bluuebunny/crossref_metadata_2025 huggingface dataset:
Gynecologic Pathology Journal Club: A 2-year, Worldwide Virtual Learning Experience With a Focus on Mentorship and Inclusion
Authors: Banet Natalie , Parra-Herran Carlos , Rabban Joseph T. , Oliva Esther , Ellenson Lora H. , Park Kay J. , Singh Naveena , Devins Kyle M. , Rashid Sameera , Talia Karen L.
Published: March 2024

Journal clubs (JCs) are a common format used in teaching institutions to promote trainee engagement and develop skills in seeking out evidence-based medicine and critically evaluating literature. Digital technology has made JC accessible to worldwide audiences, which allows for increased inclusion of globally diverse presenters and attendees. Herein we describe the experience of the first 2 years of a virtual gynecologic pathology JC designed with the goal of providing mentorship and increasing inclusivity. JC began in a virtual format in April 2020 in response to the need for remote learning during the coronavirus disease 2019 pandemic. Each JC had 1 moderator, lasted 1 hour, featured up to 3 trainees/early-career pathologists, and covered articles on gynecologic surgical pathology/cytopathology. Trainees were recruited through direct contact with moderators and advertising through social media (eg, Twitter). A template was used for all presentations, and before presenting, live practice sessions were conducted with the moderator providing constructive feedback and evaluations were provided to presenters and attendees for feedback. Recordings of the meetings were made publicly available after the event through YouTube, a society website, and emails to registrants. Fifty-nine presenters participated, covering 71 articles. Most were trainees (53/59; 89%) from North America (33/59; 56%), with additional presenters from Asia (14/59; 24%), Australia/Oceania (5/59; 8%), Africa (4/59; 7%), and Europe (3/59; 5%). An average of 20 hours were spent per month by moderators on the selection of papers, meeting preparation, and provision of mentorship/feedback. Live events had a total of 827 attendees, and 16,138 interactions with the recordings were noted. Among those who self-identified on provided surveys, the attendees were most commonly from Europe (107/290; 37%) and were overwhelmingly practicing pathologists (275/341; 81%). The experience, including mentorship, format, and content, was positively reviewed by attendees and presenters. Virtual JC is an inclusive educational opportunity to engage trainees and early-career pathologists from around the world. The format allowed for the JC to be widely viewed by attendees from multiple countries, most being practicing pathologists. Based on feedback received, virtual JC appears to expand the medical knowledge of the attendees and empower presenters to develop their expertise and communication skills.
Coinactivation of the Switch/Sucrose Nonfermenting Complex SMARCA4/BRG1 and SMARCB1/INI1 in a Cervical Mixed Carcinoma: A Case Report
Authors: Qi Yu , Qi Peng , Yao Qianlan , Sun Xiangjie , Zhou Xiaoyan , Bi Rui
Published: March 2024

SMARCB1/SMARCA4-deficient malignancies of the female genital tract are rare entities, characterized by similar histologic features, such as sheet-like growth patterns and rhabdoid cells. Previous studies have shown mutually exclusive loss of SMARCA4/BRG1 and SMARCB1/INI1. Herein, we describe a unique cervical mixed carcinoma in a 77-year-old patient. The tumor consisted of 3 components, gastric-type adenocarcinoma, squamous carcinoma, and undifferentiated carcinoma. While the undifferentiated carcinoma was negtive for CK7, CK5/6 and p63, it was positive for pan-CK. DNA-based next-generation sequencing revealed a nonsense mutation in SMARCA4, copy number loss in SMARCB1, and a nonsense mutation in ARID1A. Different molecular alterations of the switch/sucrose nonfermenting complex subunits in the present case may provide further insights into the functions of the switch/sucrose nonfermenting complex in the progression of tumors.
Effects of pain on cortical homeostatic plasticity in humans: a systematic review
Authors: Zolezzi Daniela M. , Larsen Dennis B. , McPhee Megan , Graven-Nielsen Thomas
Published: March 2024

Homeostatic plasticity (HP) is a negative feedback mechanism that prevents excessive facilitation or depression of cortical excitability (CE). Cortical HP responses in humans have been investigated by using 2 blocks of noninvasive brain stimulation with a no-stimulation block in between. A healthy HP response is characterized by reduced CE after 2 excitatory stimulation blocks and increased CE when using inhibitory stimulation. Conversely, impaired HP responses have been demonstrated in experimental and chronic pain conditions. Therefore, this systematic review aimed to provide an overview of the effect of pain on cortical HP in humans. Scopus, Embase, and PubMed were searched from inception until November 20, 2023. The included studies (1) compared experimental or clinical pain conditions with healthy controls, (2) induced HP using 2 blocks of stimulation with a no-stimulation interval, and (3) evaluated CE measures such as motor-evoked potentials. Four studies were included, consisting of 5 experiments and 146 participants, of whom 63 were patients with chronic pain and 48 were subjected to an experimental pain model. This systematic review found support for an HP impairment in pain compared with that in pain-free states, reflected by a lack of CE reduction after excitatory-excitatory HP induction over the primary motor cortex. Inhibitory-inhibitory HP induction did not produce a consistent HP response across studies, independent of pain or pain-free states. Standardization of HP induction protocols and outcome calculations is needed to ensure reproducibility and study comparison. Future HP studies may consider investigating sensory domains including nociception, which would further our understanding of abnormal HP regulation in pain conditions.
Reported Prices for High-Volume Hand Surgery in the Era of Price Transparency: Implications for Future Policy Iterations
Authors: Fahmy Joseph N. , Mead Mitchell , Chung William T. , Ibrahim Andrew M. , Chung Kevin C.
Published: March 2024

