bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of calcium stores in long-term potentiation and synaptic tagging and capture in mouse hippocampus
Authors: Koek Laura A. , Sanderson Thomas M. , Georgiou John , Collingridge Graham L.
Published: June 2024

The roles of Ca
2+
-induced calcium release in synaptic plasticity and metaplasticity are poorly understood. The present study has addressed the role of intracellular Ca
2+
stores in long-term potentiation (LTP) and a form of heterosynaptic metaplasticity known as synaptic tagging and capture (STC) at CA1 synapses in mouse hippocampal slices. The effects of two compounds, ryanodine and cyclopiazonic acid (CPA), were examined on LTP induced by three distinct induction protocols: weak (w), compressed (c) and spaced (s) theta-burst stimulation (TBS). These compounds did not significantly affect LTP induced by the wTBS (one episode of TBS; 25 stimuli) or cTBS (three such episodes with a 10 s inter-episode interval (IEI); 75 stimuli) but substantially inhibited LTP induced by a sTBS (10 min IEI; 75 stimuli). Ryanodine and CPA also prevented a small heterosynaptic potentiation that was observed with the sTBS protocol. Interestingly, these compounds also prevented STC when present during either the sTBS or the subsequent wTBS, applied to an independent input. All of these effects of ryanodine and CPA were similar to that of a calcium-permeable AMPA receptor blocker. In conclusion, Ca
2+
stores provide one way in which signals are propagated between synaptic inputs and, by virtue of their role in STC, may be involved in associative long-term memories.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Alpha-secretase inhibition impairs Group I metabotropic glutamate receptor-mediated protein synthesis, long-term potentiation and long-term depression
Authors: Mockett Bruce G. , Davies James W. T. , Mills Zoë B. , Kweon Do Y. , Abraham Wickliffe C.
Published: June 2024

Group I metabotropic glutamate receptors (Gp1-mGluRs) exert a host of effects on cellular functions, including enhancement of protein synthesis and the associated facilitation of long-term potentiation (LTP) and induction of long-term depression (LTD). However, the complete cascades of events mediating these events are not fully understood. Gp1-mGluRs trigger α-secretase cleavage of amyloid precursor protein, producing soluble amyloid precursor protein-α (sAPPα), a known regulator of LTP. However, the α-cleavage of APP has not previously been linked to Gp1-mGluR’s actions. Using rat hippocampal slices, we found that the α-secretase inhibitor tumour necrosis factor-alpha protease inhibitor-1, which inhibits both disintegrin and metalloprotease 10 (ADAM10) and 17 (ADAM17) activity, blocked or reduced the ability of the Gp1-mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) to stimulate protein synthesis, metaplastically prime future LTP and elicit sub-maximal LTD. In contrast, the specific ADAM10 antagonist GI254023X did not affect the regulation of plasticity, suggesting that ADAM17 but not ADAM10 is involved in mediating these effects of DHPG. However, neither drug affected LTD that was strongly induced by either high-concentration DHPG or paired-pulse synaptic stimulation. Our data suggest that moderate Gp1-mGluR activation triggers α-secretase sheddase activity targeting APP or other membrane-bound proteins as part of a more complex signalling cascade than previously envisioned.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Cage effects on synaptic plasticity and its modulation in a mouse model of fragile X syndrome
Authors: Volianskis Rasa , Lundbye Camilla J. , Petroff Gillian N. , Jane David. E. , Georgiou John , Collingridge Graham L.
Published: June 2024

Fragile X syndrome (FXS) is characterized by impairments in executive function including different types of learning and memory. Long-term potentiation (LTP), thought to underlie the formation of memories, has been studied in the
Fmr1
mouse model of FXS. However, there have been many discrepancies in the literature with inconsistent use of littermate and non-littermate
Fmr1
knockout (KO) and wild-type (WT) control mice. Here, the influence of the breeding strategy (cage effect) on short-term potentiation (STP), LTP, contextual fear conditioning (CFC), expression of
N
-methyl-
d
-aspartate receptor (NMDAR) subunits and the modulation of NMDARs, were examined. The largest deficits in STP, LTP and CFC were found in KO mice compared with non-littermate WT. However, the expression of NMDAR subunits was unchanged in this comparison. Rather, NMDAR subunit (GluN1, 2A, 2B) expression was sensitive to the cage effect, with decreased expression in both WT and KO littermates compared with non-littermates. Interestingly, an NMDAR-positive allosteric modulator, UBP714, was only effective in potentiating the induction of LTP in non-littermate KO mice and not the littermate KO mice. These results suggest that commonly studied phenotypes in
Fmr1
KOs are sensitive to the cage effect and therefore the breeding strategy may contribute to discrepancies in the literature.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Inducible clindamycin resistance among clinical Gram-positive cocci in a tertiary hospital in Niger Republic
Authors: Yacouba Abdourahamane , Alassoum Malika Zeidou , Soumana Boubacar Marou , Saley Sahada Moussa , Ousmane Abdoulaye , Moussa Harouna , Amatagas Saidou , Alhousseini Daouda , Doutchi Mahamadou , Chaibou Salaou , Daou Mamane , Brah Souleymane , Adehossi Eric , Olowo-Okere Ahmed , Mamadou Saidou
Published: June 2024

