bluuebunny/crossref_metadata_2025 huggingface dataset:
CaM‐dependent modulation of human CaV1.3 whole‐cell and single‐channel currents by C‐terminal CaMKII phosphorylation site S1475
Authors: Salamon Sarah , Kuzmenkina Elza , Fried Cora , Matthes Jan
Published: July 2024

Phosphorylation enables rapid modulation of voltage‐gated calcium channels (VGCC) in physiological and pathophysiological conditions. How phosphorylation modulates human CaV1.3 VGCC, however, is largely unexplored. We characterized modulation of CaV1.3 gating via S1475, the human equivalent of a phosphorylation site identified in the rat. S1475 is highly conserved in CaV1.3 but absent from all other high‐voltage activating calcium channel types co‐expressed with CaV1.3 in similar tissues. Further, it is located in the C‐terminal EF‐hand motif, which binds calmodulin (CaM). This is involved in calcium‐dependent channel inactivation (CDI). We used amino acid exchanges that mimic either sustained phosphorylation (S1475D) or phosphorylation resistance (S1475A). Whole‐cell and single‐channel recordings of phosphorylation state imitating CaV1.3 variants in transiently transfected HEK‐293 cells revealed functional relevance of S1475 in human CaV1.3. We obtained three main findings: (1) CaV1.3_S1475D, imitating sustained phosphorylation, displayed decreased current density, reduced CDI and (in‐) activation kinetics shifted to more depolarized voltages compared with both wildtype CaV1.3 and the phosphorylation‐resistant CaV1.3_S1475A variant. Corresponding to the decreased current density, we find a reduced open probability of CaV1.3_S1475D at the single‐channel level. (2) Using CaM overexpression or depletion, we find that CaM is necessary for modulating CaV1.3 through S1475. (3) CaMKII activation led to CaV1.3_WT‐current properties similar to those of CaV1.3_S1475D, but did not affect CaV1.3_S1475A, confirming that CaMKII modulates human CaV1.3 via S1475. Given the physiological and pathophysiological importance of CaV1.3, our findings on the S1475‐mediated interplay of phosphorylation, CaM interaction and CDI provide hints for approaches on specific CaV1.3 modulation under physiological and pathophysiological conditions.

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Key points

Phosphorylation modulates activity of voltage‐gated L‐type calcium channels for specific cellular needs but is largely unexplored for human CaV1.3 channels.

Here we report that S1475, a CaMKII phosphorylation site identified in rats, is functionally relevant in human CaV1.3.

Imitating phosphorylation states at S1475 alters current density and inactivation in a calmodulin‐dependent manner.

In wildtype CaV1.3 but not in the phosphorylation‐resistant variant S1475A, CaMKII activation elicits effects similar to constitutively mimicking phosphorylation at S1475.

Our findings provide novel insights on the interplay of modulatory mechanisms of human CaV1.3 channels, and present a possible target for CaV1.3‐specific gating modulation in physiological and pathophysiological conditions.
Stereocilia fusion pathology in the cochlear outer hair cells at the nanoscale level
Authors: Ikäheimo Kuu , Leinonen Saija , Lankinen Tuuli , Lindahl Maria , Saarma Mart , Pirvola Ulla
Published: July 2024

The hair bundle of cochlear hair cells comprises specialized microvilli, the stereocilia, which fulfil the role of mechanotransduction. Genetic defects and environmental noise challenge the maintenance of hair bundle structure, critically contributing to age‐related hearing loss. Stereocilia fusion is a major component of the hair bundle pathology in mature hair cells, but its role in hearing loss and its molecular basis are poorly understood. Here, we utilized super‐resolution expansion microscopy to examine the molecular anatomy of outer hair cell stereocilia fusion in mouse models of age‐related hearing loss, heightened endoplasmic reticulum stress and prolonged noise exposure. Prominent stereocilia fusion in our model of heightened endoplasmic reticulum stress, Manf (Mesencephalic astrocyte‐derived neurotrophic factor)‐inactivated mice in a background with Cadherin 23 missense mutation, impaired mechanotransduction and calcium balance in stereocilia. This was indicated by reduced FM1‐43 dye uptake through the mechanotransduction channels, reduced neuroplastin/PMCA2 expression and increased expression of the calcium buffer oncomodulin inside stereocilia. Sparse BAIAP2L2 and myosin 7a expression was retained in the fused stereocilia but mislocalized away from their functional sites at the tips. These hair bundle abnormalities preceded cell soma degeneration, suggesting a sequela from stereociliary molecular perturbations to cell death signalling. In the age‐related hearing loss and noise‐exposure models, stereocilia fusion was more restricted within the bundles, yet both models exhibited oncomodulin upregulation at the fusion sites, implying perturbed calcium homeostasis. We conclude that stereocilia fusion is linked with the failure to maintain cellular proteostasis and with disturbances in stereociliary calcium balance.

