bluuebunny/crossref_metadata_2025 huggingface dataset:
Organ-sparing treatment for T1 and T2 penile cancer: an updated literature review
Authors: Scornajenghi Carlo Maria , Asero Vincenzo , Bologna Eugenio , Basile Giuseppe , De Angelis Mario , Moschini Marco , Del Giudice Francesco
Published: June 2023

Purpose of review

Penile cancer (PeCa) is an orphan disease due to its rare incidence in high-income countries. Traditional surgical options for clinical T1–2 disease, including partial and total penectomy, can dramatically affect patient's quality of life and mental health status. In selected patients, organ-sparing surgery (OSS) has the potential to remove the primary tumor with comparable oncologic outcomes while maintaining penile length, sexual and urinary function. In this review, we aim to discuss the indications, advantages, and outcomes of various OSSs currently available for men diagnosed with PeCa seeking an organ-preserving option.

Recent findings

Patient survival largely depends on spotting and treating lymph node metastasis at an early stage. The required surgical and radiotherapy skill sets cannot be expected to be available in all centers. Consequently, patients should be referred to high-volume centers to receive the best available treatments for PeCa.

OSS should be used for small and localized PeCa (T1-T2) as an alternative to partial penectomy to preserve patient's quality of life while maintaining sexual and urinary function and penile aesthetics. Overall, there are different techniques that can be used with different response and recurrence rates. In case of tumor recurrence, partial penectomy or radical penectomy is feasible, without impacting overall survival.
The Novel SLRP Family Member Lumican Suppresses Pancreatic Cancer Cell Growth
Authors: Gao Huijie , Liu Chao , Ren Qiang , Zhang Litao , Qin Wei , Wang Huiyun , Zhang Yuntao
Published: June 2023

Objectives

The past studies clearly indicated that lumican was important in the context of pancreatic cancer (PC) onset and progression, but failed to clarify the underlying mechanistic basis for such activity. As such, we evaluated the functional importance of lumican in the context of pancreatic ductal adenocarcinoma (PDAC) to understand its mechanistic role in PC.

Methods

Lumican levels were evaluated in PDAC patient tissues via quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry approaches. The role of lumican was additionally assessed via transfecting PDAC cell lines (BxPC-3, PANC-1) with lumican knockdown or overexpression constructs and treating PDAC cell lines with exogenous recombinant human lumican.

Results

Lumican expression levels were significantly higher in pancreatic tumor tissues relative to healthy paracancerous tissues. Lumican knockdown in BxPC-3 and PANC-1 enhanced their proliferation and migration, but reduced cellular apoptosis. Alternatively, lumican overexpression and exogenous lumican exposure failed to alter the proliferative activity of these cells. Further, lumican knockdown in BxPC-3 and PANC-1 cells results in marked P53 and P21 dysregulation.

Conclusions

Lumican may suppress PDAC tumor growth by regulating P53 and P21, and the function of lumican sugar chains in the context of PC is worth studying in future studies.
Management of the Posthemangioma Nose: 5 Key Rhinoplasty Components
Authors: Chiodo Michael V. , Lisiecki Jeffrey L. , Rohrich Rod J.
Published: June 2023

Hemangiomas of the nasal tip are a relatively uncommon presentation of a common tumor. While optimal medical and surgical management of nasal tip infantile hemangiomas has been described and debated extensively in the literature, to our knowledge, there is no report of secondary aesthetic and functional rhinoplasty in these patients at skeletal maturity, until now. This special topic article provides an excellent example of the 5 key technical elements to revision rhinoplasty in the skeletally mature patient with a history of nasal tip infantile hemangioma.
Quantitative analysis of interface pressures in transfemoral prosthetic sockets
Authors: Paternò Linda , Truppa Luigi , Ibrahimi Michele , Rosini Elisa , Gruppioni Emanuele , Ricotti Leonardo , Menciassi Arianna
Published: June 2023

Background:

Among the different factors affecting socket comfort, the pressure applied on residual limb tissues is a crucial parameter for the success or failure of any prosthetic device. However, only a few incomplete data are available on people with transfemoral amputation, in this regard. This work aims at filling this gap in the literature.

Methods:

Ten people with transfemoral amputation wearing 3 different socket designs were recruited in this study: 2 ischial containment sockets featured by proximal trim lines that contain the ischial tuberosity and ramus and greater trochanter, 2 subischial sockets with proximal trim lines under the ischium level, and 6 quadrilateral sockets with proximal trim lines that contain the greater trochanter and create a horizontal seat for the ischial tuberosity. The pressure values at the anterior, lateral, posterior, and medial areas of the socket interface were recorded during 5 locomotion tasks (ie, horizontal, ascent, and descent walking, upstairs and downstairs) by using an F-Socket System (Tekscan Inc., Boston, MA). Gait segmentation was performed by exploiting plantar pressure, which was acquired by an additional sensor under the foot. Mean and standard deviation of minimum and maximum values were calculated for each interface area, locomotion task, and socket design. The mean pressure patterns during different locomotion tasks were reported, as well.