Background. Macrolide-induced resistance to clindamycin is a well-described mechanism leading to treatment failure. Herein, we determined the frequency and associated factors of inducible clindamycin resistance in Gram-positive cocci in a tertiary care hospital.
Methods. A cross-sectional descriptive study was carried out between January and December 2022. D tests were performed as recommended by EUCAST 2021 guidelines on 100 non-duplicate clinical isolates of Gram-positive cocci to determine the prevalence of methicillin resistance and inducible clindamycin resistance among the collected isolates.
Results. Of the 100 Gram-positive cocci isolates, 56 (56.0 %), 17 (17.0 %) and 27 (27.0 %) were respectively coagulase-negative staphylococci, Staphylococcus aureus and Streptococcus spp. Among Streptococcus spp., Group D Streptococci (15.0%) were the most isolated. Methicillin-resistant Staphylococcusaureus (MRSA) represented 9 (53.0 %) of S.aureus isolates. Constitutive (cMLSb) and inducible clindamycin resistance (iMLSb) phenotypes were detected in 36 (36.0%) and 14 (14,0%) of the isolates, respectively. S. aureus exhibited 38.4% of cMLSb and 13.7% of iMLSb. The result of multivariate analysis showed that age groups, gender, type of samples, provenance, and bacteria, were not significantly associated with Gram-positive cocci iMLSb phenotype.
Conclusion. The study reported for the first time a high prevalence of inducible resistance of Gram-positive cocci strains to clindamycin in Niger Republic. This suggests the urgent need for the implementation of regular screening of these isolates and the wise use of clindamycin in clinical practice.
Recent Update on the Prevalence of Sarcopenia in Koreans: Findings from the Korea National Health and Nutrition Examination Survey
Authors: Kim Shinjune , Ha Yong-Chan , Kim Deog-Yoon , Yoo Jun-Il
Published: June 2024

Background: As recognized by the World Health Organization in 2016 with its inclusion in the International Classification of Diseases, Tenth Revision as M62.84, and by South Korea in 2021 as M62.5, the diagnostic guidelines for sarcopenia vary globally. Despite its prevalence in older populations, data on sarcopenia in Koreans aged 60 and above is scarce, highlighting the need for research on its prevalence in this demographic.Methods: Utilizing the 2022 Korea National Health and Nutrition Examination Survey dataset, sarcopenia was assessed among 1,946 individuals aged 60 or older according to the Asian Working Group for Sarcopenia 2019 criteria, incorporating grip strength and bioelectrical impedance analysis measurements. Statistical analyses were performed to differentiate categorical and continuous variables using logistic regression and Student’s t-tests, respectively.Results: The prevalence of sarcopenia was found to increase with age, with the highest prevalence observed in the oldest age group (80 years and older). The overall prevalence of sarcopenia in our study population was 6.8%. Among men, the prevalence of sarcopenia was 5.5% in the 60 or older age group, 9.6% in the 70 or older age group, and 21.5% in the 80 or older age group. Among women, the prevalence of sarcopenia was 7.9%, 10.5%, and 25.9%, respectively.Conclusions: This study highlights the significant burden of sarcopenia in elderly Koreans, particularly among the oldest individuals. These findings call for targeted interventions to manage and prevent sarcopenia, along with further research on its risk factors, consequences, and effective mitigation strategies.
Temporal genomic analysis ofPlasmodium falciparumreveals increased prevalence of mutations associated with delayed clearance following treatment with artemisinin-lumefantrine in Choma District, Southern Province, Zambia
Authors: Fola Abebe A. , Kobayashi Tamaki , Shields Timothy , Hamapumbu Harry , Musonda Michael , Katowa Ben , Matoba Japhet , Stevenson Jennifer C. , Norris Douglas E. , Thuma Philip E. , Wesolowski Amy , Moss William J. , Juliano Jonathan J. , Bailey Jeffrey A.
Published: June 2024

