. The ability of
C. albicans
to colonize and establish infections is closely tied to its highly adaptable nature and capacity to resist various types of stress, including oxidative stress. Previous studies showed that four
C. albicans
proteins belonging to the flavodoxin-like protein family of quinone reductases are needed for resistance to quinones and virulence. Therefore, in this study, we examined the role of a distinct type of quinone reductase, Zta1, and found that it acts in conjunction with the flavodoxin-like proteins to protect against oxidative stress.
Lactobacillus
-driven feed fermentation regulates microbiota metabolism and reduces odor emission from the feces of pigs
Authors: Zhang Dongyan , Ji Haifeng , Wang Sixin , Liu Yajuan , Chen Meixia , Liu Hui
Published: November 2023

Fermentation by
Lactobacillus
can increase the nutritional value of feed, which is advantageous for pig production. However, the effects of
Lactobacillus
-driven feed fermentation on the emission of odors from pig feces are unclear. Here, we evaluated how feed fermentation by
Lactobacillus
affects the concentration of odor molecules in feces (CO
2
, NH
3
, H
2
S, indole, and skatole) and analyzed the changes in fecal microbiota and metabolites during fecal storage. Pigs reared on fermented feed had a higher average daily gain (ADG) and lower feed-to-gain (
F
/
G
) ratio than the control group. By the 3rd and 5th days, the concentration of CO
2
in feces from pigs in the fermentation group significantly decreased, and the contents of H
2
S, NH
3
, and skatole in the fermentation group were significantly lower than those in the control group on the 1st, 3rd, and 5th days of fecal storage. The fermentation group exhibited a higher Bacteroidetes abundance on the 3rd and 5th days. With prolonged fecal storage, the fermentation group exhibited a higher abundance of
Weissella
and
Lactobacillus
and a lower abundance of
Streptococcus
. The
Lactobacillus
fermentation group also showed lower levels of secondary amino acid metabolites, such as 6-hydroxyhexanoic acid and 5-aminopentanoic acid. The pure strain
Weissella cibaria
ZWC030, which could inhibit the production of skatole
in vitro
, was successfully isolated from the fermentation group. Overall, the study revealed the interrelationships among fecal microbiota, metabolites, and odor molecules. The findings provide a new avenue for the application of
Lactobacillus
-driven feed fermentation to promote ADG, decrease the
F
/
G
ratio in pigs during growth, and reduce environmental pollution.

IMPORTANCE

Our present study showed that dietary supplementation with feed fermented by
Lactobacillus
could promote the growth performance of pigs, regulate the microbiota, and inhibit the growth of harmful bacteria. It could prevent the accumulation of toxic substances and reduce odor emission from pig feces, thereby reducing environmental pollution. In addition, one key triumph of the present study was the isolation of
Weissella cibaria
ZWC030, and the strain could inhibit the production of skatole
in vitro
in our present results.
Antiparasitic nitazoxanide potentiates colistin against colistin-resistant
Acinetobacter baumannii
and
Escherichia coli in vitro
and
in vivo
Authors: Xu Mengxin , Yao Zhuocheng , Kong Jingchun , Tang Miran , Liu Qi , Zhang Xiaotuan , Shi Shiyi , Zheng Xiangkuo , Cao Jianming , Zhou Tieli , Wang Zhongyong
Published: November 2023

Multidrug-resistant Gram-negative bacterial infections pose a serious threat to public health and safety. Colistin is a line of defense against these infections, but colistin-resistant (COL-R) bacteria have emerged worldwide. This study aimed to explore the synergistic potential of nitazoxanide (NTZ) in combination with colistin for the treatment of COL-R
Acinetobacter baumannii
and
Escherichia coli
strains
in vitro
and
in vivo
. The checkerboard and time-killing assays indicated that NTZ in combination with colistin exhibited potent antibacterial activity against COL-R
A. baumannii
and COL-R
E. coli
. The antibiofilm activity measured by crystal violet staining and scanning electron microscopy combined with a confocal laser scanning microscope revealed that the combination of NTZ and colistin could inhibit biofilm formation and eradicate the formed biofilm. This study also demonstrated that the application of this drug combination to an
in vivo
infection model significantly increased the survival rate of
Galleria mellonella
larvae. Hemolysis tests revealed that the combination of NTZ and colistin showed no cytotoxicity. Altogether, the combination of NTZ and colistin showed promising synergistic antibacterial and antibiofilm effects
in vitro
and
in vivo
. This combination might be used as an alternative therapy for treating COL-R
A. baumannii
and COL-R
E. coli
infections.