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Key points

Stereocilia fusion is a hair cell pathology causing hearing loss.

Inactivation of Manf, a component of the endoplasmic reticulum proteostasis machinery, has a cell‐intrinsic mode of action in triggering outer hair cell stereocilia fusion and the death of these cells.

The genetic background with Cadherin 23 missense mutation contributes to the high susceptibility of outer hair cells to stereocilia fusion, evidenced in Manf‐inactivated mice and in the mouse models of early‐onset hearing loss and noise exposure.

Endoplasmic reticulum stress feeds to outer hair cell stereocilia bundle pathology and impairs the molecular anatomy of calcium regulation.

The maintenance of the outer hair cell stereocilia bundle cohesion is challenged by intrinsic and extrinsic stressors, and understanding the underlying mechanisms will probably benefit the development of interventions to promote hearing health.
Experimental Analysis of Robotic Cortical Bone Specimen Drilling Performance: Effect of Cryogen
Authors: Ha Ju-Hyung , Choe Joon-Hyeok , Seo Jae-Woo , Kim Ji-Soo , Kim Dong Min
Published: July 2024

In orthopedic surgery, precise bone screw insertion is crucial for stabilizing fractures, necessitating a preliminary cortical bone drilling procedure. However, this process can induce temperatures exceeding 70 °C due to the low thermal conductivity of cortical bone, potentially leading to thermal osteonecrosis. Furthermore, significant cutting forces and torque pose risks of tool breakage and bone damage, underlining the need for high precision and optimal processing parameters. Traditionally, drilling relies on the surgeon's experience and often results in imprecise outcomes due to inconsistent feed rates. Therefore, this study proposes the use of a 6-axis robot for controlled drilling, offering precise control over angular velocities and consistent feed rates. Additionally, explore the use of cryogenic liquid nitrogen (LN2) as a novel cooling method compared to conventional saline solutions, examining its efficacy under various cutting conditions. The results demonstrate that LN2 cooling conditions lead to a reduction in thrust and torque under specific processing conditions, and facilitate smoother chip evacuation. Additionally, LN2 significantly lowers the peak temperature around the drilling site, thus minimizing the risk of thermal osteonecrosis. Consequently, the use of a 6-axis robot provides consistent feed rates, and LN2 cooling achieves optimal processing conditions, enabling a more controlled and effective drilling process.
NOx Emissions Assessment of a Multijet Burner Operated With Premixed High Hydrogen Natural Gas Blends
Authors: Jaeschke Alexander , Ćosić Bernhard , Wassmer Dominik , Paschereit Christian Oliver
Published: July 2024

Decarbonization of gas turbine combustion creates a pressing demand for new technical solutions for the combustion process. While switching to hydrogen fuels may solve the problem of carbon emissions and associated pollutants, it can also lead to stability issues for swirl-stabilized combustors due to its increased reactivity. However, with jet flame burner systems, the required flashback safety can be achieved with high axial flow velocities even for premixed combustion of 100% hydrogen fuel. The development of such an engineering solution, however, requires significant effort to reach the maturity of today's swirl burners. This study examines the capacity of a premixed multitube jet burner to manage the chemical reactivity change over a range of volumetric blends from pure natural gas (NG) to pure hydrogen fuel. NOx emissions are measured and analyzed for atmospheric tests. The changes in emissions originate not only from altered combustion chemistry but also from changes in flame shape and turbulence intensity. To get a deeper understanding of the NOx formation process, a low-order model is designed and compared to the experimental data of technically and perfectly premixed combustion tests. Parameter variations of the low-order model are conducted to assess the influences on the NOx emission production of the multijet burner. The information on the combustion process required for the model is obtained computationally and experimentally. Therefore, flame images are recorded and analyzed.
Practical guides for x-ray photoelectron spectroscopy: Use of argon ion beams for sputter depth profiling and cleaning
Authors: Shard Alexander G. , Baker Mark A.
Published: July 2024

Ion beams are used in x-ray photoelectron spectroscopy (XPS) to clean samples and perform compositional sputter depth profiles. The purpose of this article is to compile good practice, recommendations, and useful information related to the use of argon ion sources for inexperienced users of XPS instrumentation. The most used type of ion source generates monoatomic argon ions at a range of energies from a fixed direction relative to the instrument. The angle and direction of the ion beam with respect to the surface are normally altered by manipulating the sample, and this may involve tilting the sample to change the angle of incidence or rotating the sample to change the azimuthal incidence angle. Atomic argon ion beams cause damage to the structure of the material surface, which may exhibit itself as a change in stoichiometry or topography as well as the implantation of argon atoms. Therefore, caution is required in the interpretation of XPS depth profiles. Gas cluster ion sources offer new possibilities and choices to XPS users. Gas cluster sources enable the sputtering of organic materials with high yield in comparison to inorganic materials and offer the potential for nearly damage-free depth profiling of delicate organic materials as well as low damage cleaning of inorganic materials. It may be possible to use argon clusters to reduce damage during the depth profiling of inorganic materials, but there is currently insufficient evidence to make any general recommendations.
EfpA is required for regrowth of
Mycobacterium tuberculosis
following isoniazid exposure
Authors: Roberts Adam H. , Moon Christopher W. , Faulkner Valwynne , Kendall Sharon L. , Waddell Simon J. , Bacon Joanna
Published: July 2024