The emergence of antimalarial drug resistance is an impediment to malaria control and elimination in Africa. Analysis of temporal trends in molecular markers of resistance is critical to inform policy makers and guide malaria treatment guidelines. In a low and seasonal transmission region of southern Zambia, we successfully genotyped 85.5% (389/455) ofPlasmodium falciparumsamples collected between 2013-2018 from 8 spatially clustered health centres using molecular inversion probes (MIPs) targeting key drug resistance genes. Aside from one sample carrying K13 R622I, none of the isolates carried other World Health Organization-validated or candidate artemisinin partial resistance (ART-R) mutations in K13. However, 13% (CI, 9.6-17.2) of isolates had the AP2MU S160Nmutation, which has been associated with delayed clearance following artemisinin combination therapy in Africa. This mutation increased in prevalence between 2015-2018 and bears a genomic signature of selection. During this time period, there was an increase in the MDR1 NFD haplotype that is associated with reduced susceptibility to lumefantrine. Sulfadoxine-pyrimethamine polymorphisms were near fixation. While validated ART-R mutations are rare, a mutation associated with slow parasite clearance in Africa appears to be under selection in southern Zambia.
High serum Cholesterol and Triglyceride levels in older adults: associations with sleep and nighttime behavior disorders at baseline and a prediction analysis of incidental cases at 12 months follow-up
Authors: Hallab Asma ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2024

Introduction

This study explored the association between dyslipidemia and sleep and nighttime behavior disorders (SNBD) in the elderly.

Methods

ADNI population with complete Cholesterol, Triglyceride, SNBD, and neurocognitive data were included. Logistic regression was performed to study the association between dyslipidemia and SNBD at baseline and 12 months. Relevant confounders were adjusted for.

Results

Among the 2,216 included cases, 1,045 (47%) were females, and the median age was 73 (IQR: 68, 78). At baseline, 357 (16%) had SNBD, and 327 (18%) at 12 months; 187 were incident cases.

There were more cases of baseline SNBD in the hypertriglyceridemia group than in those without (19% vs. 14%,p-value=0.003). Similarly, more follow-up SNBD cases had hypertriglyceridemia at baseline (21% vs. 16%,p-value=0.025). SNBD cases at baseline had significantly higher serum Triglyceride levels than those without (132 vs. 118mg/dL,p-value<0.001).

Only hypertriglyceridemia was significantly associated with baseline SNBD (crude OR=1.43, 95%CI: 1.13,1.80,p-value=0.003), even after adjustment for confounding factors (adj.OR=1.36, 95%CI: 1.06,1.74,p-value=0.016) and (BMI-adj.OR=1.29, 95%CI: 1.00,1.66,p-value=0.048). None of the dyslipidemia forms did predict incident cases at 12 months.

Conclusions

Hypertriglyceridemia, but not hypercholesterolemia, was associated with higher odds of SNBD. None of the dyslipidemia forms predicted incidental SNBD over 12 months.
Virological characteristics of the SARS-CoV-2 KP.3, LB.1 and KP.2.3 variants
Authors: Kaku Yu , Yo Maximilian Stanley , Tolentino Jarel Elgin , Uriu Keiya , Okumura Kaho ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Sato Kei
Published: June 2024

The SARS-CoV-2 JN.1 variant, arising from BA.2.86.1 with a substitution in the spike (S) protein, S:L455S, exhibited increased fitness and outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 and KP.3, which convergently acquired S protein substitutions such as S:R346T, S:F456L, and S:Q493E, have emerged concurrently. Furthermore, JN.1 subvariants such as LB.1 and KP.2.3, which convergently acquired S:S31del in addition to the above substitutions, have emerged and spread as of June 2024. Here we investigated the virological properties of KP.3, LB.1 and KP.2.3. We estimated the relative effective reproduction number (Re) of KP.3, LB.1, and KP.2.3 using a Bayesian multinomial logistic model based on the genome surveillance data from Canada, the UK, and the USA, where these variants have spread from March to April 2024. The Reof KP.3 is more than 1.2-fold higher than that of JN.1 and higher than or comparable to that of KP.2 in these countries. Importantly, the Revalues of LB.1 and KP.2.3 are even higher than those of KP.2 and KP.3. These results suggest that the three variants we investigated herein, particularly LB.1, and KP.2.3, will become major circulating variants worldwide in addition to KP.2 and KP.3. The pseudovirus infectivity of KP.2 and KP.3 was significantly lower than that of JN.1. On the other hand, the pseudovirus infectivity of LB.1 and KP.2.3 was comparable to that of JN.1. Neutralization assay was conducted by using four types of breakthrough infection (BTI) sera with XBB.1.5, EG.5, HK.3 and JN.1 infections as well as monovalent XBB.1.5 vaccine sera. In all four groups of BTI sera tested, the 50% neutralization titers (NT50) against LB.1 and KP.2.3 were significantly lower than those against JN.1 (2.2-3.3-fold and 2.0-2.9-fold) and even lower than those against KP.2 (1.6-1.9-fold and 1.4-1.7 fold). Although KP.3 exhibited neutralization resistance against all BTI sera tested than JN.1 (1.6-2.2-fold) with statistical significance, there were no significant differences between KP.3 and KP.2. In the case of infection-naive XBB.1.5 vaccine sera, the NT50 values of JN.1 subvariants were very low. In the case of XBB.1.5 vaccine sera after natural XBB infection, the NT50 values against KP.3, LB.1 and KP.2.3 were significantly lower than those of JN.1 (2.1-2.8-fold) and even lower than KP.2 after infection (1.4-2.0-fold). Overall, our results suggest that the S substitutions convergently acquired in the JN.1 subvariants contribute to immune evasion, and therefore, increase their Rewhen compared to parental JN.1. More importantly, LB.1 and KP.2.3 exhibited higher pseudovirus infectivity and more robust immune resistance than KP.2. These data suggest that S:S31del is critical to exhibit increased infectivity, increased immune evasion, and therefore, potentially contributes to increased Re.
Two Decades of Rheumatology Research (2000-2023): A Dynamic Topic Modeling Perspective
Authors: Madrid-García Alfredo , Freites-Núñez Dalifer , Rodríguez-Rodríguez Luis
Published: June 2024