IMPORTANCE

Colistin is used as a last resort in many infections caused by multidrug-resistant Gram-negative bacteria; however, colistin-resistant (COL-R) is on the rise. Hence, it is critical to develop new antimicrobial strategies to overcome COL-R. We found that nitazoxanide (NTZ) combined with colistin showed notable synergetic antibacterial activity. These findings suggest that the NTZ/colistin combination may provide an effective alternative route to combat COL-R
A. baumannii
and COL-R
Escherichia coli
infections.
Supplemental Material: Early uplift and exhumation of the Tanggula granitoid pluton since the Late Cretaceous: Implications for the stepwise topographic growth model in the eastern Qiangtang terrane
Authors: Lu Lu , et al.
Published: November 2023

Table S1: A compilation of low-temperature thermochronology (LTT) data in the eastern Qiangtang terrane. Table S2: Apatite U-Pb dating results for samples from the Tanggula granitoid pluton. Table S3: Biotite 40Ar-39Ar furnace step-heating analytical results for samples from the Tanggula granitoid pluton. Table S4: K-feldspar 40Ar-39Ar furnace step-heating analytical results for samples from the Tanggula granitoid pluton. Table S5: Zircon fission-track data of samples from the Tanggula granitoid pluton. Table S6: Apatite fission-track data of samples from the Tanggula granitoid pluton. Table S7: Single-grain zircon (U-Th)He data of samples from the Tanggula granitoid pluton. 
Supplemental Material: Early uplift and exhumation of the Tanggula granitoid pluton since Late Cretaceous: Implications for the stepwise topographic growth model in the eastern Qiangtang terrane
Authors: Lu Lu , et al.
Published: November 2023

Table S1: A compilation of LTT data in the eastern Qiangtang terrane. Table S2: Apatite U-Pb dating results for samples from the Tanggula granitoid pluton. Table S3: Biotite 40Ar-39Ar furnace step-heating analytical results for samples from the Tanggula granitoid pluton. Table S4: K-feldspar 40Ar-39Ar furnace step-heating analytical results for samples from the Tanggula granitoid pluton. Table S5: Zircon fission track data of samples from the Tanggula granitoid pluton. Table S6: Apatite fission track data of samples from the Tanggula granitoid pluton. Table S7: Single grain zircon (U-Th)He data of samples from the Tanggula granitoid pluton.
Cell-Penetrating Peptides as Vehicles for Delivery of Therapeutic Nucleic Acids. Mechanisms and Application in Medicine
Authors: Timotievich Ekaterina D. , Shilovskiy Igor P. , Khaitov Musa R.
Published: November 2023

Currently, nucleic acid therapeutics are actively developed for the treatment and prophylactic of metabolic disorders and oncological, inflammatory, and infectious diseases. A growing number of approved nucleic acid-based drugs evidences a high potential of gene therapy in medicine. Therapeutic nucleic acids act in the cytoplasm, which makes the plasma membrane the main barrier for the penetration of nucleic acid-based drugs into the cell and requires development of special vehicles for their intracellular delivery. The optimal carrier should not only facilitate internalization of nucleic acids, but also exhibit no toxic effects, ensure stabilization of the cargo molecules, and be suitable for a large-scale and low-cost production. Cell-penetrating peptides (CPPs), which match all these requirements, were found to be efficient and low-toxic carriers of nucleic acids. CPPs are typically basic peptides with a positive charge at physiological pH that can form nanostructures with negatively charged nucleic acids. The prospects of CPPs as vehicles for the delivery of therapeutic nucleic acids have been demonstrated in numerous preclinical studies. Some CPP-based drugs had successfully passed clinical trials and were implemented into medical practice. In this review, we described different types of therapeutic nucleic acids and summarized the data on the use of CPPs for their intracellular delivery, as well as discussed, the mechanisms of CPP uptake by the cells, as understanding of these mechanisms can significantly accelerate the development of new gene therapy approaches.
Determinants of government spending on primary healthcare: a global data analysis
Authors: Erlangga Darius , Powell-Jackson Timothy , Balabanova Dina , Hanson Kara
Published: November 2023

In 2018 global leaders renewed their political commitment to primary healthcare (PHC) ratifying the Declaration of Astana emphasising the importance of building a sustainable PHC system based on accessible and affordable delivery models strengthened by community empowerment. Yet, PHC often remains underfunded, of poor quality, unreliable and not accountable to users which further deprives PHC of funding. This paper analyses the determinants of PHC expenditure in 102 countries, and quantitatively tests the influence of a set of economic, social and political determinants of government expenditure on PHC. The analysis is focused on the determinants of PHC funding from government sources as the government is in a position to make decisions in relation to this expenditure as opposed to out-of-pocket spending which is not in their direct control. Multivariate regression analysis was done to determine statistically significant predictors.