Background:

In 2021, the United States enacted a law requiring hospitals to report prices for health care services. Across several health care services, poor compliance and wide variation in pricing was found. This study was performed to investigate variation in reporting and listed prices by hospital features for high-volume hand procedures, including carpal tunnel release, trigger finger release, de Quervain tenosynovitis release, and carpometacarpal arthroplasty.

Methods:

The Turquoise Health price transparency database was used to obtain listed prices and linked to hospital characteristics from the 2021 Annual American Hospital Association Survey. This study used descriptive statistics and generalized linear regression.

Results:

The analytic cohort included 2652 hospitals from across the United States. The highest rate of price reporting was in the Midwest (52% [n = 836]) and lowest in the South (39% [n = 925]). Compared with commercial insurers ($3609 [95% CI, $3414 to $3805]), public insurance rates were significantly lower (Medicare: $1588 [95% CI, $1484 to $1693], adjusted difference −$2021, P < 0.001; Medicaid: $1403 [95% CI, $1194 to $1612], adjusted difference −$2206, P < 0.001). Listed rates for self-pay patients were not statistically different from commercial rates.

Conclusions:

Although pricing for high-volume elective hand procedures is frequently reported, a high proportion of hospitals do not report prices. These data highlight the need for future transparency policy to include pricing for high-volume hand surgery to give patients the ability to make financially informed choices. These results are a valuable aid for surgeons and patients to promote financially conscious decisions.
A collaborative multidisciplinary trauma program improvement team improves VTE chemoprophylaxis guideline compliance in non-operative stable TBI
Authors: Al Tannir Abdul Hafiz , Golestani Simin , Tentis Morgan , Maring Morgan , Biesboer Elise A. , Dodgion Christopher , Murphy Patrick B. , Holena Daniel N. , Trevino Colleen M. , Peschman Jacob R. , Carver Thomas W. , Milia David J. , Schellenberg Morgan , de Moya Marc A. , Morris Rachel S.
Published: March 2024

BACKGROUND

Delays in initiating venous thromboembolism (VTE) prophylaxis in patients suffering from traumatic brain injury (TBI) persist despite guidelines recommending early initiation. We hypothesized that the expansion of a Trauma Program Performance Improvement (PI) team will improve compliance of early (24–48 hours) initiation of VTE prophylaxis and will decrease VTE events in TBI patients.

METHODS

We performed a single-center retrospective review of all TBI patients admitted to a Level I trauma center before (2015–2016,) and after (2019–2020,) the expansion of the Trauma Performance Improvement and Patient Safety (PIPS) team and the creation of trauma process and outcome dashboards. Exclusion criteria included discharge or death within 48 hours of admission, expanding intracranial hemorrhage on CT scan, and a neurosurgical intervention (craniotomy, pressure monitor, or drains) prior to chemoprophylaxis initiation.

RESULTS

A total of 1,112 patients met the inclusion criteria, of which 54% (n = 604) were admitted after Trauma PIPS expansion. Following the addition of a dedicated PIPS nurse in the trauma program and creation of process dashboards, the time from stable CT to VTE prophylaxis initiation decreased (52 hours to 35 hours; p < 0.001) and more patients received chemoprophylaxis at 24 hours to 48 hours (59% from 36%, p < 0.001) after stable head CT. There was no significant difference in time from first head CT to stable CT (9 vs. 9 hours; p = 0.15). The Contemporary group had a lower rate of VTE events (1% vs. 4%; p < 0.001) with no increase in bleeding events (2% vs. 2%; p = 0.97). On multivariable analysis, being in the Early cohort was an independent predictor of VTE events (adjusted odds ratio, 3.74; 95% confidence interval, 1.45–6.16).

CONCLUSION

A collaborative multidisciplinary Trauma PIPS team improves guideline compliance. Initiation of VTE chemoprophylaxis within 24 hours to 48 hours of stable head CT is safe and effective.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Bet-hedging and variability in plant development: seed germination and beyond
Authors: Abley Katie , Goswami Rituparna , Locke James C. W.
Published: March 2024

When future conditions are unpredictable, bet-hedging strategies can be advantageous. This can involve isogenic individuals producing different phenotypes, under the same environmental conditions. Ecological studies provide evidence that variability in seed germination time has been selected for as a bet-hedging strategy. We demonstrate how variability in germination time found in Arabidopsis could function as a bet-hedging strategy in the face of unpredictable lethal stresses. Despite a body of knowledge on how the degree of seed dormancy versus germination is controlled, relatively little is known about how differences between isogenic seeds in a batch are generated. We review proposed mechanisms for generating variability in germination time and the current limitations and new possibilities for testing the model predictions. We then look beyond germination to the role of variability in seedling and adult plant growth and review new technologies for quantification of noisy gene expression dynamics. We discuss evidence for phenotypic variability in plant traits beyond germination being under genetic control and propose that variability in stress response gene expression could function as a bet-hedging strategy. We discuss open questions about how noisy gene expression could lead to between-plant heterogeneity in gene expression and phenotypes.