Background

Rheumatology has experience notably changes in last decades. New drugs, including biologic agents and janus kinase inhibitors, have bloosom. Concepts such aswindow of opportunity,arthralgia suspicious for progression, ordifficult-to-treat rheumatoid arthritishave appeared; and new management approaches and strategies such astreat-to-targethave become popular. Statistical learning methods, gene therapy, telemedicine or precision medicine are other advancements that have gained relevance in the field. To better characterise the research landscape and advances in rheumatology, automatic and efficient approaches based on natural language processing should be used. The objective of this study is to use topic modeling techniques to uncover key topics and trends in the rheumatology research conducted in the last 23 years.

Methods

This study analysed 96,004 abstracts published between 2000 and December 31, 2023, drawn from 34 specialised rheumatology journals obtained from PubMed. BERTopic, a novel topic modeling approach that considers semantic relationships among words and their context, was used to uncover topics. Up to 30 different models were trained. Based on the number of topics, outliers and topic coherence score, two of them were finally selected, and the topics manually labeled by two rheumatologists. Word clouds and hierarchical clustering visualizations were computed. Finally, hot and cold trends were identified using linear regression models.

Results

Abstracts were classified into 45 and 47 topics. The most frequent topics were rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. Expected topics such as COVID-19 or JAK inhibitors were identified after conducting the dynamic topic modeling. Topics such as spinal surgery or bone fractures have gained relevance in last years, however, antiphospholipid syndrome, or septic arthritis have lost momentum.

Conclusions

Our study utilized advanced natural language processing techniques to analyse the rheumatology research landscape, and identify key themes and emerging trends. The results highlight the dynamic and varied nature of rheumatology research, illustrating how interest in certain topics have shifted over time.
Mutation and cell state compatibility is required and targetable in Ph+acute lymphoblastic leukemia minimal residual disease
Authors: Winter Peter S. , Ramseier Michelle L. , Navia Andrew W. , Saksena Sachit , Strouf Haley , Senhaji Nezha , DenAdel Alan , Mirza Mahnoor , An Hyun Hwan , Bilal Laura , Dennis Peter , Leahy Catharine S. , Shigemori Kay , Galves-Reyes Jennyfer , Zhang Ye , Powers Foster , Mulugeta Nolawit , Gupta Alejandro J. , Calistri Nicholas , Van Scoyk Alex , Jones Kristen , Liu Huiyun , Stevenson Kristen E. , Ren Siyang , Luskin Marlise R. , Couturier Charles P. , Amini Ava P. , Raghavan Srivatsan , Kimmerling Robert J. , Stevens Mark M. , Crawford Lorin , Weinstock David M. , Manalis Scott R. , Shalek Alex K. , Murakami Mark A.
Published: June 2024

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

HIGHLIGHTS

Relapse after remission on TKI can harbor mutations in ABL1, RAS, or neither

Mutations and development-like cell state dictate fitness in residual disease

Co-targeting cell state and ABL1 markedly reduces MRD

Biophysical measurements provide an integrative, rapid measurement of cell state
Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer
Authors: Gómez-Banoy Nicolás , Ortiz Eduardo , Jiang Caroline S. , Dagher Christian , Sevilla Carlo , Girshman Jeffrey , Pagano Andrew , Plodkowski Andrew , Zammarrelli William A. , Mueller Jennifer J. , Aghajanian Carol , Weigelt Britta , Makker Vicky , Cohen Paul , Osorio Juan C.
Published: June 2024

Background

Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.