Efflux of antibiotics is an important survival strategy in bacteria.
Mycobacterium tuberculosis
has approximately sixty efflux pumps, but little is known about the role of each pump or the substrates they efflux. The putative efflux pump, EfpA, is a member of the major facilitator superfamily and has been shown to be essential by saturation transposon mutagenesis studies. It has been implicated in the efflux of isoniazid (INH), which is a first-line drug used to treat tuberculosis (TB). This is supported by evidence from transcriptional profiling showing that
efpA
is induced in response to INH exposure. However, its roles in the physiology and adaptation of
M. tuberculosis
to antibiotics have yet to be determined. In this study, we describe the repression of
efpA
in
M. tuberculosis,
using CRISPR interference (CRISPRi) to knockdown the expression of this essential gene and the direct effect of this on the ability of
M. tuberculosis
to survive exposure to INH over a 45-day time course. We determined that wild-type levels of
efpA
were required for recovery of
M. tuberculosis
following INH exposure and that, after 45 days of INH exposure, only a few viable colonies were recoverable from
efpA
-repressed
M. tuberculosis
. We conclude that EfpA is required for recovery of
M. tuberculosis
following INH exposure, which could reduce the efficacy of INH
in vivo
, and that EfpA may have a role in the development of resistance during drug therapy.
Echinococcus multilocularis
serpin regulates macrophage polarization and reduces gut dysbiosis in colitis
Authors: Li Xiaolu , Liu Yihui , Zou Yang , Zhang Jiayun , Wang Yugui , Ding Yingying , Shi Zhiqi , Guo Xiaola , Zhang Shaohua , Yin Hong , Guo Aijiang , Wang Shuai
Published: July 2024

Helminths serve as principal regulators in modulating host immune responses, and their excretory-secretory proteins are recognized as potential therapeutic agents for inflammatory bowel disease. Nevertheless, our comprehension of the mechanisms underlying immunoregulation remains restricted. This investigation delves into the immunomodulatory role of a secretory protein serpin (
Emu
-serpin), within the larval stage of
Echinococcus multilocularis
. Our observations indicate that
Emu
-serpin effectively alleviates dextran sulfate sodium-induced colitis, yielding a substantial reduction in immunopathology and an augmentation of anti-inflammatory cytokines. Furthermore, this suppressive regulatory effect is concomitant with the reduction of gut microbiota dysbiosis linked to colitis, as evidenced by a marked impediment to the expansion of the pathobiont taxa Enterobacteriaceae.
In vivo
experiments demonstrate that
Emu
-serpin facilitates the expansion of M2 phenotype macrophages while concurrently diminishing M1 phenotype macrophages, alongside an elevation in anti-inflammatory cytokine levels. Subsequent
in vitro
investigations involving RAW264.7 and bone marrow macrophages reveal that
Emu
-serpin induces a conversion of M2 macrophage populations from a pro-inflammatory to an anti-inflammatory phenotype through direct inhibition. Adoptive transfer experiments reveal the peritoneal macrophages induced by
Emu
-serpin alleviate colitis and gut microbiota dysbiosis. In summary, these findings propose that
Emu
-serpin holds the potential to regulate macrophage polarization and maintain gut microbiota homeostasis in colitis, establishing it as a promising candidate for developing helminth therapy for preventing inflammatory diseases.
Lipoteichoic acid biosynthesis by
Staphylococcus aureus
is controlled by the MspA protein
Authors: Bonini Dora , Duggan Seána , Alnahari Alaa , Brignoli Tarcisio , Strahl Henrik , Massey Ruth C.
Published: July 2024

Staphylococcus aureus
produces a plethora of virulence factors critical to its ability to establish an infection and cause disease. We have previously characterized a small membrane protein, MspA, which has pleiotropic effects on virulence and contributes to
S. aureus
pathogenicity
in vivo
. Here we report that
mspA
inactivation triggers overaccumulation of the essential cell wall component, lipoteichoic acid (LTA), which, in turn, decreases autolytic activity and leads to increased cell size due to a delay in cell separation. We show that MspA directly interacts with the enzymes involved in LTA biosynthesis (LtaA, LtaS, UgtP, and SpsB), interfering with their normal activities. MspA, in particular, interacts with the type I signal peptidase SpsB, limiting its cleavage of LtaS into its active form. These findings suggest that MspA contributes to maintaining a physiological level of LTA in the cell wall by interacting with and inhibiting the activity of SpsB, thereby uncovering a critical role for the MspA protein in regulating cell envelope biosynthesis and pathogenicity.