Results:

Considering all subjects irrespective of socket design, the mean pressure range resulted 45.3 (posterior)–106.7 (posterior) kPa in horizontal walking; 48.3 (posterior)–113.8 (posterior) kPa in ascent walking; 50.8 (posterior)–105.7 (posterior) kPa in descent walking; 47.9 (posterior)–102.9 (lateral) kPa during upstairs; and 41.8 (posterior)–84.5 (anterior) kPa during downstairs. Qualitative differences in socket designs have been found.

Conclusions:

These data allow for a comprehensive analysis of pressures acting at the tissue-socket interface in people with transfemoral amputation, thus offering essential information for the design of novel solutions or to improve existing ones, in this field.
A NETWORK PHARMACOLOGY-BASED TREATMENT ANALYSIS OF LUTEOLIN FOR REGULATING PYROPTOSIS IN ACUTE LUNG INJURY
Authors: Zhang Danying , Li Yifan , Jiang Weiwei , Li Wenfang , Yuan Xiaowei , Lin Zhaofen
Published: June 2023

Background: Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome, are complicated pulmonary inflammatory conditions for which standard therapeutics are still not well established. Although increasing research has indicated the anti-inflammatory, anticancer, and antioxidant effects of luteolin, especially in lung diseases, the molecular mechanisms underlying luteolin treatment remain largely unclear. Methods: The potential targets of luteolin in ALI were explored using a network pharmacology-based strategy and further validated in a clinical database. The relevant targets of luteolin and ALI were first obtained, and the key target genes were analyzed using a protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The targets of luteolin and ALI were then combined to ascertain the relevant pyroptosis targets, followed by Gene Ontology analysis of core genes and molecular docking of key active compounds to the antipyroptosis targets of luteolin in resolving ALI. The expression of the obtained genes was verified using the Gene Expression Omnibus database. In vivo and in vitro experiments were performed to explore the potential therapeutic effects and mechanisms of action of luteolin against ALI. Results: Fifty key genes and 109 luteolin pathways for ALI treatment were identified through network pharmacology. Key target genes of luteolin for treating ALI via pyroptosis were identified. The most significant target genes of luteolin in ALI resolution included AKT1, NOS2, and CTSG. Compared with controls, patients with ALI had lower AKT1 expression and higher CTSG expression. Luteolin simply reduced systemic inflammation and lung tissue damage in septic mice. Furthermore, we blocked AKT1 expression and found luteolin reduced the degree of lung injury and affected NOS2 levels. Conclusions: As demonstrated by a network pharmacology approach, luteolin may exert an antipyroptosis effect on ALI via AKT1, NOS2, and CTSG.
Exploring subcolony differences in foraging and reproductive success: the influence of environmental conditions on a central place foraging seabird
Authors: Pulvirenti Jessica , Reina Richard D. , Chiaradia Andre
Published: June 2023

While differences in foraging and reproductive success are well studied between seabird colonies, they are less understood at a smaller subcolony scale. Working with little penguins (Eudyptula minor) at Phillip Island, Australia, we used an automated penguin monitoring system and performed regular nest checks at two subcolonies situated 2 km apart during the 2015/2016 breeding seasons. We examined whether foraging and reproductive success differed between subcolonies. We used satellite data to examine how sea surface temperature, as environmental pressure, in the foraging regions from each subcolony influenced their foraging performance. In the pre-laying and incubation breeding stages, the birds from one subcolony had a lower foraging success than birds from the other. However, this pattern was reversed between the subcolonies in the guard and post-guard stages. Breeding success data from the two subcolonies from 2004–2018 showed that reproductive success and mean egg-laying had a negative relationship with sea surface temperature. We highlighted that variation in foraging and reproductive success can arise in subcolonies, likely due to different responses to environmental conditions and prey availability. Differences at the subcolony level can help refine, develop and improve appropriate species management plans for conserving a range of colonial central place seabirds.
Fine-scale intraspecific niche partitioning in a highly mobile, marine megafauna species: implications for ecology and conservation
Authors: Silver-Gorges Ian , Ceriani Simona A. , Fuentes Mariana M. P. B.
Published: June 2023

A species may partition its realized ecological niche along bionomic and scenopoetic axes due to intraspecific competition for limited resources. How partitioning manifests depends on resource needs and availability by and for the partitioning groups. Here we demonstrate the utility of analysing short- and long-term stable carbon and nitrogen isotope ratios from imperiled marine megafauna to characterize realized niche partitioning in these species. We captured 113 loggerhead sea turtles (Caretta caretta) at a high-use area in the eastern Big Bend, Florida, between 2016 and 2022, comprising 53 subadults, 10 adult males and 50 adult females. We calculated trophic niche metrics using established and novel methods, and constructed Bayesian ellipses and hulls, to characterize loggerhead isotopic niches. These analyses indicated that loggerheads partition their realized ecological niche by lifestage, potentially along both bionomic (e.g. trophic) and/or scenopoetic (e.g. habitat, latitude or longitude) axes, and display different characteristics of resource use within their niches. Analysis of stable isotopes from tissues with different turnover rates enabled this first characterization of intraspecific niche partitioning between and within neritic lifestages in loggerhead turtles, which has direct implications for ongoing research and conservation efforts for this and other imperiled marine species.
Semantic interference affects speech production by increasing disfluencies, not errors
Authors: Rapoeye Kelly , Hartsuiker Robert J. , Pistono Aurélie
Published: June 2023