Methods

We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status.

Results

524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals.

Conclusion

Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.

Funding

NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).
BMAL1-HIF2α heterodimers contribute to ccRCC
Authors: Mello Rebecca M. , Gomez Ceballos Diego , Sandate Colby R. , Agudelo Daniel , Jouffe Celine , Uhlenhaut Nina Henriette , Thomä Nicolas H. , Simon M. Celeste , Lamia Katja A.
Published: June 2024

Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock geneBMAL1is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion ofBMAL1reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higherBMAL1in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasingBMAL1sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
Switchable microscale stress response of actin-vimentin composites emerges from scale-dependent interactions
Authors: Pinchiaroli Julie , Saldanha Renita , Patteson Alison E , Robertson-Anderson Rae M. , Gurmessa Bekele J.
Published: June 2024

The mechanical properties of the mammalian cell regulate many cellular functions and are largely dictated by the cytoskeleton, a composite network of protein filaments, including actin, microtubules, and intermediate filaments. Interactions between these distinct filaments give rise to emergent mechanical properties that are difficult to generate synthetically, and recent studies have made great strides in advancing our understanding of the mechanical interplay between actin and microtubule filaments. While intermediate filaments play critical roles in the stress response of cells, their effect on the rheological properties of the composite cytoskeleton remains poorly understood. Here, we use optical tweezers microrheology to measure the linear viscoelastic properties and nonlinear stress response of composites of actin and vimentin with varying molar ratios of actin to vimentin. We reveal a surprising, nearly opposite effect of actin-vimentin network mechanics compared to single-component networks in the linear versus nonlinear regimes. Namely, the linear elastic plateau modulus and zero-shear viscosity are markedly reduced in composites compared to single-component networks of actin or vimentin, whereas the initial response force and stiffness are maximized in composites versus single-component networks in the nonlinear regime. While these emergent trends are indicative of distinct interactions between actin and vimentin, nonlinear stiffening and longtime stress response appear to both be dictated primarily by actin, at odds with previous bulk rheology studies. We demonstrate that these complex, scale-dependent effects arise from the varied contributions of network density, filament stiffness, non-specific interactions, and poroelasticity to the mechanical response at different spatiotemporal scales. Cells may harness this complex behavior to facilitate distinct stress responses at different scales and in response to different stimuli to allow for their hallmark multifunctionality.
Combined aerobic and resistance exercise training alters the spatial transcriptome of skeletal muscle in young adults
Authors: Stec Michael J. , Graham Zachary A. , Su Qi , Adler Christina , Ni Min , Rouzic Valerie Le , Golann David R. , Ferrara Patrick J. , Halasz Gabor , Sleeman Mark W. , Lavin Kaleen M. , Broderick Timothy J. , Bamman Marcas M.
Published: June 2024

Chronic exercise training substantially improves skeletal muscle function and performance. The repeated demands and stressors of each exercise bout drive coordinated molecular adaptations within multiple cell types in muscle tissue, leading to enhanced neuromuscular recruitment and contractile function, stem cell activation, myofiber hypertrophy, mitochondrial biogenesis, and angiogenesis, among others. To comprehensively profile molecular changes induced by combined resistance and endurance exercise training, we employed spatial transcriptomics coupled with immunofluorescence and computational approaches to resolve effects on myofiber and mononuclear cell populations in human muscle. By computationally identifying fast and slow myofibers using immunofluorescence data of spatially sequenced tissue sections, we identified fiber type-specific, exercise-induced gene expression changes that correlated with muscle functional improvements. Additionally, spatial transcriptome profiling and integration of human muscle single cell RNAseq data identified an exercise-induced shift in interstitial cell populations coincident with angiogenesis. Overall, these data provide a unique spatial molecular profiling resource for exploring muscle adaptations to exercise, and provide a pipeline and rationale for future studies in human muscle.
Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia
Authors: Lanman Nadia A. , Meco Era , Fitchev Philip , Kolliegbo Andree K. , Broman Meaghan M. , Filipovich Yana , Kothandaraman Harish , Cresswell Gregory M. , Talaty Pooja , Antoniak Malgorzata , Brumer Svetlana , Glaser Alexander P. , Higgins Andrew M. , Helfand Brian T. , Franco Omar E. , Crawford Susan E. , Ratliff Timothy L. , Hayward Simon W. , Vickman Renee E.
Published: June 2024