IMPORTANCE

The
S. aureus
cell envelope, comprising the cytoplasmic membrane, a thick peptidoglycan layer, and the anionic polymers lipoteichoic acid and wall teichoic acids, is fundamental for bacterial growth and division, as well as being the main interface between the pathogen and the host. It has become increasingly apparent that the synthesis and turnover of cell envelope components also affect the virulence of
S. aureus
. In this study, we show that MspA, an effector of
S. aureus
virulence, contributes to the maintenance of normal levels of lipoteichoic acid in the cell wall, with implications on cell cycle and size. These findings further our understanding of the connections between envelope synthesis and pathogenicity and suggest that MspA represents a promising target for the development of future therapeutic strategies.
Draft genome sequences of two
Gluconobacter
strains isolated from spoiled orange juice
Authors: Ariano Ky , Farrington Tayler , Schweiger Paul
Published: July 2024

Here, we present the draft genome sequences of two
Gluconobacter
strains that were isolated from spoiled orange juice.
Gluconobacter
are members of the acetic acid bacteria and are known for their unique metabolism and use in industry. Understanding acetic acid bacteria diversity is essential for engineering further optimized industrial strains.
Draft genome assemblies of one
Lactobacillus gasseri
strain and two
Lactobacillus jensenii
strains isolated from voided urine samples
Authors: Kula Alex , Stegman Natalie , Putonti Catherine
Published: July 2024

We present the draft genome for three
Lactobacillus
strains isolated from female urine specimens:
Lactobacillus gasseri
UMB1673,
Lactobacillus jensenii
UMB1855, and
Lactobacillus jensenii
UMB5069. Focusing on strains within the female urinary microbiome can provide a more well-rounded understanding of the microbial community and its influence on health and disease.
The construction of the Giza pyramids chronicled by human copper contamination
Authors: Younes Gamal , Kaniewski David , Marriner Nick , Morhange Christophe , Sheisha Hader , Odler Martin , Wang Yanna , Chen Zhongyuan , El-Qady Gad , Saleem Amr , Véron Alain
Published: July 2024

Although the construction of the Giza necropolis necessitated the creation of an extensive array of metal tools, the significance of these early instances of metallurgy, and the contamination they left, has been overlooked in favor of understanding pyramid building techniques. We geochemically analyzed a sediment core from the Khufu harbor, on the Nile floodplain at Giza, Egypt, to track the construction of the necropolis, with a particular focus on copper contamination deriving from metallurgical activities. We found that significant local contamination occurred during the regnal years of Kings Khufu, Khafre, and Menkaure, consistent with metalworking during the preparation and construction of the edifices. While the pyramid complex led to the creation of an outstanding cultural legacy for humanity, it also marked the onset of significant human-caused metal contamination at Giza.
Supplemental Material: Abrupt structural deformation changes from the boundary to the interior of a craton basin: Implications for the long-term stability of cratonic blocks
Authors: Huang Lei , et al.
Published: July 2024

Figure S1: Strike-slip faults in the West Siberrian Basin. Figure S2: Changes of global in-plane stress with depth. 
The Ionospheric Electric Field Perturbation with an Increase in Radon Emanation
Authors: Denisenko V. V. , Rozanov E. V. , Belyuchenko K. V. , Bessarab F. S. , Golubenko K. S. , Klimenko M. V.
Published: July 2024

Due to the increase in radon emanation, the conductivity in the surface layer of air increases, which causes variations in the electric fields in the low atmosphere and according to some hypotheses in the ionosphere. There are well-known proposals on the possibility of using such ionospheric disturbances as precursors of earthquakes. In this study, the ionospheric electric fields are calculated in the framework of a quasi-stationary model of the conductor consisting of the atmosphere, including the ionosphere. The consequences of the paradoxical point of view on the decrease in the conductivity of surface air with an increase in radon content are also considered. It is shown that even with extreme radon emanation, the obtained calculated perturbations of the ionospheric electric field are three to four orders of magnitude smaller than the supposed precursors of earthquakes.
Examining the availability and readiness of health facilities to provide cervical cancer screening services in Nepal: a cross-sectional study using data from the Nepal Health Facility Survey
Authors: Acharya Kiran , Bhattarai Navaraj , Dahal Rudra , Bhattarai Asmita , Paudel Yuba Raj , Dharel Dinesh , Aryal Kabita , Adhikari Kamala
Published: July 2024

Objective

We assessed the availability and readiness of health facilities to provide cervical cancer screening services in Nepal.

Design

Cross-sectional study.

Setting

We used secondary data from a nationally representative 2021 Nepal Health Facility Survey, specifically focusing on the facilities offering cervical cancer screening services.