This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Development of an all-in-one real-time PCR assay for simultaneous detection of spotted fever group rickettsiae, severe fever with thrombocytopenia syndrome virus and orthohantavirus hantanense prevalent in central China
Authors: Wang Cuixiang , Chen liangjun , Li xingrong , Gu jihong , Xiang yating , Fang Liang , Chen Lili , Li Yirong
Published: March 2024

Central China has been reported to be one of the most important endemic areas of zoonotic infection by spotted fever group rickettsiae(SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and orthohantavirus hantanense(HTNV). Due to similar clinical symptoms, it is challenging to make a definite diagnosis rapidly and accurately in the absence of microbiological tests. In the present study, an all-in-one real-time PCR assay was developed for the simultaneous detection of nucleic acids from SFGR, SFTSV and HTNV. Three linear standard curves for determining SFGR-ompA, SFTSV-Land HTNV-Lwere obtained within the range of 101-106copies/μL, with the PCR amplification efficiencies ranging from 93.46% to 96.88% and the regression coefficients R2of >0.99. The detection limit was 1.108 copies/μL for SFGR-ompA, 1.075 copies/μL for SFTSV-Land 1.006 copies/μL for HTNV-L, respectively. Both the within-run and within-laboratory coefficients of variation on the cycle threshold (Ct) values were within the range of 0.53%-2.15%. It was also found there was no statistical difference in the Ct values between with and without other non-target bloodborne virus nucleic acids (PSFGR-ompA=0.186, PSFTSV-L=0.612, PHTNV-L=0.298). The sensitivity, specificity, positive and negative predictive value were all 100% for determining SFGR-ompAand SFTSV-L, 97%, 100%, 100% and 99.6% for HTNV-L, respectively. Therefore, the all-in-one real-time PCR assay appears to be a reliable, sensitive, rapid, high-throughput and low cost-effective method to diagnose the zoonotic infection by SFGR, SFTSV and HTNV.

Author Summary

Spotted fever, severe fever with thrombocytopenia syndrome (SFTS), and hemorrhagic fever with renal syndrome (HFRS) sporadically have outbreaks in central China. Due to the similarities in clinical symptoms and the absence of reliable diagnostic methods, clinical diagnosis and treatment frequently result in misdiagnosis or missed diagnosis. Thus, the development of a fast and accurate diagnostic method is crucial for prevention and precise treatment. In this study, we designed an all-in-one real-time PCR assay to differentiate spotted fever group rickettsiae(SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and orthohantavirus hantanense(HTNV). The geneompAof SFGR, as well as the gene segmentLof SFTSV and HTNV, were used as targets to design primers and probes for amplification. Through the verification of nucleic acid and clinical sample detection, the sensitivity of this detection method exceeded 97%, and its specificity was 100%.

This new assay could be applied in epidemiology and clinical diagnosis, to control new outbreaks, reduce diagnostic and identification time, and improve test efficiency.
Cross-Sectional and Longitudinal Evaluation of Heart-to-Brachium Pulse Wave Velocity for Cardiovascular Disease Risk
Authors: Sugawara Jun , Tanaka Hirofumi , Yamashina Akira , Tomiyama Hirofumi
Published: March 2024

BACKGROUND

Heart-brachium pulse wave velocity (hbPWV) is a measure of proximal aortic stiffness and does not require the technical placement of transducers. To characterize age-associated changes and the clinical utilities of heart-brachium pulse wave velocity (hbPWV), we conducted both cross-sectional and longitudinal analyses and used brachial-ankle pulse wave velocity (baPWV) as a comparative measure.

METHODS

Various measures of CVD risk factors and arterial stiffness were obtained in 7,868 adults in the cross-sectional study. In the longitudinal study, 3,710 adults were followed for 9.1 ± 2.0 years. Repeated-measures correlation (rmcorr) and regression analyses were used to characterize associations of PWVs with age and Framingham’s general CVD risk score (FRS).

RESULTS

In the cross-sectional study, hbPWV showed a stronger linear (r=0.796) association with age than baPWV (r=0.554). In the longitudinal study, hbPWV also showed a significantly higher rmcorr coefficient with age than baPWV (rrm=0.511 vs. 0.307, P<0.0001). Age-related increases in hbPWV were fairly steady starting from young adults while baPWV displayed accelerated increases with age. A receiver operating characteristic curve analysis indicated that hbPWV depicted a more robust ability to stratify general cardiovascular disease (CVD) risk compared with baPWV (AUC=0.913 vs. 0.833, P<0.0001). The results of the 10-year follow-up study were consistent with the findings of the cross-sectional investigation.