Our analysis found that some economic factors—namely Gross Domestic Product (GDP) per capita, government commitment to health and tax revenue raising capacity—were strongly associated with per capita government spending on PHC. We also found that control of corruption was strongly associated with the level of total spending on PHC, while voice and accountability were positively associated with greater government commitment to PHC as measured by government spending on PHC as a share of total government health spending.

Our analysis takes a step towards understanding of the drivers of PHC expenditure beyond the level of national income. Some of these drivers may be beyond the remit of health policy decision makers and relate to broader governance arrangements and political forces in societies. Thus, efforts to prioritise PHC in the health agenda and increase PHC expenditure should recognise the constraints within the political landscapes and engage with a wide range of actors who influence decisions affecting the health sector.
‘What we lacked was the courage to take decisions that differed from the rest of the world’: expert perspectives on the role of evidence in COVID-19 policymaking in Iraq
Authors: Alshalah Ali , Douedari Yazan , Howard Natasha
Published: November 2023

Introduction

Iraq reported its first COVID-19 case on 24 February 2020 and formed a national committee and advisory committees to support its response. While global experts have suggested that the COVID-19 pandemic provided an exceptional opportunity for advancing evidence-informed policymaking (EIPM), no research has examined this in Iraq. Therefore, this study aimed to examine evidence use in COVID-19 policymaking in Iraq.

Methods

This qualitative study employed semi-structured interviews with 20 Iraqi policymakers and researchers. Data were analysed thematically in Arabic using inductive coding.

Findings

Participants described COVID-19 policy in Iraq as based on research conducted in other countries, with poor access and quality of routine data and lack of national research priorities and academic freedom as barriers to national research production. Most researchers influenced policy individually, with universities and other research bodies not seen as contributing to policy development. Public non-compliance could be traced to mistrust in both political and healthcare systems and became particularly problematic during the pandemic. Proposed strategies to increase national research production included dedicated funding, establishing communication and collaboration for research priority setting, and protection of academic freedom.

Conclusion

Sociopolitical and economic realities in Iraq were unsupportive of national or subnational evidence generation even before the COVID-19 pandemic, and government relied on international evidence and policy transfer rather than contextually informed EIPM. Strengthening evidence-informed infectious disease policymaking and policy transfer would thus require governmental focus on improving the quality and relevance of Iraqi research, engagement between researchers and policymakers, and processes of evidence use and policy transfer.
Add-on pramipexole for anhedonic depression: study protocol for a randomised controlled trial and open-label follow-up in Lund, Sweden
Authors: Lindahl Jesper , Asp Marie , Ståhl Darya , Tjernberg Johanna , Eklund Moa , Björkstrand Johannes , van Westen Danielle , Jensen Jimmy , Månsson Kristoffer , Tornberg Åsa , Svensson Martina , Deierborg Tomas , Ventorp Filip , Lindqvist Daniel
Published: November 2023

Introduction

Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low function and quality of life. There are currently no specific and effective treatments for anhedonia. Some trials have shown that dopamine agonist pramipexole is efficacious for treating depression, but more data is needed before it could become ready for clinical prime time. Given its mechanism of action, pramipexole might be a useful treatment for a depression subtype characterised by significant anhedonia and lack of motivation—symptoms associated with dopaminergic hypofunction. We recently showed, in an open-label pilot study, that add-on pramipexole is a feasible treatment for depression with significant anhedonia, and that pramipexole increases reward-related activity in the ventral striatum. We will now confirm or refute these preliminary results in a randomised controlled trial (RCT) and an open-label follow-up study.