Outcome measures

We defined the readiness of health facilities to provide cervical cancer screening services using the standard WHO service availability and readiness assessment manual.

Results

The overall readiness score was 59.1% (95% CI 55.4% to 62.8%), with more equipment and diagnostic tests available than staff and guidelines. Public hospitals (67.4%, 95% CI 63.0% to 71.7%) had the highest readiness levels. Compared with urban areas, health facilities in rural areas had lower readiness. The Sudurpashchim, Bagmati and Gandaki provinces had higher readiness levels (69.1%, 95% CI 57.7% to 80.5%; 60.1%, 95% CI 53.4% to 66.8%; and 62.5%, 95% CI 56.5% to 68.5%, respectively). Around 17% of facilities had trained providers and specific guidelines to follow while providing cervical cancer screening services. The basic healthcare centres (BHCCs) had lower readiness than private hospitals. Facility types, province and staff management meetings had heterogeneous associations with three conditional quantile scores.

Conclusion

The availability of cervical cancer screening services is limited in Nepal, necessitating urgent action to expand coverage. Our findings suggest that efforts should focus on improving the readiness of existing facilities by providing training to healthcare workers and increasing access to guidelines. BHCCs and healthcare facilities in rural areas and Karnali province should be given priority to enhance their readiness.
Long-term cohort study of patients presenting with hypercapnic respiratory failure
Authors: Chung Yewon , Garden Frances L , Marks Guy B , Vedam Hima
Published: July 2024

Objective

We sought to describe the long-term prognosis for a population-based cohort of people with hypercapnic respiratory failure (HRF) and the associations between underlying diagnoses and the risks of death and rehospitalisation.

Methods

We performed a historical cohort study of all persons with HRF in the Liverpool local government area in New South Wales, Australia, in the 3-year period from 2013 to 2015. Cohort members were identified using arterial blood gas results from Liverpool Hospital demonstrating pH ≤7.45 and PaCO2>45 mm Hg within 24 hours of presentation. Linked health data were obtained from statewide registries with a minimum follow-up period of 6 years. The primary outcomes were time to death from any cause and the standardised mortality ratio (SMR) which compares the observed to the expected number of deaths in the same population. Secondary outcomes were time to rehospitalisation and the associations between death and/or hospitalisation and underlying diagnoses.

Results

The cohort comprised 590 adults aged between 15 and 101 years. Overall, 415 (70.3%) participants died in the follow-up period. Among those who survived the index admission, the probability of survival at 1, 3 and 5 years was 81%, 59% and 45%, respectively. The overall SMR was 9.2 (95% CI 7.6 to 11.0), indicating a near 10-fold risk of death than otherwise expected for age. Most (91%) survivors experienced rehospitalisation, with median (IQR) time to readmission of 3.9 (1.2–10.6) months. Congestive cardiac failure and neuromuscular disease were associated with an increased risk of death, whereas chronic obstructive pulmonary disease and sleep disordered breathing increased the risk of rehospitalisation.

Conclusions

HRF is associated with poor survival and high risk of rehospitalisation in the 5 years following an index event. The underlying disease appears to have some influence on overall survival and subsequent hospitalisations.
Use of oral moist tobacco (snus) in puberty and its association with asthma in the population-based RHINESSA study
Authors: López-Cervantes Juan Pablo , Schlünssen Vivi , Senaratna Chamara , Accordini Simone , Callejas Francisco Javier , Franklin Karl A , Holm Mathias , Jogi Nils Oskar , Malinovschi Andrei , Oudin Anna , Sigsgaard Torben , Thorarinsdottir Elin Helga , Janson Christer , Bertelsen Randi Jacobsen , Svanes Cecilie
Published: July 2024

Objectives

To investigate the association of early snus use initiation (≤15 years of age) with asthma and asthma symptoms.

Design

Cross-sectional analysis of a population-based cohort.

Setting

Study centres in Norway, Sweden, Iceland, Denmark and Estonia, from 2016 to 2019.

Participants

9002 male and female participants above 15 years of age of the Respiratory Health in Northern Europe, Spain and Australia study.

Main outcome measures

Current asthma and asthma symptoms.

Results

The median age of study participants was 28 years (range 15–53) and 58% were women. 20% had used snus, 29% men and 14% women. Overall, 26% of males and 14% of females using snus started ≤15 years of age. Early snus use initiation was associated with having three or more asthma symptoms (OR 2.70; 95% CI 1.46 to 5.00) and a higher asthma symptom score (β-coefficient (β) 0.35; 95% CI 0.07 to 0.63) in women. These associations were weak in men (OR 1.23; 95% CI 0.78 to 1.94; β 0.16; 95% CI −0.06 to 0.38, respectively). There was evidence for an association of early snus initiation with current asthma (OR 1.72; 95% CI 0.88 to 3.37 in women; OR 1.31; 95% CI 0.84 to 2.06 in men). A sensitivity analysis among participants without smoking history showed stronger estimates for all three outcomes, in both men and women, statistically significant for three or more asthma symptoms in women (OR 3.28; 95% CI 1.18 to 9.10). Finally, no consistent associations with asthma outcomes were found for starting snus after age 15 years.