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated byTREM2andMARCOexpression, significantly accumulate with increased prostate volume.TREM2+andMARCO+macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+macrophages have significantly higher neutral lipid than TREM2−macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues.In vitrostudies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2+and MARCO+macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.
Identification of a gene expression signature of vascular invasion and recurrence in stage I lung adenocarcinoma via bulk and spatial transcriptomics
Authors: Steiner Dylan , Sultan Lila , Sullivan Travis , Liu Hanqiao , Zhang Sherry , LeClerc Ashley , Alekseyev Yuriy O. , Liu Gang , Mazzilli Sarah A. , Zhang Jiarui , Rieger-Christ Kimberly , Burks Eric J. , Beane Jennifer , Lenburg Marc E.
Published: June 2024

Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI+compared with VI-tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42×10-6) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI-LUAD (HR=2.76; p=0.003). To determine our VI predictor’s robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2×10-16) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.
Fine-scale cellular deconvolution via generalized maximum entropy on canonical correlation features
Authors: Kamm Jack
Published: June 2024

We propose a method for estimating probability distributions over single cells, which we apply to fine-scale cellular deconvolution, which quantifies the composition of external bulk RNAseq samples at high resolution (i.e. at the single-cell or neighborhood level). Our method is based on a computationally-efficient convex optimization problem, which is also generalization of the Maximum Entropy method. Our method has a much higher resolution than traditional approaches that require computing gene expression profiles at the cell-type level, and also compares favorably to recent high-resolution cellular deconvolution methods, with orders-of-magnitude speedup in computational efficiency. We implement this method in a Python package quipcell, available athttps://github.com/genentech/quipcell.
Efficacy and Safety of Metronomic Capecitabine in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis
Authors: Gupta Nandini , Verma Neelkant , Patel Bhoomika
Published: June 2024

Background and Objective

Metronomic capecitabine has been found to be useful in several types of cancers such as pancreatic cancer, breast cancer, gastrointestinal cancers, nasopharyngeal carcinoma, metastatic colorectal cancer etc. This unique systematic literature review and meta-analysis was undertaken to assess the effectiveness and safety of metronomic capecitabine as a treatment regimen for hepatocellular carcinoma.

Method

A systematic search of major databases was performed. Eight studies that dealt with the use of metronomic capecitabine for HCC were selected, seven were non-RCTs, and one was an RCT. Meta-analysis of these studies was performed using Review manager v5.3 and STATA 15.1 software. The pooled prevalence of OS, PFS, ORR, Grade 1-2 AE, Grade 3-4 AEs were determined, including publication bias and sensitivity analysis.

Result

Eight studies met the inclusion criteria, combining the pooled data of 476 patients from safety and efficacy studies. The pooled prevalence of DCR and ORR achieved with metronomic capecitabine were 36% (95% CI 32-41) and 7% (95% CI 5-9) respectively. The median PFS and median OS were 3.57 months (95% CI 3.29-3.85) and 11.75 months (95% CI 10.56-12.95) respectively. The incidence of 3-4 grade AEs and 1-2 grade AEs were 38% (95% CI 32-44) and 73% (95% CI 67-79) respectively.

Conclusion

This meta-analysis highlights metronomic capecitabine as a potential second-line therapy for HCC. However, effective management of capecitabine’s side effects is essential.
An immunoediting map of human cancers
Authors: Gan Rui , Ren Xianwen
Published: June 2024

Understanding how cancer immunoediting sculpts tumor microenvironments is essential to disentangling tumor immune evasion mechanisms and developing immunotherapies. Here, we construct a comprehensive immunoediting map of human cancers via single-cell deconvolution of 11057 tumor-derived samples across 33 cancer types from TCGA and comparison with 17382 healthy samples across 30 tissues from GTEx. The map covers >1000 different cell states across all the major immune cell types. Mast cells, megakaryocytes, macrophages, neutrophils, plasma cells and T cells are up-regulated across a wide range of tumor types while natural killer cells and platelets are down-regulated in most tumor types, suggesting common cancer immunoediting events. While tumor heterogeneity is higher than the normal corresponding tissues, significant immune homogeneity exists among different tumor types compared with the distinct immune composition among normal tissues and organs. Our study provides a new holistic perspective to understanding cancer immunoediting. Our findings may provide important hints for developing novel cancer immunotherapies, and the high-resolution immunoediting map may serve as a rich resource for further pan-cancer investigation.
Determination of the absolute concentration of Rayleigh particles via scattering microscopy
Authors: Lee Il-Buem , Moon Hyun-Min , Park Jin-Sung , Lee Se-Hwan , Lee Jaewon , Park Sung Hun , Lee Seungwoo , Hong Seok-Cheol , Cho Minhaeng
Published: June 2024