Methods and analysis

Eighty patients with major depression (bipolar or unipolar) or dysthymia and significant anhedonia according to the Snaith Hamilton Pleasure Scale (SHAPS) are randomised to either add-on pramipexole or placebo for 9 weeks. Change in anhedonia symptoms per the SHAPS is the primary outcome, and secondary outcomes include change in core depressive symptoms, apathy, sleep problems, life quality, anxiety and side effects. Accelerometers are used to assess treatment-associated changes in physical activity and sleep patterns. Blood and brain biomarkers are investigated as treatment predictors and to establish target engagement. After the RCT phase, patients continue with open-label treatment in a 6-month follow-up study aiming to assess long-term efficacy and tolerability of pramipexole.

Ethics and dissemination

The study has been approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. The study is externally monitored according to Good Clinical Practice guidelines. Results will be disseminated via conference presentations and peer-reviewed publications.

Trial registration number

NCT05355337andNCT05825235.
Effect of double quantum dot asymmetry on electron localization
Authors: Filikhin Igor , Karoui Abdennaceur , Zatezalo Tanja , Kruchinin Sergei P. , Vlahovic Branislav
Published: November 2023

In this paper, we study the localization of an electron in a binary quantum system formed by a pair of quantum dots (QDs). The traditional theoretical consideration of such systems is limited to the symmetrical case when QDs in such double quantum dot (DQD) are assumed identical in all respects. In this paper, we model the effects of breaking QD similarities in a DQD by studying two-dimensional (2D) DQDs as a double quantum well (DQW). This is done by solving the Schrödinger equation, with parameters chosen to describe an InAs/GaAs heterostructure. We calculate the energy spectrum of the electron confinement and the spectral distribution of localized/delocalized spatial states. Both symmetric and asymmetric QW shapes are considered and their effects are compared. The effects of symmetry breaking are explained within the framework of the two-level system theory. We delineate the QW weak and strong coupling cases in DQW. In particular, we show that the coherence in ideal DQW is unstable in the case of a weak QW coupling. Within the framework of the proposed approach, a charge qubit realized on a DQD is discussed and, as an example, a qubit based on an almost ideal DQD is proposed.
FRACTAL DIMENSIONS OF THE LOGARITHM OF CONTINUOUS FUNCTIONS
Authors: LIU PEIZHI
Published: November 2023

This paper investigates the variation of fractal dimensions of continuous functions under operations. It is found that the Box dimension of the logarithm of positive continuous functions remains constant, and any nonzero real power of a positive continuous function can keep fractal dimensions variation closed. The study also discusses the fractal dimension of logarithmic function with bases of fractal functions, and the corresponding fractal dimension is determined by the function with the larger fractal dimension.
Human–Robot Teaming Challenges for the Military and First Response
Authors: Adams Julie A. , Scholtz Jean , Sciarretta Albert
Published: November 2023

The integration of more artificial intelligence (AI)–enabled robots for the military and first response domains is necessary to support long-duration deployments in uncertain and dynamic environments while lessening humans’ exposure to threats and dangers. The effective integration of AI-enabled robots as teammates with humans will provide support and enhance overall mission performance; however, the majority of current research on human–robot interaction focuses only on the robot team supervisor. The true integration of robots into military and first response missions will require a breadth of human roles that span from the highest command level to the dismounted in situ personnel working directly with robots. All human roles within the hierarchy must understand and maintain direct control of the robot teammates. This article maps existing human roles from the literature to a military mission, presents technical challenges associated with this future human–robot teaming, and provides potential solutions and recommendations to propel the field forward toward human–robot teams that can achieve domain-relevant missions.
Correlating Oxygen Electrode Degradation to Cr Vaporization from Metallic Interconnects in Solid Oxide Cell Stacks
Authors: Talic Belma , Norrman Kion , Sand Tommy , Froitzheim Jan , Hendriksen Peter Vang
Published: November 2023

Symmetrical cells consisting of La0.58Sr0.4Co0.2Fe0.8O3-δ
(LSCF) oxygen electrodes screen printed on both sides of a Ce0.9Gd0.1O2-δ
(CGO) electrolyte were tested at 800 °C while being held close to a piece of Crofer 22 APU alloy. The alloy was either just pre-oxidized or coated with MnCo2O4 and heat treated prior to the exposure test to elucidate the effects of different Cr vaporization rates. Degradation of the symmetrical cells was monitored by electrochemical impedance spectroscopy, and TOF-SIMS, SEM and EDX analysis were used to examine Cr deposition on the electrodes after the exposure. The results show that the degradation rate of the symmetrical cell is directly proportional to the concentration of gaseous Cr(VI)-species, which had been assessed in a previous experiment. The Cr vaporization rate from Crofer 22 APU with a dense MnCo2O4 coating was measured in moisturized air up with up to 40% H2O and found to be invariant with respect to the steam activity. The degradation rate of symmetrical cells was accelerated by humidity in the air, but, noteworthy, this was found also in the absence of a Cr source.
Exploring the Influence Mechanism of Porous Transport Layer Structure and Type on Performance in Proton Exchange Membrane Electrolyzer
Authors: Zhu Xiaohong , Zhang Junyu , Du Shaojie , Dang Jian , Yang Mingye , Liu Biao , Ma Jugang , Yang Fuyuan , Ouyang Minggao
Published: November 2023