Conclusions

Snus initiation in puberty was associated with higher likelihood of asthma and asthma symptoms, with the highest estimates in females and those without smoking history. These results raise concerns about the health adversities of early snus initiation and emphasise the need for public health initiatives to protect young people from this tobacco product.
HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B
Authors: Vecchi Andrea , Rossi Marzia , Tiezzi Camilla , Fisicaro Paola , Doselli Sara , Gabor Elena Adelina , Penna Amalia , Montali Ilaria , Ceccatelli Berti Camilla , Reverberi Valentina , Montali Anna , Fletcher Simon P , Degasperi Elisabetta , Sambarino Dana , Laccabue Diletta , Facchetti Floriana , Schivazappa Simona , Loggi Elisabetta , Coco Barbara , Cavallone Daniela , Rosselli Del Turco Elena , Massari Marco , Pedrazzi Giuseppe , Missale Gabriele , Verucchi Gabriella , Andreone Pietro , Brunetto Maurizia Rossana , Lampertico Pietro , Ferrari Carlo , Boni Carolina
Published: July 2024

Objective

Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on.

Design

53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core‐related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy.

Results

Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values.

Conclusions

PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.
Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis
Authors: Kreimeyer Henriette , Gonzalez Carlos G , Fondevila Marcos F , Hsu Cynthia L , Hartmann Phillipp , Zhang Xinlian , Stärkel Peter , Bosques-Padilla Francisco , Verna Elizabeth C , Abraldes Juan G , Brown Robert S , Vargas Victor , Altamirano Jose , Caballería Juan , Shawcross Debbie L , Louvet Alexandre , Lucey Michael R , Mathurin Philippe , Garcia-Tsao Guadalupe , Bataller Ramón , Investigators AlcHepNet , Gonzalez David J , Schnabl Bernd
Published: July 2024

Objective

Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils.

Design

In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet).

Result

Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days.

Conclusions

We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.
Epidemiology and association of neighbourhood marginalisation on violent knife assaults in Ontario: a population-based case-control study
Authors: Evans Christopher , Li Wenbin , Matskiv George , Brogly Susan
Published: July 2024

Background

Violent knife assaults (‘stabbings’) are underappreciated as a source of morbidity and mortality. The two objectives of this study were to describe the epidemiology of stabbing injuries in the population of Ontario, Canada and to assess the associations between two measures of neighbourhood marginalisation—material deprivation and housing instability, and the risk of stabbing injury.

Methods

We conducted a population-based case-control study over 2004–18 using linked administrative data. Cases suffered a stabbing injury resulting in an emergency department visit, hospitalisation or death. Four age and sex-matched controls were matched to each case. Multivariate logistic regression was used to assess the associations between neighbourhood material deprivation as well as housing instability and the risk of injury. Mean annualised injury incidences were estimated using the number of cases identified divided by the total population of Ontario for that year.

Results

We identified 26 657 individuals with a stabbing injury, of which 724 (2.7%) were fatal. The mean annualised incidence was 13.4 per 100 000 (95% CI: 12.7 to 15.9). Victims were disproportionately young (median age 25 years; IQR: 20–37 years) males (84.1%), from large urban centres (77.5%), and in the lowest income quintile (39.3%). In multivariate models, neighbourhood material deprivation (OR 1.45, 95% CI: 1.43 to 1.47) and housing instability (OR 1.4, 95% CI: 1.22 to 1.26) were associated with risk of injury.

Conclusions

Stabbing injuries are a substantial public health problem that affects individuals of all ages and demographics but disproportionately affects younger men in urban settings. There is a weak association between residence in marginalised neighbourhoods and the risk of stabbing injury. Future studies should aim to better understand the nature of this association and consider opportunities for public health interventions to reduce the burden of violent knife injuries.
Prediction of the mechanism of suicide among Minnesota residents using data from the Minnesota violent death reporting system (MNVDRS)
Authors: Waller Daniel C. , Wolfson Julian , Gingerich Stefan , Wright Nate , Ramirez Marizen R.
Published: July 2024

Background

Suicide remains a major public health problem, and firearms are used in approximately half of all such incidents. This study sought to predict the occurrence of suicide specifically by firearm, as opposed to any other means of suicide, in order to help inform possible life-saving interventions.

Methods

This study involved data from the Minnesota Violent Death Reporting System. Models evaluated whether data beyond basic demographics generated increased prediction accuracy. Models were built using random forests, logistic regression and data imputation. Models were evaluated for prediction accuracy using the area under the curve analysis and for proper calibration.