Several studies have shown that different types of disfluency occur depending on the language production stage at which people experience difficulties. The current study combined a network task and a picture–word interference task to analyse whether lexical-semantic difficulty triggers errors and disfluencies in connected-speech production. The participants produced more disfluencies in the presence of a semantically related distractor word than an unrelated distractor word, while few semantic errors were made. These results support the hypothesis that difficulties at distinct stages of language production lead to distinct patterns of disfluency, with lexical-semantic difficulties leading to self-corrections and silent pauses. The results also have implications for the role of the monitoring system in connected-speech production.
A glimpse into the foraging and movement behaviour of
Nyctalus aviator
; a complementary study by acoustic recording and GPS tracking
Authors: Niga Yoshifumi , Fujioka Emyo , Heim Olga , Nomi Akito , Fukui Dai , Hiryu Shizuko
Published: June 2023

Species of open-space bats that are relatively large, such as bats from the genus
Nyctalus
, are considered as high-risk species for collisions with wind turbines (WTs). However, important information on their behaviour and movement ecology, such as the locations and altitudes at which they forage, is still fragmentary, while crucial for their conservation in light of the increasing threat posed by progressing WT construction. We adopted two different methods of microphone array recordings and GPS-tracking capturing data from different spatio-temporal scales in order to gain a complementary understanding of the echolocation and movement ecology of
Nyctalus aviator
, the largest open-space bat in Japan. Based on microphone array recordings, we found that echolocation calls during natural foraging are adapted for fast flight in open-space optimal for aerial-hawking. In addition, we attached a GPS tag that can simultaneously monitor feeding buzz occurrence, and confirmed that foraging occurred at 300 m altitude and that the flight altitude in mountainous areas is consistent with the turbine conflict zone, suggesting that the birdlike noctule is a high-risk species in Japan. Further investigations on this species could provide valuable insights into their foraging and movement ecology, facilitating the development of a risk assessment regarding WTs.
Hydrodynamic interactions between squirmers near walls: far-field dynamics and near-field cluster stability
Authors: Théry A. , Maaß C. C. , Lauga E.
Published: June 2023

Confinement increases contacts between microswimmers in dilute suspensions and affects their interactions. In particular, boundaries have been shown experimentally to lead to the formation of clusters that would not occur in bulk fluids. To what extent does hydrodynamics govern these boundary-driven encounters between microswimmers? We consider theoretically the symmetric boundary-mediated encounters of model microswimmers under gravity through far-field interaction of a pair of weak squirmers, as well as the lubrication interactions occurring after contact between two or more squirmers. In the far field, the orientation of microswimmers is controlled by the wall and the squirming parameter. The presence of a second swimmer influences the orientation of the original squirmer, but for weak squirmers, most of the interaction occurs after contact. We thus analyse next the near-field reorientation of circular groups of squirmers. We show that a large number of swimmers and the presence of gravity can stabilize clusters of pullers, while the opposite is true for pushers; to be stable, clusters of pushers thus need to be governed by other interactions (e.g. phoretic). This simplified approach to the phenomenon of active clustering enables us to highlight the hydrodynamic contribution, which can be hard to isolate in experimental realizations.
A secure future? Human urban and agricultural land use benefits a flightless island-endemic rail despite climate change
Authors: Lévêque Lucile , Amin Rahil J. , Buettel Jessie , Carver Scott , Brook Barry
Published: June 2023

Identifying environmental characteristics that limit species' distributions is important for contemporary conservation and inferring responses to future environmental change. The Tasmanian native hen is an island endemic flightless rail and a survivor of a prehistoric extirpation event. Little is known about the regional-scale environmental characteristics influencing the distribution of native hens, or how their future distribution might be impacted by environmental shifts (e.g. climate change). Using a combination of local fieldwork and species distribution modelling, we assess environmental factors shaping the contemporary distribution of the native hen, and project future distribution changes under predicted climate change. We find 37% of Tasmania is currently suitable for the native hens, owing to low summer precipitation, low elevation, human-modified vegetation and urban areas. Moreover, in unsuitable regions, urban areas can create ‘oases’ of habitat, able to support populations with high breeding activity by providing resources and buffering against environmental constraints. Under climate change predictions, native hens were predicted to lose only 5% of their occupied range by 2055. We conclude that the species is resilient to climate change and benefits overall from anthropogenic landscape modifications. As such, this constitutes a rare example of a flightless rail to have adapted to human activity.
A Case Report of disseminated Streptococcus pneumoniae infection complicated by infective endocarditis, septic arthritis and epidural abscess in an immunocompetent patient
Authors: Dean Kimberley Rose , Koirala Archana , Samarasekara Harsha
Published: June 2023