The anode porous transport layer (PTL) plays a crucial role in improving the energy density of proton exchange membrane (PEM) electrolyzer. The influence mechanism of PTL structural parameters and types on electrolysis performance has been investigated based on the voltage decomposition method and surface morphology characterization in this study. Among the Ti-Powder PTLs, which have relatively fixed and low porosity of 28%, PTL-1 with pore diameter of 4.5 μm performs the best, whereas PTL-4 with pore diameter of 62 μm shows the highest ohmic and mass transport over-potential. Specifically, the Ti-Fiber PTL exhibits changes in both porosity and pore diameter. PTL-6 with 50% porosity and PTL-8 with 75% porosity demonstrate superior performance. And this article develops an equivalent ohmic resistance model of the catalyst layer (CL) and proposes the concept of “substrate deadband” at the PTL-CL interface from the perspective of reaction interface construction. Based on the comparative evaluation of Ti-Powder PTL and Ti-Fiber PTL, it shows that the latter has a higher potential for performance improvement. Furthermore, the structure of Ti-Fiber PTL has been optimized and the current density has increased by 26.2% @ 2V, indicating a direction for the application and manufacturing of next-generation PTL.
Facile and Sensitive Acetylene Black-Based Electrochemical Sensor for the Detection of Imatinib
Authors: Li Shun , Tian Qingwu , Xu Xuanming , Xuan Chao , Yang Xiaomin , Sun Shukai , Zhou Tingting
Published: November 2023

A facile and sensitive electrochemical sensor for determining imatinib (IMA) was constructed by modifying a glassy carbon electrode (GCE) with a nanocarbon material, acetylene black (AB). The electrochemical behavior of IMA on the prepared GCE/AB was studied using electrochemical techniques, namely, differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy. The direct determination of IMA by the GCE/AB sensor was accomplished using DPV under optimized conditions. The method verification showed that the oxidation peak current was proportional to the concentrations of IMA in the linear ranges of 0.01–0.5 and 0.5–4 μM, with correlation coefficients of 0.9856 and 0.9946, respectively. The limit of detection of the GCE/AB sensor was 0.15 nM. Moreover, the GCE/AB sensor showed good precision and accuracy. Finally, the GCE/AB sensor was successfully applied to determine IMA in human serum samples, and the recoveries were satisfactory.
Chitosan-Bidens pilosa Extract-Based Coating with Enhanced Free Radical Scavenging, Antifungal, and Water Barrier Properties: Metabolite Profiling, Film Characterization, and Raspberry Preservation
Authors: Nxumalo Kwanele A. , Fawole Olaniyi A.
Published: November 2023

Chitosan (Ch) was functionalized with Bidens pilosa (BP) extract at 1, 3, or 5% to form Ch-1 BP, Ch-3 BP, and Ch-5 BP, respectively. Ch without plant extract was used as a control. The composite films were characterized and tested for antifungal properties in the agar disc diffusion approach and antioxidant capacity in the 2,2-diphenyl-1-picrylhydrazyl assay. Chitosan films fused with B. pilosa extract inhibited the growth of P. expansum with a 10 mm inhibition diameter compared to control films (3.33 mm). Ch-1 BP exhibited the highest (79.13%) radical scavenging activity (RSA), and control films had the lowest RSA (50.97%). Liquid chromatography-mass spectrometry analysis identified 20 metabolites, including phenolic acids (9), organic acids (8), monosaccharides (1), amino acids (1), flavonoids (1), and six unknown polyphenols. Chitosan-based composite coating (Ch-1% BP) exhibited the lowest weight loss percentage (16.74%) and decay incidence (17.3%), while the untreated fruit showed higher weight loss and decay incidence (48.33% and 83.2%, respectively). The effectiveness of chitosan-enriched coating in maintaining the postharvest quality of raspberry fruit suggests that this plant could be a postharvest agent for controlling microbial spoilage and protecting against oxidative stress, ultimately resulting in extended storage in horticultural crops.
Clinical and Immunologic Features of Germline Pathogenic Variant–Positive Patients with Melanoma
Authors: Shen Alan , Arbesman Michelle , Lodha Roshan , Rayman Patricia , Bungo Brandon , Ni Ying , Chan Timothy , Gastman Brian , Ko Jennifer , Diaz-Montero C. Marcela , Arbesman Joshua , Funchain Pauline
Published: November 2023