Results

Results showed that models constructed with social determinants and personal history data led to increased prediction accuracy in comparison to models constructed with basic demographic information only. The study identified an optimised ‘top 20’ variables model with a 73% chance of correctly discerning relative incident risk for a pair of individuals. Age, height/weight, employment industry/occupation, sex and education level were found to be most highly predictive of firearm suicide in the study’s ‘top 20’ model.

Conclusions

The study demonstrated that the use of a firearm in a death by suicide, as opposed to any other means of suicide, can be reasonably well predicted when an individual’s social determinants and personal history are considered. These predictive models could help inform many prevention strategies, such as safe storage practices, background checks for firearm purchases or red flag laws.
The evolving contribution of MRI measures towards the prediction of secondary progressive multiple sclerosis
Authors: Ananthavarathan Piriyankan , Sahi Nitin , Chung Karen , Haider Lukas , Prados Ferran , Trip S Anand , Ciccarelli Olga , Barkhof Frederik , Tur Carmen , Chard Declan T
Published: July 2024

Background

In multiple sclerosis (MS), both lesion accrual and brain atrophy predict clinical outcomes. However, it is unclear whether these prognostic features are equally relevant throughout the course of MS. Among 103 participants recruited following a clinically isolated syndrome (CIS) and followed up over 30 years, we explored (1) whether white matter lesions were prognostically more relevant earlier and brain atrophy later in the disease course towards development of secondary progressive (SP) disease; (2) if so, when the balance in prognostic contribution shifts and (3) whether optimised prognostic models predicting SP disease should include different features dependent on disease duration.

Methods

Binary logistic regression models were built using age, gender, brain lesion counts and locations, and linear atrophy measures (third ventricular width and medullary width) at each time point up to 20 years, using either single time point data alone or adjusted for baseline measures.

Results

By 30 years, 27 participants remained CIS while 60 had MS (26 SPMS and 16 MS-related death). Lesions counts were prognostically significant from baseline and at all later time points while linear atrophy measure models reached significance from 5 years. When adjusted for baseline, in combined MRI models including lesion count and linear atrophy measures, only lesion counts were significant predictors. In combined models including relapse measures, Expanded Disability Status Scale scores and MRI measures, only infratentorial lesions were significant predictors throughout.

Conclusions

While SPMS progression is associated with brain atrophy, in predictive models only infratentorial lesions were consistently prognostically significant.
Critical reviews of exposure assessment in carcinogenic hazard identification: the IARCMonographsexperience
Authors: Middleton Daniel R S , Wedekind Roland , Hall Amy L , Suonio Eero , DeBono Nathan , Vermeulen Roel , Fritschi Lin , Stewart Patricia A , Schubauer-Berigan Mary K
Published: July 2024

Objectives

To summarise the rationale, workflow and recommendations for the conduct of exposure assessment critiques in key human studies evaluated for International Agency for Research on Cancer (IARC)Monographson the Identification of Carcinogenic Hazards.

Methods

Approaches to evaluating exposure assessment quality in human cancer and mechanistic studies were reviewed according to the precepts outlined in the IARCMonographsPreamble, using two agents as case studies. Exposure assessment ‘domains’, that is, salient aspects of exposure assessment for the agent under evaluation, were selected for review across the key human studies.

Results

The case studies of night shift work (volume 124) and 1,1,1-trichloroethane (volume 130) used a common approach, tailored to the agents’ specific exposure scenarios, to evaluate exposure assessment quality. Based on the experiences of IARC Working Groups to date, the implementation of exposure assessment critique requires the need for agent-specific knowledge, consideration of the validity of time-varying exposure metrics related to duration and intensity, and transparent, concise reviews that prioritise the most important strengths and limitations of exposure assessment methods used in human studies.

Conclusions

Exposure assessment has not historically been a fully appreciated component for evaluating the quality of epidemiological studies in cancer hazard identification. Exposure assessment critique in key human cancer and mechanistic studies is now an integral part of IARCMonographsevaluations and its conduct will continue to evolve as new agents are evaluated. The approaches identified here should be considered as a potential framework by others when evaluating the exposure assessment component of epidemiological studies for systematic reviews.
Bitter taste of the tobacco industry interference in Brazil
Authors: Szklo André Salem , Carvalho Adriana , Coutinho Marques de Pinho Mariana , Carvalho de Souza Mirian , Bertoni Neilane , Luiz Oliveira da Silva Andre
Published: July 2024

Objective

Although Brazil became the first country worldwide to ban the sale of all tobacco products with any additive that could alter their flavours and tastes in 2012, its implementation was effectively halted by tobacco industry lawsuits, including a constitutional challenge filed in the Federal Supreme Court in 2013. This study aimed at examining, for the first time in the country, the evolution over time of the new registrations of tobacco products with additives that would have been banned if not for the tobacco industry’s interference (’counterfactual scenario’).