CONCLUSIONS

hbPWV exhibits steady and more pronounced increases from an early age and may be more effective in stratifying general CVD risk.

NOVELTY AND RELEVANCE

What Is New?

Using the cross-sectional and longitudinal study designs in a large cohort of middle-aged Japanese workers, we confirmed that hbPWV, a promising method for assessing proximal aortic stiffness, undergoes a linear augmentation with age, commencing from an early life stage onward, rendering it a potential marker for discerning CVD risk.

What Is Relevant?

The stiffening of the arterial wall with advancing age is particularly pronounced in the proximal aorta and contributes importantly to elevated risks of CVD, cardiovascular events, and all-cause mortalities.

Clinical/Pathophysiological Implications?

Early-life assessment of proximal aortic stiffening through hbPWV has the potential to mitigate the pervasive impact of CVD on a global scale.
Identification of bazedoxifene for the treatment of LGMD R2 by high throughput screening
Authors: Bruge Celine , Bourg Nathalie , Pellier Emilie , Tournois Johana , Polentes Jerome , Benabides Manon , Grossi Noella , Bigot Anne , Brureau Anthony , Richard Isabelle , Nissan Xavier
Published: March 2024

LGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. We report here the development of anin vitrohigh-throughput assay using immortalized myoblasts and monitored reallocation of an aggregated mutant form of dysferlin (DYSFL1341P). Using this assay, we screened a library of 2239 drugs and identified two autophagy inducers, namely saracatinib and bazedoxifene, as potential drugs to repurpose for LGMD R2 patients carrying theDYSFL1341Pmutation. Functional characterization of these drugs revealed that saracatinib and bazedoxifene had a protective effect on the plasma membrane in osmotic shock assay. While saracatinib restores functionality in membrane resealing through a specific rescue of L1341P dysferlin from degradation, bazedoxifene demonstrates an additional protective effect on dysferlin KO mice muscle fibers. Finally, further investigations into the molecular mechanism of action of bazedoxifene revealed an induction of autophagy flux, which may underlie the molecule’s effect on the survival of LGMD R2 myofibers.
The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine
Authors: Kamath Srinivas , Hunter Alexander , Collins Kate , Wignall Anthony , Joyce Paul
Published: March 2024

Background and Purpose

Antipsychotics like olanzapine are associated with significant metabolic dysfunction, attributable to gut microbiota dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiota has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting, with most reports observing weight loss rather than gain. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiota to explore the hypothesis of “gut neutrality” for lurasidone exposure.

Experimental Approach

Using a Sprague-Dawley rat model, the impact of olanzapine and lurasidone administration on the gut microbiota was explored. Faecal and blood samples were collected weekly over a 21-day period to analyse changes to the gut microbiota and related metabolic markers.

Key Results

Lurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating gut microbiota through increases in mean OTUs (+50 OTUs) and alpha diversity (+0.5 increase in Shannon’s index). This novel finding suggests an underlying mechanism for lurasidone’s metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs (−75 OTUs) and substantial compositional variation, suggesting a decrease in microbial richness. Microbiota alterations correlated with metabolic dysfunction, evidenced through a statistically significant 30% increase in weight gain, increase in pro-inflammatory cytokine expression, and increase in blood triglycerides and glycaemic levels.

Conclusion and Implications

The study challenges the notion that all antipsychotics disrupt the gut microbiota similarly and highlights the potential benefits of gut positive or neutral antipsychotics like lurasidone in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia.

Bullet point summary

-

What is already known:

Olanzapine induces weight gain by disrupting the gut microbiome.

The impact of lurasidone on the gut microbiome is unknown and weight gaining propensities unclear.

-

What this study adds:

Lurasidone positively modulates gut microbiota through enhancement of microbial diversity and richness.

Potential mechanisms underlying lurasidone’s weight and metabolic neutrality are elucidated.

-

Clinical significance:

Gut neutral antipsychotics like lurasidone could be favourable alternatives for patients unable to tolerate olanzapine.

Personalised treatment for schizophrenia considering individual sensitivities to metabolic effects is emphasised.
Testing the mettle of METAL: A comparison of phylogenomic methods using a challenging but well-resolved phylogeny
Authors: Braun Edward L. , Oliveros Carl H. , White Carreiro Noor D. , Zhao Min , Glenn Travis C. , Brumfield Robb T. , Braun Michael J. , Kimball Rebecca T. , Faircloth Brant C.
Published: March 2024