Purpose:

Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)–positive patients with melanoma from gPV-negative patients with melanoma.

Experimental Design:

Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells.

Results:

In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13–0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016–0.86; P = 0.03) and numerically improved in later-stage (IIB–IV) patients (HRadj, 0.34; 95% CI, 0.10–1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB–IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA).

Conclusions:

gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.
Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant Prostate Cancer
Authors: Bennett Lynda , Jaiswal Praveen Kumar , Harkless Ryan V. , Long Tiha M. , Gao Ning , Vandenburg Brianna , Selman Phillip , Durdana Ishrat , Lastra Ricardo R. , Vander Griend Donald , Adelaiye-Ogala Remi , Szmulewitz Russell Z. , Conzen Suzanne D.
Published: November 2023

In castration-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic “bypass” mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic prostate cancer patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs). For example, in the context of ARSi, we found that GR activation resulted in upregulation of protein kinase inhibitor beta (PKIB) mRNA and protein levels, leading to nuclear accumulation of the cAMP-dependent protein kinase A catalytic subunit (PKA-c). Increased PKA-c, in turn, is associated with increased cAMP response element-binding protein phosphorylation and activity. Furthermore, enzalutamide and SGRM combination therapy in mice bearing CRPC xenografts delayed CRPC progression compared with enzalutamide therapy alone, and reduced tumor PKIB mRNA expression. Supporting the clinical importance of GR/PKA signaling activation in CRPC, we found a significant enrichment of both cAMP pathway signaling-associated gene expression and high NR3C1 (GR) activity in patient-derived xenograft models and metastatic human CRPC samples. These findings suggest a novel mechanism linking CRPC-induced GR transcriptional activity with increased cAMP signaling in AR-antagonized CRPC. Furthermore, our findings suggest that GR-specific modulation in addition to AR antagonism may delay GR+ CRPC time to recurrence, at least in part, by inhibiting tumor cAMP/PKA pathways.
Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors
Authors: Krebs Markus , Kotlyar Mischa J. , Fahl Julian , Janaki Raman Sudha , Röhrig Florian , Marquardt André , Kübler Hubert , Kneitz Burkhard , Schulze Almut , Kalogirou Charis
Published: November 2023

Introduction: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers. Methods: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt reexpressing RCC4 and 786-O cells. Results: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression – as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels. Conclusion: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.
MEK Inhibitor-Associated Ocular Hypertension
Authors: Collet David A. , Canestraro Julia , Abou-Alfa Ghassan K. , Abramson David H. , Diamond Eli L. , Francis Jasmine H.
Published: November 2023

Introduction: Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension. Case Presentations: In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients’ IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy. Discussion/Conclusion: This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.
Exaptation and Evolutionary Adaptation in Nociceptor Mechanisms Driving Persistent Pain
Authors: Walters Edgar T.
Published: November 2023