Streptococcus pneumoniae is a highly virulent, vaccine preventable pathogen which can cause disease on a spectrum from benign to fatal. Apart from pneumonia, it commonly causes septicaemia and meningitis. This case report describes an unusual range of complications in a middle, aged Caucasian female presenting to a regional hospital, without any risk known factors for severe disease. Progressing from episode of otitis media, her condition rapidly progressed to mastoid sinusitis, septic arthritis, infective endocarditis epidural abscesses and multiple subcutaneous abscesses. Following quick identification of S pneumoniae from a positive blood culture, she was treated with high dose benzylpenicillin and ceftriaxone and aggressive source control by surgery, enabling a good clinical recovery.
Insights into the challenging multi-country outbreak of Mpox: a comprehensive review
Authors: Bhat Shreyas , Saha Sumana , Garg Tanisha , Sehrawat Himanshu , Chopade Balu Ananda , Gupta Vandana
Published: June 2023

Human monkeypox virus (hMpoxV) is of zoonotic origin and is closely related to the once-dreaded smallpox virus. It is largely endemic to the African continent but has moved out of the endemic regions as sporadic clusters in the past 20 years, raising concerns worldwide. Human Mpox is characterized by a mild to severe, self-limiting infection, with mortality ranging from less than 1% to up to 10% during different outbreaks caused by different clades of MpoxV. Bushmeat hunting is one of the primary reasons for its transmission from animals to humans. Various international and national health regulatory bodies are closely monitoring the disease and have laid down guidelines to manage and prevent hMpox cases. Emergency Use Status has been granted to Tecovirimat and Brincidofovir to treat severe cases and vaccination with the smallpox vaccine is recommended for high-risk group individuals. Strategies to repurpose and discover novel therapeutics and vaccines to control the outbreak are being researched. The current Mpox outbreak that has mainly affected men as approximately 96% of all cases are reported in men, is probably the result of a complex intersection of various factors. This necessitates a strong One Health response coordination involving human, animal and environmental health institutions. This review is an attempt to provide an all-inclusive overview of the biology, history, epidemiology, pathophysiology, diagnosis and management of hMpox in context to the recent 2022–2023 multi-country outbreak which is termed by WHO a ‘Public Health Emergency of International Concern (PHEIC)’.
Microbial Associates of the Elm Leaf Beetle: Uncovering the Absence of Resident Bacteria and the Influence of Fungi on Insect Performance
Authors: Schott Johanna , Rakei Juliette , Remus-Emsermann Mitja , Johnston Paul , Mbedi Susan , Sparmann Sarah , Hilker Monika , Paniagua Voirol Luis R.
Published: June 2023

Microbial symbionts play crucial roles in the biology of many insects. While bacteria have been the primary focus of research on insect-microbe symbiosis, recent studies suggest that fungal symbionts may be just as important. The elm leaf beetle (ELB,Xanthogaleruca luteola) is a serious pest species of elm (Ulmus minor). Using culture-dependent and independent methods, we investigated the abundance and species richness of bacteria and fungi throughout various ELB life stages and generations, while concurrently analysing microbial communities on elm leaves. No persistent bacterial community was found to be associated with the ELB or elm leaves. By contrast, fungi were persistently present in the beetle’s feeding life stages and on elm leaves. Fungal community sequencing revealed a predominance of the generaPenicilliumandAspergillusin insects and on leaves. Culture-dependent surveys showed a high prevalence of two fungal colony morphotypes closely related toPenicillium lanosocoeruleumandAspergillus flavus. Among these, thePenicilliummorphotype was significantly more abundant on feeding-damaged compared to intact leaves, suggesting that the fungus thrives in the presence of the ELB. We assessed whether the detected prevalent fungal morphotypes influenced ELB’s performance by rearing insects on i) surface-sterilised leaves, ii) leaves inoculated withPenicilliumspores, and iii) leaves inoculated withAspergillusspores. Insects feeding onPenicillium-inoculated leaves gained more biomass and tended to lay larger egg clutches than those consuming surface-sterilised leaves orAspergillus-inoculated leaves. Our results demonstrate that the ELB does not harbour resident bacteria and that it might benefit from associating withPenicilliumfungi.

Importance

Our study provides insights into the still understudied role of microbial symbionts in the biology of the ELB, a major pest of elms. Contrary to expectations, we found no persistent bacterial symbionts associated with the ELB or elm leaves. Our research thus contributes to the growing body of knowledge that not all insects rely on bacterial symbionts. While no persistent bacterial symbionts were detectable in the ELB and elm leaf samples, our analyses revealed the persistent presence of fungi, particularlyPenicilliumandAspergilluson both elm leaves and in the feeding ELB stages. Moreover, when ELB were fed with fungus-treated elm leaves, we detected a potentially beneficial effect ofPenicilliumon the ELB’s development and fecundity. Our results highlight the significance of fungal symbionts in the biology of this insect.
A Bioluminescent Activity Dependent (BLADe) Platform for Converting Neuronal Activity to Photoreceptor Activation
Authors: Crespo Emmanuel L. , Pal Akash , Prakash Mansi , Silvagnoli Alexander D. , Zaidi Zohair , Gomez-Ramirez Manuel , Tree Maya O. , Shaner Nathan C. , Lipscombe Diane , Moore Christopher , Hochgeschwender Ute
Published: June 2023