The evolutionary histories of different genomic regions typically differ from each other and from the underlying species phylogeny. This makes species tree estimation challenging. Here, we examine the performance of phylogenomic methods using a well-resolved phylogeny that nevertheless contains many difficult nodes, the species tree of living birds. We compared trees generated by maximum likelihood (ML) analysis of concatenated data, gene tree summary methods, and SVDquartets. We also conduct the first empirical test of a “new” method called METAL (Metric algorithm for Estimation of Trees based on Aggregation of Loci), which is based on evolutionary distances calculated using concatenated data. We conducted this test using a novel dataset comprising more than 4,000 ultraconserved element (UCE) loci from almost all bird families and two existing UCE and intron datasets sampled from almost all avian orders. We identified “reliable clades” very likely to be present in the true avian species tree and used them to assess method performance. ML analyses of concatenated data recovered almost all reliable clades with less data and greater robustness to missing data than other methods. METAL recovered many reliable clades, but only performed well with the largest datasets. Gene tree summary methods (weighted ASTRAL and weighted ASTRID) performed well; they required less data than METAL but more data than ML concatenation. SVDquartets exhibited the worst performance of the methods tested. In addition to the methodological insights, this study provides a novel estimate of avian phylogeny with almost 99% of the currently recognized avian families. Only one of the 181 reliable clades we examined was consistently resolved differently by ML concatenation versus other methods, suggesting that it may be possible to achieve consensus on the deep phylogeny of extant birds.
RNA Polymerase II hypertranscription at histone genes in cancer FFPE samples
Authors: Henikoff Steven , Zheng Ye , Paranal Ronald M. , Xu Yiling , Greene Jacob E. , Henikoff Jorja G. , Russell Zachary R. , Szulzewsky Frank , Thirimanne H. Nayanga , Kugel Sita , Holland Eric C. , Ahmad Kami
Published: March 2024

Genome-wide hypertranscription is common in hu-man cancer and predicts poor prognosis. To under-stand how hypertranscription might drive cancer, we applied our FFPE-CUTAC method for mapping RNA Polymerase II (RNAPII) genome-wide in formalin-fixed paraffin-embedded (FFPE) sections. We demonstrate global RNAPII elevations in mouse gliomas and assort-ed human tumors in small clinical samples and discov-er regional elevations corresponding tode novoHER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at replication-coupled histone genes correlated with WHO grade in meningiomas, ac-curately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneu-ploidy in cancer, with general implications for precision oncology.
DeepKymoTracker: A tool for accurate construction of cell lineage trees for highly motile cells
Authors: Fedorchuk Khelina , Russell Sarah M. , Zibaei Kajal , Yassin Mohammed , Hicks Damien G.
Published: March 2024

Time-lapse microscopy has long been used to record cell lineage trees. Successful construction of a lineage tree requires tracking and preserving the identity of multiple cells across many images. If a single cell is misidentified the identity of all its progeny will be corrupted and inferences about heritability may be incorrect. Successfully avoiding such identity errors is challenging, however, when studying cells such as T lymphocytes. These are highly motile and readily change shape from one image to the next. To address this problem, we developed DeepKymoTracker, a pipeline for combined tracking and segmentation. Central to DeepKymoTracker is the use of a seed, a marker which transmits information about cell position and identity between sets of images during tracking, as well as between tracking and segmentation steps. The seed allows a 3D convolutional neural network (CNN) to detect and associate cells across several consecutive images in an integrated way, reducing the risk of a single poor image corrupting cell identity. DeepKymoTracker was trained extensively on synthetic and experimental T lymphocyte images. It was benchmarked against five publicly available, automatic cell-analysis tools and outperformed them in almost all respects. The software is written in pure Python and is freely available. We suggest this tool is particularly suited to the tracking of cells in suspension, whose fast motion makes lineage assembly particularly difficult.

Author Summary

Cell lineage trees provide a striking visual representation of cellular decision-making and fate determination in a proliferating clone. Traditionally, these trees have been recorded using time-lapse microscopy movies of a dividing clone. Extracting lineage trees of T lymphocytes from microscopy movies is particularly challenging, however, because the cells are highly motile, readily change shape, and are easily damaged by excessive illumination and frame rates. Here we present a deep-learning approach to extracting cell lineage trees from movies of proliferating T cells. Using 3D convolutional neural networks for tracking and separate networks for segmentation we were able to reduce misidentification errors and record cell lineage trees with high fidelity. In benchmark tests, our algorithm was found to outperform all other state-of-the-art algorithms in both tracking and segmentation.
Decoding the Baltic Sea's Past and Present: A simple Molecular Index for Ecosystem Assessment
Authors: Schmidt Alexandra , Roman Juliane , Andren Elinor , Kremp Anke , Kaiser Jerome , Arz Helge Wolfgang , Dellwig Olaf , Balint Miklos , Epp Laura Saskia
Published: March 2024