Background: Several evolutionary explanations have been proposed for why chronic pain is a major clinical problem. One is that some mechanisms important for driving chronic pain, while maladaptive for modern humans, were adaptive because they enhanced survival. Evidence is reviewed for persistent nociceptor hyperactivity (PNH), known to promote chronic pain in rodents and humans, being an evolutionarily adaptive response to significant bodily injury, and primitive molecular mechanisms related to cellular injury and stress being exapted (co-opted or repurposed) to drive PNH and consequent pain. Summary: PNH in a snail (Aplysia californica), squid (Doryteuthis pealeii), fruit fly (Drosophila melanogaster), mice, rats, and humans has been documented as long-lasting enhancement of action potential discharge evoked by peripheral stimuli, and in some of these species as persistent extrinsically driven ongoing activity and/or intrinsic spontaneous activity (OA and SA, respectively). In mammals, OA and SA are often initiated within the protected nociceptor soma long after an inducing injury. Generation of OA or SA in nociceptor somata may be very rare in invertebrates, but prolonged afterdischarge in nociceptor somata readily occurs in sensitized Aplysia. Evidence for the adaptiveness of injury-induced PNH has come from observations of decreased survival of injured squid exposed to predators when PNH is blocked, from plausible survival benefits of chronic sensitization after severe injuries such as amputation, and from the functional coherence and intricacy of mammalian PNH mechanisms. Major contributions of cAMP-PKA signaling (with associated calcium signaling) to the maintenance of PNH both in mammals and molluscs suggest that this ancient stress signaling system was exapted early during the evolution of nociceptors to drive hyperactivity following bodily injury. Vertebrates have retained core cAMP-PKA signaling modules for PNH while adding new extracellular modulators (e.g., opioids) and cAMP-regulated ion channels (e.g., TRPV1 and Nav1.8 channels). Key Messages: Evidence from multiple phyla indicates that PNH is a physiological adaptation that decreases the risk of attacks on injured animals. Core cAMP-PKA signaling modules make major contributions to the maintenance of PNH in molluscs and mammals. This conserved signaling has been linked to ancient cellular responses to stress, which may have been exapted in early nociceptors to drive protective hyperactivity that can persist while bodily functions recover after significant injury.
Altered Auditory Feedback Improves Speech Intelligibility in Individuals Diagnosed with Parkinson’s Disease: A Pilot Study
Authors: Kaipa Ramesh , McLain Natalie , Kaipa Roha Mariam
Published: November 2023

Introduction: The purpose of the current study was to evaluate speech intelligibility and speech rate in individuals with Parkinson’s disease using altered auditory feedback (AAF) in comparison to age-matched healthy controls. Based on prior research, it is hypothesized that the use of AAF will improve participants’ speech intelligibility. Methods: Five individuals with Parkinson’s disease (clinical group) and five age-matched healthy controls aged 50 years and above participated in this pre-/post-group experiment. All participants completed reading and monologue tasks with and without AAF. The AAF delayed the participants’ auditory feedback by 150 ms and altered it by 1/20 octave. Thirty-two naïve listeners listened to the recorded participants’ speech samples (with and without AAF) randomly and rated the participants’ speech intelligibility. Results: Results of the mixed model ANOVA revealed that participants in the control group had significantly higher speech intelligibility scores than the participants in the clinical group. Post hoc tests indicated that only participants in the clinical group were more intelligible with AAF than without AAF. Participants in the clinical group had better speech intelligibility when reading the passage than speaking the monologue. With regards to speech rate, participants spoke more slowly with AAF than without. Finally, there was a negative correlation between speech rate and speech intelligibility. Discussion: The current findings support our hypothesis that AAF improves speech intelligibility in people with Parkinson’s disease, though not in healthy controls. Future research should evaluate the long-term effect of AAF use on speech intelligibility in people with Parkinson’s disease.
Espacialidade e estetização no romance "10:04", de Ben Lerner
Authors: Jardim Matheus Camargo
Published: November 2023

O objetivo deste texto é fazer um breve mapeamento da representação do espaço e do processo de estetização capitalista a partir da leitura cerrada do primeiro parágrafo e de trechos homólogos do romance 10:04, de Ben Lerner. A partir da análise, procuraremos demonstrar como os elementos estéticos são trabalhados pelo autor a partir da seleção e organização dos dados materiais concretos e como essa articulação expressa a técnica composicional de montagem.
Upholding Banker’s Duty of Confidentiality in Tanzania: an Examination of Legislative and Judicial Responses
Authors: Temu Goodluck
Published: November 2023

Trust and confidence are the foundations of a banker-customer relationship. As a result, any information customers submit to their bankers is expected to be kept confidential. This expectation can only be met if the relevant legislative frameworks are in place to ensure that bankers are held accountable for their confidentiality agreements. While there is legislation in place to protect the privacy of customer information in Tanzania, a growing number of laws, notably those dealing with crime prevention and control, have been enacted, with the consequence of undermining bankers’ confidentiality obligations. Therefore, this article examines how recent legislative and judicial developments have addressed the confidentiality obligations imposed on bankers. In general, it has been observed and established that the protection of customers’ information provided by banking laws is usually degraded by other laws, particularly those pertaining to crime prevention, hence weakening banker’s duty of confidentiality.