We developed a platform that utilizes a calcium-dependent luciferase to convert neuronal activity into activation of light sensing domains within the same cell. The platform is based on aGaussialuciferase variant with high light emission split by calmodulin-M13 sequences that depends on influx of calcium ions (Ca2+) for functional reconstitution. In the presence of its luciferin, coelenterazine (CTZ), Ca2+influx results in light emission that drives activation of photoreceptors, including optogenetic channels and LOV domains. Critical features of the converter luciferase are light emission low enough to not activate photoreceptors under baseline condition and high enough to activate photosensing elements in the presence of Ca2+and luciferin. We demonstrate performance of this activity-dependent sensor and integrator for changing membrane potential and driving transcription in individual and populations of neuronsin vitroandin vivo.
MAPS: Pathologist-level cell type annotation from tissue images through machine learning
Authors: Shaban Muhammad , Bai Yunhao , Qiu Huaying , Mao Shulin , Yeung Jason , Yeo Yao Yu , Shanmugam Vignesh , Chen Han , Zhu Bokai , Nolan Garry P. , Shipp Margaret A. , Rodig Scott J. , Jiang Sizun , Mahmood Faisal
Published: June 2023

Highly multiplexed protein imaging is emerging as a potent technique for analyzing protein distribution within cells and tissues in their native context. However, existing cell annotation methods utilizing high-plex spatial proteomics data are resource intensive and necessitate iterative expert input, thereby constraining their scalability and practicality for extensive datasets. We introduce MAPS (Machine learning forAnalysis ofProteomics inSpatial biology), a machine learning approach facilitating rapid and precise cell type identification with human-level accuracy from spatial proteomics data. Validated on multiple in-house and publicly available MIBI and CODEX datasets, MAPS outperforms current annotation techniques in terms of speed and accuracy, achieving pathologist-level precision even for challenging cell types, including tumor cells of immune origin. By democratizing rapidly deployable and scalable machine learning annotation, MAPS holds significant potential to expedite advances in tissue biology and disease comprehension.
SARS-CoV-2 testing in the Slovak Republic from March 2020 to September 2022 – summary of the pandemic trends
Authors: Janostiakova Nikola , Gnip Andrej , Kodada Dominik , Saade Rami , Blandova Gabriela , Mikova Emilia , Tibenska Elena , Repiska Vanda , Minarik Gabriel
Published: June 2023

The COVID-19 pandemic has been part of Slovakia since March 2020. Intensive laboratory testing ended in October 2022, when the number of tests dropped significantly, but the state of the pandemic continues to this day. For the management of COVID-19, it is important to find an indicator that can predict pandemic changes in the community. The average daily/weekly Ct value with a certain time delay can predict changes in the number of cases of SARS-CoV-2 infection, which can be a useful indicator for the healthcare system. The study analyzed the results of 1,420,572 RT-qPCR tests provided by one accredited laboratory during the ongoing pandemic in Slovakia from March 2020 to September 2022. The total positivity of the analyzed tests was 24.64%. The average Ct values found were the highest in the age group of 3-5 years, equal to the number 30.75; the lowest were in the age group > 65 years, equal to the number 27. The average weekly Ct values ranged from 22.33 (pandemic wave week) to 30.12 (summer week). We have summarized the results of SARS-CoV-2 diagnostic testing in Slovakia with the scope defined by the rate and positivity of tests carried out at Medirex a.s. laboratories.
No sex differences in oxygen uptake or extraction kinetics in the moderate or heavy exercise intensity domains
Authors: Solleiro Pons Maria , Bernert Lina , Hume Emily , Hughes Luke , Williams Zander , Burnley Mark , Ansdell Paul
Published: June 2023

The integrative response to exercise differs between sexes, with oxidative energy contribution purported as a potential mechanism. The present study investigated whether this difference was evident in the kinetics of oxygen uptake (V□O2) and extraction (HHb+Mb) during exercise.

Sixteen adults (8 males, 8 females, age: 27±5 years) completed three experimental visits. Incremental exercise testing was performed to obtain lactate threshold and V□O2peak. Subsequent visits involved three six-minute cycling bouts at 80% of lactate threshold and one 30-minute bout at a work rate 30% between the lactate threshold and power at V□O2peak. Pulmonary gas exchange and near-infrared spectroscopy of the vastus lateralis were used to continuously sample V□O2and HHb+Mb, respectively. The phase II V□O2kinetics were quantified using mono-exponential curves during moderate and heavy exercise. Slow component amplitudes were also quantified for the heavy intensity domain.

Relative V□O2peakvalues were not different between sexes (p=0.111). Males achieved ∼30% greater power outputs (p=0.002). In the moderate and heavy intensity domains, the relative amplitude of the phase II transition was not different between sexes for V□O2(∼24 and ∼40% V□O2peak,p≥0.179) and HHb+Mb (∼20 and ∼32% ischemia,p≥0.193). Similarly, there were no sex differences in the time constants for V□O2(∼28 s,p≥0.385) or HHb+Mb (∼10s,p≥0.274). In the heavy intensity domain, neither V□O2(p≥0.686) or HHb+Mb (p≥0.432) slow component amplitudes were different between sexes.

The oxidative response to moderate and heavy intensity exercise did not differ between males and females, suggesting similar dynamic responses of oxidative metabolism during intensity-matched exercise.