Methods

We used the newly available public database on the registration of tobacco products developed by the Health Regulatory Agency (from 2008 onwards). All types of tobacco products intended for the domestic market that contained ‘banned additives in a counterfactual scenario’ and were registered between January 1 and December 31 of each year were selected.

Results

Between 2012 and 2023, a total of 1112 new registrations of tobacco products with ‘banned additives’ were recorded. The spread of hookah tobacco registrations started in 2014, and by 2023, the cumulative incidence of registrations containing ‘banned additives’ was 641. Both manufactured cigarettes and hookah products reached their peaks in new registrations in 2020.

Conclusions

After 12 years since the resolution intended to ban all additives that change the aroma and taste of tobacco products in Brazil, primarily to prevent smoking initiation, the tobacco industry’s interference continues to successfully block its implementation. Countries facing similar challenges in tobacco control could consider generating comparable national data that might help expose the adverse impacts of tobacco industry interference on public health.
Gestational physical activity alters offspring brain APP processing in an age-specific manner
Authors: Mohammad A. , Ruegsegger G.N. , Olver T.D. , MacPherson R.E.K.
Published: July 2024

Maternal exercise is beneficial for offspring brain development. Amyloid precursor protein (APP) influences neurogenesis and synaptic plasticity. Cleavage products of APP are implicated in the proliferation of neural progenitor cells and neuronal network development. Our study aimed to investigate differences in APP processing in active or sedentary offspring of dams who were exposed to voluntary wheel running with and without a western diet throughout gestation. Female Wistar rats (7–8 weeks old) were fed a normal chow or western diet and randomized into voluntary wheel run or sedentary conditions. Dams returned to sedentary conditions post-parturition. The pups were weaned at 6 weeks after which point half of the samples were collected, while the rest of the pups remained on a normal diet, separated into sedentary or voluntary wheel run groups, and collected 12 weeks later. In utero exposure to maternal exercise was associated with higher neuronal nuclear protein, higher soluble APPα and lower soluble APPβ in offspring prefrontal cortex tissue at 6, but not 18 weeks of age. Neuronal nuclear protein is exclusive to mature neurons implying that offspring of mothers who exercised could have more neuron maturation potentially influenced by the higher APPα content at this early developmental stage. The voluntary wheel run offspring groups had a higher mature/pro brain derived neurotrophic factor ratio compared to the sedentary counterparts. The maternal effects were isolated to the juvenile 6-week-old pups, while the differences in the adult offspring were caused by their own exercise status.
Exploration of soliton structures in the Hirota–Maccari system with stability analysis
Authors: Alam Noor , Ma Wen-Xiu , Ullah Mohammad Safi , Seadawy Aly R. , Akter Mahinur
Published: July 2024

In this research, the modified extended tanh-function (METF) and the extended Jacobi elliptic function expansion (EJEFE) techniques are used to investigate the generation and detection of soliton structures in the Hirota–Maccari (HM) model. Consequently, we obtain soliton solutions with advanced structures, including singular bright soliton, dark soliton, periodic waves, breather waves, periodic breather waves, and multiple bright and dark breather waves. In addition, a lump-type breather wave is also included in the presented solutions. Stability analysis of the obtained solutions is addressed by employing the Hamiltonian technique. 3D surfaces and 2D visuals of the outcomes are represented with the help of a computer application. These findings contribute to understanding nonlinear wave phenomena with potential applications in optics, fluid dynamics, and plasma physics.
A User Study on Explainable Online Reinforcement Learning for Adaptive Systems
Authors: Metzger Andreas , Laufer Jan , Feit Felix , Pohl Klaus
Published: July 2024

Online reinforcement learning (RL) is increasingly used for realizing adaptive systems in the presence of design time uncertainty because Online RL can leverage data only available at run time. With Deep RL gaining interest, the learned knowledge is no longer represented explicitly but hidden in the parameterization of the underlying artificial neural network. For a human, it thus becomes practically impossible to understand the decision-making of Deep RL, which makes it difficult for (1) software engineers to perform debugging, (2) system providers to comply with relevant legal frameworks, and (3) system users to build trust. The explainable RL technique XRL-DINE, introduced in earlier work, provides insights into why certain decisions were made at important time steps. Here, we perform an empirical user study concerning XRL-DINE involving 73 software engineers split into treatment and control groups. The treatment group is given access to XRL-DINE, while the control group is not. We analyze (1) the participants’ performance in answering concrete questions related to the decision-making of Deep RL, (2) the participants’ self-assessed confidence in giving the right answers, (3) the perceived usefulness and ease of use of XRL-DINE, and (4) the concrete usage of the XRL-DINE dashboard.
A Perspectival Mirror of the Elephant
Authors: Luo Queenie , Puett Michael J. , Smith Michael D.
Published: July 2024

Investigating language bias on Google, ChatGPT, YouTube, and Wikipedia.