Marginal sea ecosystems, such as the Baltic Sea, are severely affected by anthropogenic pressures, such as climate warming, pollution, and eutrophication, which increased in the course of the past century. Biodiversity monitoring data and assessment of environmental status in such systems have typically been carried out only for the past few decades, if at all, and knowledge on pre-impact stability and good ecological status is limited. An extension of monitoring time series can potentially be achieved through analyses of paleoecological records, e.g. for phytoplankton, which form the base of the food web and are highly susceptible to environmental changes. Within the phytoplankton community, dinoflagellates and diatoms play a significant role as primary producers, and their relative dominance in the spring bloom, calculated as Dia/Dino index, is used as an indicator for the environmental status of the Baltic Sea. To extend time series on the dominance patterns and include non-fossilized dinoflagellates, we here establish a simple droplet digital PCR (ddPCR) reaction on ancient DNA from sediment cores that decodes phytoplankton dynamics. We focus on two common spring bloom species, the diatom Skeletonema marinoi and the dinoflagellate Apocalathium malmogiense, for which we evaluate a DNA based dominance index. It performs very well in comparison to DNA metabarcoding and modern monitoring and can elucidate past species dominance across the past century in three basins of the Baltic and across millennia in two of these basins. For the past century, we see a dominance shift already starting before the mid-20th century in two of the Baltic Sea basins, thus substantially predating current monitoring programs. Shifts are only partly coeval among the cores and the index shows different degrees of stability. This pattern is confirmed across millennia, where a long-term stable relationship between the diatom and the dinoflagellate is observed in the Eastern Gotland Basin, while data from the Gulf of Finland bear testimony to a much more unstable relationship. This confirms that good ecological status based on the dominance pattern of diatoms and dinoflagellates must be established locally and exemplifies how sediment core DNA can be employed to extend monitoring data.
Beyond Kaftrio : mechanistic insights to maximize N1303K-CFTR rescue
Authors: Pranke Iwona , Capurro Valeria , Chevalier Benoit , Pesce Emanuela , Tomati Valeria , Pastorino Cristina , Hatton Aurelie , Urien Saik , Lena Mariateresa , Dréano Elise , Bocciardi Renata , Zara Federico , Pantano Stefano , Terlizzi Vito , Lucanto Cristina , Costa Stefano , Claut Laura , Daccò Valeria , Poli Piercarlo , Maschio Massimo , Fabrizzi Benedetta , Caporelli Nicole , Cipolli Marco , Volpi Sonia , Jung Vincent , Roger Kevin , Chedevergne Frederique , Cosson Laure , Macey Julie , LeBihan Jean , Weiss Laurence , Grenet Dominique , Viala Laurence LeClainche , Douvry Benoit , Ravoninjatovo Bruno , Audousset Camille , Tatopoulos Aurélie , Thiriez Bénédicte Richaud , Baravalle Melissa , Thouvenin Guillaume , Labbé Guillaume , Mittaine Marie , Reix Philippe , Durieu Isabelle , Mankikian Julie , Bui Stéphanie , Kelly-Aubert Mairead , Nguyen–Khoa Thao , Khoukh Karim , Martin Clémence , Guerrera Chiarra , Silva Jennifer Da , di Carli Paola , Castellani Carlo , Cresta Federico , Galietta Luis , Guillemaut Anne , Bouazza Naim , Girodon Emmanuelle , Remus Natacha , Burgel Pierre Régis , Sermet-Gaudelus Isabelle , Hinzpeter Alexandre , Pedemonte Nicoletta
Published: March 2024

Introduction

N1303K is the fourth most frequent Cystic Fibrosis (CF) causing mutation. People with CF (pwCF) clinical status can be improved by Elexacaftor(ELX)/Tezacaftor(TEZ)/Ivacaftor (ETI) combotherapy. We investigated the mechanism underlying N1303K-CFTR rescue.

Methods

N1303K-CFTR expression and maturation was evaluated by Western Blot in cell lines and Human Nasal Epithelial Primary Cells (HNECs). Cell surface expression was studied by nanoluciferase complementation assay and TurboID proximity labeling. Functional rescue was testedin vitroby YFP-Based Assay and Short Circuit Current.

Results

Correction by ELX/TEZ increases N1303K-CFTR amounts, but not its maturation in CFTR-expressing HEK and 16HBEge cell lines and in HNECs. In control conditions, N1303K-CFTR is more distributed at the cell surface and significantly more surface partners are identified in the N1303K-CFTR interactome as compared to F508del-CFTR in HEK cells. ELX/TEZ induces a global stabilization of N1303K-CFTR without favoring its plasma membrane relocation in contrast to F508del-CFTR which is redistributed to the membrane. ETI increases N1303K-CFTR activity in HNECs and can be increased by API co-potentiation with a predicted increase in Forced Expiratory Volume in 1 second (ppFEV1) by respectively 13(2)% and 18%(3). This is consistent with a gain in ppFEV1 reported in pwCF carrying the N1303K mutation and additional improvement by API in a patient.

Conclusion

These results support the expansion of ETI approval to N1303K mutation but highlight different mechanisms of action than for F508del.
Cysteine restriction induces ferroptosis depending on the polyamine biosynthetic pathway in hepatic cancer cells
Authors: Tada Keisuke , Nishizawa Hironari , Shima Hiroki , Muto Akihiko , Wada Motoshi , Igarashi Kazuhiko
Published: March 2024

Background and Aims

Metabolic activities are also known to affect responses and disease processes of the liver which is a central organ for organismal metabolism. Liver diseases such as intestinal failure associated liver disease (IFALD) and hepatocellular carcinoma are known to be affected by nutrition contents, but the mechanisms behind them remain unclear. In this study, we aimed to reveal the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase (MAT), which plays the central role in methionine metabolism by synthesizingS-adenosylmethionine (SAM).