New and Noteworthy

This study demonstrated no sex differences in the oxidative response to moderate and heavy intensity cycling exercise. The change in oxygen uptake and deoxyhaemoglobin were modelled with mono-exponential curve fitting, which revealed no differences in the rate of oxidative energy provision between sexes. This provides insight into previously reported sex differences in the integrative response to exercise.
T-cell inflammation is prognostic of survival in patients with high-risk neuroblastoma enriched for an adrenergic signature
Authors: Kaufman Maria E. , Vayani Omar R. , Moore Kelley , Chlenski Alexandre , Wu Tong , Chavez Gepoliano , Lee Sang Mee , Desai Ami V. , He Chuan , Cohn Susan L. , Applebaum Mark A.
Published: June 2023

Purpose

T-cell inflammation (TCI) has been shown to be a prognostic marker in neuroblastoma, a tumor comprised of cells that can exist in two epigenetic states, adrenergic (ADRN) and mesenchymal (MES). We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers.

Patients and Methods

We detected lineage-specific, single-stranded super-enhancers defining ADRN and MES specific genes. Publicly available neuroblastoma RNA-seq data from GSE49711 (Cohort 1) and TARGET (Cohort 2) were assigned MES, ADRN, and TCI scores. Tumors were characterized as MES (top 33%) or ADRN (bottom 33%), and TCI (top 67% TCI score) or non-inflamed (bottom 33% TCI score). Overall survival (OS) was assessed using the Kaplan-Meier method, and differences were assessed by the log-rank test.

Results

We identified 159 MES genes and 373 ADRN genes. TCI scores were correlated with MES scores (R=0.56, p<0.001 and R=0.38, p<0.001) and anticorrelated withMYCN-amplification (R=-0.29, p<0.001 and -0.18, p=0.03) in both cohorts. Among Cohort 1 patients with high-risk, ADRN tumors (n=59), those with TCI tumors (n=22) had superior OS to those with non-inflammed tumors (n=37) (p=0.01), though this comparison did not reach significance in Cohort 2. TCI status was not associated with survival in patients with high-risk MES tumors in either cohort.

Conclusions

High inflammation scores were correlated with improved survival in some high-risk patients with, ADRN but not MES neuroblastoma. These findings have implications for approaches to treating high-risk neuroblastoma.
Reverse Engineering of Feedforward Cortical-Hippocampal Neural Networks Relevant for Preclinical Disease Modelling
Authors: Hanssen Katrine Sjaastad , Winter-Hjelm Nicolai , Niethammer Salome Nora , Kobro-Flatmoen Asgeir , Witter Menno P. , Sandvig Axel , Sandvig Ioanna
Published: June 2023

Engineered biological neural networks are indispensable tools for investigating neural function in both healthy and diseased states from the subcellular to the network level. Neurons in vitro self-organize over time into networks of increasing structural and functional complexity, thus maintaining emergent dynamics of neurons in the brain. While in vitro neural network model systems have advanced significantly over the past decade, there is still a need for models able to recapitulate topological and functional organization of brain networks. Especially relevant in this context are interfaces which can support the establishment of multinodal interconnected networks of different neural populations, which at the same time enable control of the direction of connectivity between the nodes. An added required feature of such interfaces is compatibility with electrophysiological techniques and optical imaging tools to facilitate studies of neural network structure-function dynamics. In this study, we applied a custom-designed microfluidic device with Tesla-valve inspired microchannels for structuring multinodal neural networks with controllable feedforward connectivity between rat primary cortical and hippocampal neurons. By interfacing these devices with nanoporous microelectrode arrays, we demonstrate how both spontaneously evoked and stimulation induced activity propagates, as intended, in a feedforward pattern between the different interconnected neural nodes. Moreover, we show that these multinodal networks exhibit functional dynamics suggestive of capacity for both segregated and integrated activity. To advocate the broader applicability of this model system, we also provide proof of concept of long-term culturing of subregion- and layer specific neurons extracted from the entorhinal cortex and hippocampus of adult Alzheimers-model mice and rats. We show that these neurons re-form structural connections and develop spontaneous spiking activity after 15 days in vitro. Our results thus highlight the suitability and potential of our approach for reverse engineering of biologically and anatomically relevant multinodal neural networks supporting the study of dynamic structure-function relationships in both healthy and pathological conditions.
Coarse-grained molecular dynamics simulations of lipid-protein interactions in SLC4 proteins
Authors: Zhekova Hristina R. , Ramirez-Echemendía Daniel P. , Sejdiu Besian I. , Pushkin Alexander , Tieleman D. Peter , Kurtz Ira
Published: June 2023