Nanoparticles are crucial in diverse fields such as healthcare, electronics, and energy. Their small size allows them to cross biological barriers, enhancing drug delivery but also posing health risks. Accurate characterization of nanoparticles is essential for assessing their safety and efficacy, particularly in medical applications. Traditional methods such as dynamic light scattering and mass spectrometry have limitations in sensitivity and range of application. To address these challenges, we introduce the interferometric Concentration Analyzer and Ultrasmall Nanoparticle Tracker (iCAUNT), a technique for detecting and quantifying nanoparticles smaller than one-tenth of the imaging light wavelength. As a non-invasive method, iCAUNT provides precise size and concentration measurements of biological and synthetic nanoparticles, offering significant potential for diagnostics, therapeutics, and broader nanoscience applications.
A Computational Workflow for Analysis of Missense Mutations in Precision Oncology
Authors: Khan Rayyan Tariq , Pokorna Petra , Stourac Jan , Borko Simeon , Arefiev Ihor , Planas-Iglesias Joan , Dobias Adam , Pinto Gaspar , Szotkowska Veronika , Sterba Jaroslav , Slaby Ondrej , Damborsky Jiri , Mazurenko Stanislav , Bednar David
Published: June 2024

Every year, more than 19 million cancer cases are diagnosed, and this number continues to increase annually. Since standard treatment options have varying success rates for different types of cancer, understanding the biology of an individual’s tumour becomes crucial, especially for cases that are difficult to treat. Personalised high-throughput profiling, using next-generation sequencing, allows for a comprehensive examination of biopsy specimens. Furthermore, the widespread use of this technology has generated a wealth of information on cancer-specific gene alterations. However, there exists a significant gap between identified alterations and their proven impact on protein function. Here, we present a bioinformatics pipeline that enables fast analysis of a missense mutation’s effect on stability and function in known oncogenic proteins. This pipeline is coupled with a predictor that summarises the outputs of different tools used throughout the pipeline, providing a single probability score, achieving the balanced accuracy above 86%. The pipeline incorporates a virtual screening method to suggest potential FDA/EMA-approved drugs to be considered for treatment. We showcase three case studies to demonstrate the timely utility of this pipeline. To facilitate access and analysis of cancer-related mutations, we have packaged the pipeline as a web server, which is freely available athttps://loschmidt.chemi.muni.cz/predictonco/.
Targeting miRNA for Colorectal Cancer:In SilicoIdentification and Physics-basedDe NovoModeling of Oncogenic miR-135b for Small Molecule RNA Therapy
Authors: Demir Berat , Oktay Lalehan , Durdağı Serdar
Published: June 2024

Colorectal cancer is one of the leading causes of cancer deaths worldwide. In the current study, we have identified miR-135b, a microRNA to be differentially expressed in colorectal cancer, through an analysis of the differentially expressed miRNAs from the Gene Expression Omnibus database. Subsequently, the target genes associated with miR-135b were pinpointed, and pathway and functional enrichment analyses were performed to gain a comprehensive understanding of the underlying biological processes involved. Ade novothree-dimensional model of its tertiary structure was developed for small-molecule targeting at the Dicer cleavage site. Dicer binds to the terminal loop region of the pre-miRNA and cleaves to generate double stranded miRNA duplex. The miRNA duplex is unwound, one of the strands, guide miRNA, is loaded into the RNA-induced silencing complex (RISC) for miRNA-mRNA target interaction and post-transcriptional gene silencing. Following results from molecular docking simulations initiated with the ChemDiv miRNA-targeted small molecule library (∼20.000 compounds), top-scoring compound’s commercial analogues were then searched within the ZINC library using SwissSimilarity. These analogues were docked to the Dicer cleavage site and their optimized docking scores were obtained. These top-scoring molecules were then subject to all-atom molecular dynamics simulations and post-simulation analyses were conducted to assess the dynamic interactions between the miRNA and the selected hit ligands.
Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS)
Authors: Subramanian Balajikarthick , Williams Sarah , Karp Sophie , Hennino Marie-Flore , Jacas Sonako , Lee Miriam , Riella Cristian V. , Alper Seth L. , Higgs Henry N. , Pollak Martin R.
Published: June 2024