Methods

Mouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide (PI) and annexin V staining followed by flow cytometry. Inhibitors of ferroptosis (Fer-1), autophagy (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and DFMO) were used.

Results

Cysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction-induced cell death was also suppressed by knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction.

Conclusions

These results suggest that SAM-polyamine metabolism is a critical modulator of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically in cancer cells without affecting normal cells in the liver.

Graphical abstrct
Exploring Abeta42 Monomer Diffusion Dynamics on Fibril Surfaces through Molecular Simulations
Authors: Ma Yuan-Wei , Wang Guan-Fang , Chen Hong-Yi , Tsai Min-Yeh
Published: March 2024

This study provides critical insights into the role of surface-mediated secondary processes in Alzheimer’s disease, particularly regarding the aggregation of Abeta42 peptides. Employing coarse-grained molecular dynamics simulations, we focus on elucidating the molecular intricacies of these secondary processes beyond primary nucleation. Central to our investigation is the analysis of a freely diffusing Abeta42 monomer on pre-formed fibril structures. We conduct detailed calculations of the monomer’s diffusion coefficient on fibril surfaces (as a one-dimensional case), along with various monomer orientations. Our findings reveal a strong and consistent correlation between the monomer’s diffusion coefficient and its orientation on the surface. Further analysis differentiates the effects of parallel and perpendicular alignments with respect to the fibril axis. Additionally, we explore how different fibril surfaces influencèmonomer dynamics by comparing the C-terminal and N-terminal surfaces. We find that the monomer exhibits lower diffusion coefficients on the N-terminal surface. Differences in surface roughness (SR), quantified using root-mean-square distances, significantly affect monomer dynamics, thereby influencing the secondary aggregation process. Importanly, this study underscores that fibril twisting acts as a regulatory niche, selectively influencing these orientations and their diffusion properties necessary for facilitating fibril growth within biologically relevant time scales. This discovery opens new avenues for targeted therapeutic strategies aimed at manipulating fibril dynamics to mitigate the progression of Alzheimer’s disease.
Menopause has not evolved as a general trait in mammals: A response to ‘Do mammals have menopause?’
Authors: Chapman Simon N. , Ellis Samuel , Lahdenperä Mirkka , Croft Darren P. , Lummaa Virpi
Published: March 2024

Reproductive senescence is widespread across mammals, but only a small number of species have physiological reproductive cessation and an extended post-reproductive lifespan. A recent commentary in Cell by Winkler & Goncalves (2023) suggests that menopause is actually a widespread trait of mammals, which would change our understanding of senescence and have implications for the study of menopause in humans. Here, we identify three main issues with the methodology of this commentary: the use of captive populations, the use of maximal lifespan, and misinterpretations of the data sources. We show that this methodology does not support the conclusions at the species-level, and conclude that, in line with the predictions of classic life-history theory, menopause is indeed a rare trait.
Proteomic profiling of IDH-wildtype Glioblastoma Tissue and Serum uncovers prognostic Subtypes and Marker Candidates
Authors: Werner Tilman , Schäfer Agnes , Hennes Michael , Cosenza Contreras Miguel , Espadas Guadalupe , Sabido Eduard , Cook Lena , Pagenstecher Axel , Pinter Niko , Feilen Tobias , Grote Alexander , Nimsky Christopher , Bartsch Jörg Walter , Schilling Oliver
Published: March 2024

Background

IDH-wildtype glioblastoma (GBM) is the most prevalent primary brain cancer with a 5-year survival rate below 10%. Despite combined treatment through extensive resection and radiochemotherapy, nine out of ten patients develop recurrences. The lack of targeted treatment options and reliable diagnostic markers for recurrent tumors remain major challenges.

Methods & Aims

In this study, we present the proteomic characterization of tissue and serum from 55 initial GBM tumors and five matching recurrences, which we investigated for proteomic tumor subtypes and proteomic signatures associated with recurrence.

Results

Primary tumors revealed four distinct subgroups through hierarchical clustering: a neuronal cluster with elevated mature neuron markers, an innate immunity cluster with increased protease expression, a mixed cluster, and a stem-cell cluster. Neurodevelopmental and inflammatory processes were identified as key factors influencing clustering, with proteolytic activity increasing relative to the degree of inflammation. An analysis comprising proteins with lower coverage confirmed and expanded this pattern. Patients in the neuronal cluster exhibited significantly longer survival compared to those in the stem-cell cluster. In a patient-matched differential expression analysis, five recurrent tumors displayed significantly altered protein expression compared to their primary counterparts, emphasizing the proteomic plasticity of recurrent tumors. Investigation of serum proteomes before and after surgery, using a depletion-based protocol, revealed highly patient-specific and stable proteome compositions, despite a notable increase in inflammation markers post-surgery. However, the levels of circulating proteolytic products matched to the proteolytic activity within the tissue and one fragment of proteolysis activated receptor 2 (PAR2) consistently dropped in abundance after removal of inflamed tumors.