The SLC4 family of secondary bicarbonate transporters is responsible for the transport of HCO3−, CO32−, Cl−, Na+, K+, NH3and H+necessary for regulation of pH and ion homeostasis. They are widely expressed in numerous tissues throughout the body and function in different cell types with different membrane properties. Potential lipid roles in SLC4 function have been reported in experimental studies, focusing mostly on two members of the family: AE1 (Cl−/HCO3−exchanger) and NBCe1 (Na+-CO32−cotransporter). Previous computational studies of the outward facing (OF) state of AE1 with model lipid membranes revealed enhanced protein-lipid interactions between cholesterol (CHOL) and phosphatidylinositol bisphosphate (PIP2). However, the protein-lipid interactions in other members of the family and other conformation states are still poorly understood and this precludes the detailed studies of a potential regulatory role for lipids in the SLC4 family. In this work, we performed multiple 50 µs coarse-grained molecular dynamics simulations on three members of the SLC4 family with different transport modes: AE1, NBCe1 and NDCBE (a Na+-CO32−/Cl−exchanger), in model HEK293 membranes consisting of CHOL, PIP2, phosphatidylcholine (POPC), phosphatidylethanolamine (POPE), phosphatidylserine (POPS), and sphingomyelin (POSM). The recently resolved inward-facing (IF) state of AE1 was also included in the simulations. Lipid-protein contact analysis of the simulated trajectories was performed with the ProLint server, which provides a multitude of visualization tools for illustration of areas of enhanced lipid-protein contact and identification of putative lipid binding sites within the protein matrix. We observed enrichment of CHOL and PIP2 around all proteins with subtle differences in their distribution depending on the protein type and conformation state. Putative binding sites were identified for CHOL, PIP2, POPC, and POSM in the three studied proteins and their potential roles in the SLC4 transport function, conformational transition and protein dimerization were discussed.

Statement of significance

The SLC4 protein family is involved in critical physiological processes like pH and blood pressure regulation and maintenance of ion homeostasis. Its members can be found in various tissues. A number of studies suggest possible lipid regulation of the SLC4 function. However, the protein-lipid interactions in the SLC4 family are still poorly understood. Here we make use of long coarse-grained molecular dynamics simulations to assess the protein-lipid interactions in three SLC4 proteins with different transport modes, AE1, NBCe1, and NDCBE. We identify putative lipid binding sites for several lipid types of potential mechanistic importance, discuss them in the framework of the known experimental data and provide a necessary basis for further studies on lipid regulation of SLC4 function.
A note on p-value multiple-testing adjustment for two-step genome-wide gene-environment interactions scans
Authors: Lewinger Juan Pablo , Kawaguchi Eric S. , Gauderman W. James
Published: June 2023

Two-step testing is the state-of-the art approach for performing genome-wide interaction scans (GWIS). It is computationally efficient and yields higher power than standard single-step-based GWIS for virtually all biologically plausible scenarios. However, while two-step tests control the genome-wide type I error rate at the desired level, the lack of associated valid p-values can make it difficult for users to compare with single step-results. We show how multiple-testing adjusted p-values can be defined for two-step test based on standard multiple-testing theory, and how they can be in turn scaled to make valid comparisons with single-step tests possible.
Prevalence, knowledge, causes, and practices of self-medication during the COVID-19 pandemic in Bangladesh: A cross-sectional survey
Authors: Trisha Sadia Mahmud , Ahmed Sanjana Binte , Uddin Md Fahim , Tabassum Tahsin Tasneem , Rahman Nur-A-Safrina , Gupta Mridul , Samiha Maisha , Moulee Shahra Tanjim , Al Sakir Dewan Ibna , Podder Vivek
Published: June 2023

Background

During the COVID-19 pandemic, self-medication (SM) has become a critical element in the healthcare system. SM can ease the burden on hospitals and medical resources by treating minor illnesses. However, inappropriate SM practices can lead to adverse drug reactions, drug resistance, and incorrect diagnoses, resulting in poor health outcomes.

Methods

To evaluate the prevalence, knowledge, causes, and practices of SM among the Bangladeshi population during the COVID-19 outbreak, a cross-sectional survey with structured questionnaires was conducted in Chittagong from March to May 2022. The survey included 265 participants, with an average age of 35.09 years, and a multiple-choice questionnaire was used to gather information.

Results

The study found that 64.15% of respondents had sufficient knowledge of SM, while 35.8% had insufficient knowledge. The primary reasons for SM during the pandemic were the influence of friends/family (90.74%), fear of infection or contact with COVID-19 cases (73.15%), and fear of quarantine or self-isolation (72.22%). Analgesics/pain relievers (84%) were the most commonly used drugs for SM for COVID-19 prevention and treatment. Antiulcerants/anti acid (42%), Vitamin C and Multivitamin (42%), and Antibiotics (32%) were also frequently used.

Conclusion

This study suggests that SM is prevalent among Chittagong City residents, particularly those with less than a tertiary education. The study highlights the importance of building awareness about SM practices and taking necessary steps to control them.
Photoacoustic Imaging as a Novel Non-Invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats
Authors: Weis Victoria G. , Cruz-Diaz Nildris , Rauh Jessica L. , Ellison Maryssa A. , Yamaleyeva Liliya M. , Welch Cherrie D. , Zeller Kristen A. , Weis Jared A.
Published: June 2023

Background

Within the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health.

Methods

Ultrasound and photoacoustic images were acquired in 2-day and 4-day old neonatal rats. For PAI assessment of intestinal tissue oxygenation, an inspired gas challenge was performed using hypoxic, normoxic, and hyperoxic inspired oxygen (FiO2). For intestinal motility, oral administration of ICG contrast agent was used to compare control animals to an experimental model of loperamide-induced intestinal motility inhibition.