Inverted formin-2 (INF2) gene mutations are among the most common causes of genetic focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth (CMT) disease. Recent studies suggest that INF2, through its effects on actin and microtubule arrangement, can regulate processes including vesicle trafficking, cell adhesion, mitochondrial calcium uptake, mitochondrial fission, and T-cell polarization. Despite roles for INF2 in multiple cellular processes, neither the human pathogenic R218Q INF2 point mutation nor the INF2 knock-out allele is sufficient to cause disease in mice. This discrepancy challenges our efforts to explain the disease mechanism, as the link between INF2-related processes, podocyte structure, disease inheritance pattern, and their clinical presentation remains enigmatic. Here, we compared the kidney responses to puromycin aminonucleoside (PAN) induced injury between R218Q INF2 point mutant knock-in and INF2 knock-out mouse models and show that R218Q INF2 mice are susceptible to developing proteinuria and FSGS. This contrasts with INF2 knock-out mice, which show only a minimal kidney phenotype. Co-localization and co-immunoprecipitation analysis of wild-type and mutant INF2 coupled with measurements of cellular actin content revealed that the R218Q INF2 point mutation confers a gain-of-function effect by altering the actin cytoskeleton, facilitated in part by alterations in INF2 localization. Differential analysis of RNA expression in PAN-stressed heterozygous R218Q INF2 point-mutant and heterozygous INF2 knock-out mouse glomeruli showed that the adhesion and mitochondria-related pathways were significantly enriched in the disease condition. Mouse podocytes with R218Q INF2, and an INF2-mutant human patient’s kidney organoid-derived podocytes with an S186P INF2 mutation, recapitulate the defective adhesion and mitochondria phenotypes. These results link INF2-regulated cellular processes to the onset and progression of glomerular disease. Thus, our data demonstrate that gain-of-function mechanisms drive INF2-related FSGS and explain the autosomal dominant inheritance pattern of this disease.
Cross-Modality Synthetic Data Augmentation using GANs: Enhancing Brain MRI and Chest X-ray Classification
Authors: Dhawan Kunaal , Nijhawan Siddharth S.
Published: June 2024

II.

Brain MRI scans and chest X-ray imaging are pivotal in diagnosing and managing neurological and respiratory diseases, respectively. Given their importance in diagnosis, the datasets to train the artificial intelligence (AI) models for automated diagnosis remain scarce. As an example, annotated chest X-ray datasets, especially those containing rare or abnormal cases like bacterial pneumonia, are scarce. Conventional dataset collection methods are labor-intensive and costly, exacerbating the data scarcity issue. To overcome these challenges, we propose a specialized Generative Adversarial Network (GAN) architecture for generating synthetic chest X-ray data representing healthy lungs and various pneumonia conditions, including viral and bacterial pneumonia. Additionally, we extended our experiments to brain MRI scans by simply swapping the training dataset and demonstrating the power of our GAN approach across different medical imaging contexts. Our method aims to streamline data collection and labeling processes while addressing privacy concerns associated with patient data. We demonstrate the effectiveness of synthetic data in facilitating the development and evaluation of machine learning algorithms, particularly leveraging an EfficientNet v2 model. Through comprehensive experimentation, we evaluate our approach on both real and synthetic datasets, showcasing the potential of synthetic data augmentation in improving disease classification accuracy across diverse pathological conditions. Indeed, the classifier performance when trained with fake + real data on brain MRI classification task shows highest accuracy at 85.9%. Our findings underscore the promising role of synthetic data in advancing automated diagnosis and treatment planning for pneumonia, other respiratory conditions, and brain pathologies.
Implicit bias in Critical Care Data: Factors affecting sampling frequencies and missingness patterns of clinical and biological variables in ICU Patients
Authors: Shi Junming (Seraphina) , Hubbard Alan E. , Fong Nicholas , Pirracchio Romain
Published: June 2024

The presence of missing values in Electronic Health Records (EHRs) is a widespread and inescapable issue. Publicly available data sets mirror the incompleteness found in EHRs. Although the existing literature largely approaches missing data as a random phenomenon, the mechanisms behind these missing values are often not random with respect to important characteristics of the patients. Similarly, the sampling frequency of clinical or biological parameters is likely informative. The possible informative nature of patterns in missing data is often overlooked. For both missingness and sampling frequency, we hypothesize that the underlying mechanism may be at least consistent with implicit bias.

To investigate this important issue, we introduce a novel analytical framework designed to rigorously examine missing data and sampling frequency in EHRs. We utilize the MIMIC-III dataset as a case study, given its frequent use in training machine learning models for healthcare applications. Our approach incorporates Targeted Machine Learning (TML) to study the impact of a series of demographic variables, including protected attributes such as age, sex, race, and ethnicity on the rate of missing data and sampling frequency for key clinical and biological variables in critical care settings. Our results expose underlying differences in the sampling frequency and missing data patterns of vital sign measurements and laboratory tests between different demographic groups. In addition, we find that these measurement patterns can provide significant predictive insights into patient outcomes. Consequently, we urge a reevaluation of the conventional understanding of missing data and sampling frequencies in EHRs. Acknowledging and addressing these biases is essential for advancing equitable and accurate healthcare through machine learning applications.