Conclusion

Overall, we describe a large proteomic GBM cohort. We identified distinct tumor subgroups, molecular patterns of recurrence, and matching proteomic patterns in the bloodstream, which may improve risk prediction for recurrent GBM.
TabHLH27 orchestrates root growth and drought tolerance to enhance water use efficiency in wheat
Authors: Wang Dongzhi , Zhang Xiuxiu , Cao Yuan , Batool Aamana , Xu Yongxin , Qiao Yunzhou , Li Yongpeng , Wang Hao , Lin Xuelei , Bie Xiaomin , Zhang Xiansheng , Jing Ruilian , Dong Baodi , Tong Yiping , Teng Wan , Liu Xigang , Xiao Jun
Published: March 2024

Cultivating high-yield wheat under limited water resources is essential for sustainable agriculture in semiarid regions. Amid water scarcity, plants activate drought response signaling, yet the delicate balance between drought tolerance and development remains unclear. Through genome-wide-association study (GWAS) and transcriptome profiling, we identified a wheat atypical basic helix-loop-helix (bHLH) transcription factor (TF), TabHLH27-A1, as a promising quantitative trait locus (QTL) candidate for both relative root dry weight (DW.R%) and spikelet number per spike (SPS) in wheat. TabHLH27-A1/B1/D1 knockout reduced wheat drought tolerance, yield, and water use efficiency (WUE).TabHLH27-A1exhibited rapid induction with PEG treatment, gradually declining over days. It activated stress response genes such asTaCBL8-B1andTaCPI2-A1while inhibiting root growth genes likeTaSH15-B1andTaWRKY70-B1under short-term PEG stimulus. The distinct transcriptional regulation of TabHLH27-A1 involved diverse interacting factors such as TaABI3-D1 and TabZIP62-D1. Natural variations ofTabHLH27-A1influences its transcriptional responses to drought stress, withTabHLH27-A1Hap-IIassociated with stronger drought tolerance, larger root system, more spikelets, and higher WUE in wheat. Significantly, the eliteTabHLH27-A1Hap-IIwas selected during the breeding process in China, and introgression ofTabHLH27-A1Hap-IIallele improves drought tolerance and grain yield, especially under water-limited conditions. Our study highlights TabHLH27-A1’s role in balancing root growth and drought tolerance, providing a genetic manipulation locus for enhancing WUE in wheat.
Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma
Authors: Motahari Zahra , Lepe Javier J. , Bautista Malia R. , Hoerig Clay , Plant-Fox Ashley S. , Das Bhaskar , Fowler Christie D. , Magge Suresh N. , Bota Daniela A.
Published: March 2024

Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma.

Methods

Multiple in vitro assays were performed using human DAOY (SHH activated tp53 mutant) and D425 (non-SHH group 3) cells. The impact of BT9 on cellular growth, death, migration, invasion, and metabolic activity were quantified using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. Survival following 50mg/kg BT9 treatment was assessedin vivoin immunodeficient mice intracranially implanted with D425 cells.

Results

Compared to control, BT9 treatment led to a significant reduction in medulloblastoma cell growth (DAOY, 24hrs IC50: 3.6uM, 48hrs IC50: 2.3uM, 72hrs IC50: 2.1uM; D425 24hrs IC50: 3.4uM, 48hrs IC50: 2.2uM, 72hrs IC50: 2.1uM) and a significant increase in cell death (DAOY, 24hrs p=0.0004, 48hrs p<0.0001; D425, 24hrs p=0.0001, 48hrs p=0.02). In DAOY cells, 3uM BT9 delayed migration, and significantly decreased DAOY and D425 cells invasion (p < 0.0001). Ourin vivostudy, however, did not extend survival in xenograft mouse model of group3 medulloblastoma compared to vehicle-treated controls.

Conclusions

Ourin vitrodata showed BT9 antitumor efficacy in DAOY and D425 cell lines suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.
Measuring instability in chronic human intracortical neural recordings towards stable, long-term brain-computer interfaces
Authors: Pun Tsam Kiu , Khoshnevis Mona , Hosman Thomas , Wilson Guy H. , Kapitonava Anastasia , Kamdar Foram , Henderson Jaimie M. , Simeral John D. , Vargas-Irwin Carlos E. , Harrison Matthew T. , Hochberg Leigh R.
Published: March 2024

Intracortical brain-computer interfaces (iBCIs) enable people with tetraplegia to gain intuitive cursor control from movement intentions. To translate to practical use, iBCIs should provide reliable performance for extended periods of time. However, performance begins to degrade as the relationship between kinematic intention and recorded neural activity shifts compared to when the decoder was initially trained. In addition to developing decoders to better handle long-term instability, identifying when to recalibrate will also optimize performance. We propose a method to measure instability in neural data without needing to label user intentions. Longitudinal data were analyzed from two BrainGate2 participants with tetraplegia as they used fixed decoders to control a computer cursor spanning 142 days and 28 days, respectively. We demonstrate a measure of instability that correlates with changes in closed-loop cursor performance solely based on the recorded neural activity (Pearsonr= 0.93 and 0.72, respectively). This result suggests a strategy to infer online iBCI performance from neural data alone and to determine when recalibration should take place for practical long-term use.