Results

PAI demonstrated progressive increases in oxygen saturation (sO2) as FiO2 increased, while the pattern of oxygen localization remained relatively consistent in both 2-day and 4-day old neonatal rats. Analysis of intraluminal ICG contrast enhanced PAI images yielded a map of the motility index in control and loperamide treated rats. From PAI analysis, loperamide significantly inhibited intestinal motility, with a 32.6% decrease in intestinal motility index scores in 4-day old rats.

Conclusion

These data establish the feasibility and application of PAI to non-invasively and quantitatively measure intestinal tissue oxygenation and motility. This proof-of-concept study is an important first step in developing and optimizing photoacoustic imaging to provide valuable insight into intestinal health and disease to improve the care of premature infants.

Highlights

Intestinal tissue oxygenation and intestinal motility are important biomarkers of intestinal physiology in health and disease of premature infants.

This proof-of-concept preclinical rat study is the first to report application of photoacoustic imaging for the neonatal intestine.

Photoacoustic imaging is demonstrated as a promising non-invasive diagnostic imaging method for quantifying intestinal tissue oxygenation and intestinal motility in premature infants.

Graphical abstract
Cell cycle-dependent organization of a bacterial centromere through multi-layered regulation of the ParABS system
Authors: Kaljević Jovana , Le Tung B. K. , Laloux Géraldine
Published: June 2023

The accurate distribution of genetic material is crucial for all organisms. In most bacteria, chromosome segregation is achieved by the ParABS system, in which the ParB-bound centromereparSis actively partitioned by ParA. While this system is highly conserved, its adaptation in organisms with unique lifestyles and its regulation between developmental stages remain unexplored.Bdellovibrio bacteriovorusis a predatory bacterium proliferating through polyploid replication and non-binary division inside other bacteria. Our study reveals the subcellular dynamics and multi-layered regulation of the ParABS system, coupled to the cell cycle ofB. bacteriovorus. We found that ParA:ParB ratios fluctuate between predation stages, their balance being critical for cell cycle progression. Moreover, theparSchromosomal context in non-replicative cells, combined with ParB depletion at cell division, critically contribute to the unique cell cycle-dependent organization of the centromere in this bacterium, highlighting new levels of complexity in chromosome segregation and cell cycle control.

Author summary

The precise distribution of genetic material to the progeny is essential for all living organisms, and the ParABS system is critical for this process in bacteria. Our study provides novel insights into the regulation of this system in a predatory bacterium that exhibits a non-canonical cell cycle, in which the chromosome is copied and segregated multiple times during growth inside a prey bacterium. Our work reveals the subcellular dynamics and multi-level regulation of the ParABS system in this bacterium, which results in the unique cell-cycle dependent assembly of the segregation complex at the chromosomal centromere. Our findings provide a deeper understanding of the adaptation of the ParABS system across bacterial species and developmental stages.
Deciphering the role of the OmpC-Mla system in bile salt resistance
Authors: Zhu Feifan , Chong Zhi-Soon , Chng Shu-Sin
Published: June 2023

The outer membrane (OM) of Gram-negative bacteria presents a formidable barrier against external insults, in part contributing to the survival of Enterobacteriaceae in the mammalian gut. The lipid asymmetry of the OM, where lipopolysaccharides (LPS) form a tight outer layer of low permeability, effectively restricts the passage of toxic substances across the bilayer. In the gut, however, bile salts pose a unique challenge to the bacterial cell due to their ability to form micelles and solubilize membranes; yet, mechanisms to prevent dissolution of the OM by such detergents are not well understood. In this study, we define a distinct role in bile salt resistance for the OmpC-Mla system inEscherichia coli, which is better known for its function in maintaining OM lipid asymmetry. We show that cells lacking a functional OmpC-Mla system are sensitive to bile salts, but only at or above critical micellar concentrations. Furthermore, we observe that these cells still exhibit bile salt sensitivity even when defects in OM lipid asymmetry have been corrected, suggesting that the OmpC-Mla system contributes to bile salt resistance independent of its role in lipid asymmetry. Finally, we demonstrate that MlaD, one of the key lipid-binding components of the system, displays specific binding to bile salts in vitro. Since the OmpC-Mla system maintains OM lipid asymmetry by transporting mislocalized PLs, our findings here support a model where this system also additionally removes bile salts that have intercalated into the OM, to ultimately prevent dissolution and disruption of this important barrier.

IMPORTANCE

Bile salts are important components secreted into the human gut to help solubilize fats from our diet, yet they also possess anti-microbial properties due to their corresponding ability to dissolve bacterial membranes. For Enterobacteriaceae to survive in the gut environment, these bacterial cells must prevent intracellular build-up of bile salts by either restricting entry or by pumping out these molecules. Ultimately, they must resist bile salt-mediated dissolution of their membranes, particularly their outer membranes, which serve as a protective barrier against toxic substances. In this study, we reveal that a known lipid transport system inEscherichia colihas a distinct role in bile salt resistance independent of its role in maintaining outer membrane lipid asymmetry; it does so likely by removing bile salts from the outer membrane, thus preventing dissolution. Our work highlights the possibility of targeting this lipid transport system for the treatment of Enterobacteriaceae infections.