bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of shared decision-making with financial toxicity and coping actions in adult patients with cancer: a nationwide study in China
Authors: Liu Meicen , Huang Dengmin , Ma Jing , Wei Wenqiang , Liu Yuanli
Published: September 2024

Objective

Evidence on the impact of shared decision-making (SDM) on the financial toxicity (FT) of patients with cancer in real clinical settings is lacking. Using a nationwide patient survey in China, we aimed to identify the prevalence of SDM, FT as well as its consequent coping actions, and investigate their associations in adult patients with cancer.

Methods

A cross-sectional survey was administered to patients with cancer near discharge at 33 tertiary public cancer hospitals across China between January and March 2021. The FT was measured using the COST (comprehensive score for financial toxicity) tool and was categorized into 3 groups: no (COST 26-44), mild (COST 14-25), and moderate or severe (COST 0-13) FT. SDM was measured using 2 items from patient’s perspective. The surveyed questionnaire also included patient’s coping actions, demographics, and clinical information. Multinomial logistic regression was used to investigate the association between SDM and FT, and for sensitivity analysis, linear regression was also used taking the COST score as a dependent variable. Pearson’s chi-square tests were used for association analyses of coping actions with FT and SDM.

Results

A total of 5008 adult patients with cancer were included, of which 26.18%, 54.13%, and 19.69% patients were categorized as no FT, mild FT, and moderate or severe FT with the average COST score of 21.0 for all patients. Besides, 3943 (78.73%) patients reported a better SDM. Better SDM had significantly lower odds of developing high FT than worse SDM (adjusted ORmild vs no 0.50, 95% CI 0.39-0.56; adjusted ORmoderate or severe vs no 0.63, 95% CI 0.50-0.80). In sensitivity analysis, better SDM was significantly associated with higher COST scores (β: 1.34, 95% CI 0.85-1.83), which indicated lower FT. Patients with higher FT were more likely to take adverse coping actions including treatment nonadherence, limiting basic health service expense, reducing leisure activity expense, and loan.

Conclusions

Adult patients with cancer reporting worse SDM tended to experience higher FT and those with higher FT tended to take adverse coping actions. Understanding the impact of SDM on FT is crucial to inform early interventions designed to mitigate FT and consequent coping actions in cancer care practice.
C2-domain abscisic acid-related proteins regulate the dynamics of a plasma membrane H+-ATPase in response to alkali stress
Authors: Guo Ai-Yu , Wu Wen-Qiang , Liu Wen-Cheng , Zheng Yuan , Bai Di , Li Yan , Xie Jie , Guo Siyi , Song Chun-Peng
Published: September 2024

Arabidopsis (Arabidopsis thaliana) H+-ATPase1 (AHA1), a plasma membrane (PM)-localized H+-ATPase, plays a key role in plant alkali stress tolerance by pumping protons from the cytoplasm to the apoplast. However, its molecular dynamics are poorly understood. We report that many C2-domain ABA-related (CAR) protein family members interact with AHA1 in Arabidopsis. Single or double mutants of CAR1, CAR6, and CAR10 had no obvious phenotype of alkali stress tolerance, while their triple mutants showed significantly higher tolerance to this stress. The disruption of AHA1 largely compromised the increased alkali stress tolerance of the car1car6car10 mutant, revealing a key role of CARs in AHA1 regulation during the plant's response to a high alkali pH. Furthermore, variable-angle total internal reflection fluorescence microscopy was used to observe AHA1-mGFP5 in intact Arabidopsis seedlings, revealing the presence of heterogeneous diffusion coefficients and oligomerization states in the AHA1 spots. In the aha1 complementation lines, alkali stress curtailed the residence time of AHA1 at the PM and increased the diffusion coefficient and particle velocity of AHA1. In contrast, the absence of CAR proteins decreased the restriction of the dynamic behavior of AHA1. Our results suggest that CARs play a negative role in plant alkali stress tolerance by interacting with AHA1 and provide a perspective to investigate the regulatory mechanism of PM H+-ATPase activity at the single-particle level.
Role of lumbar puncture level on the onset of epidural labor analgesia: a randomized controlled trial
Authors: Zhou Rui , Cao Yuansheng , Chen Xuemeng , Peng Yanhua , Xiong Chao , Zhai Wenhu , Zhang Xianjie , Zhou Yukai , Xiong Lize
Published: September 2024

Objective

To compare the speed of achieving painless uterine contractions in parturients undergoing epidural analgesia at different lumbar puncture levels.

Methods

This study is a randomized controlled trial at a tertiary A hospital with a history of over 80 years in Sichuan Province, China. Parturients aged 22–40 years old scheduled for vaginal delivery under epidural analgesia were recruited. Eligible patients were randomly allocated into lumbar 2-3 (L2-3) or lumbar 3-4 (L3-4) groups. Epidural analgesia was performed through the interspaces according to grouping. The primary outcome was the percentage of painless uterine contractions 15 min after the initiation of analgesia. The secondary outcomes included the percentage of painless status at 5 and 10 min, sensory block plane, motor block evaluation, adverse events of parturients, epidural analgesic consumption, Apgar score, and the parturients' evaluation of analgesia.

Results

Between April 2023 and August 2023, a total of 150 women were finally recruited, and 136 of them were analyzed (68 in each group). In comparison with the L3-4 groups, there was a significantly larger proportion of painless uterine contractions at 5, 10, and 15 min after analgesia initiation in the L2-3 group (20.6% vs. 7.4%, 52.9% vs. 26.5%, and 80.9% vs. 64.7%, P = .026, .002, and .034, respectively). Similarly, the pain scores were lower in the L2-3 group at 5, 10, and 15 min than that in the L3-4 group (5(4,7) vs. 6(5,7), 3(2,5) vs. 4(3,6), and 2(1,3) vs. 3(2,5), P = .006, .004, and .020, respectively). Furthermore, puncturing through the L2-3 interspace contributed to a higher evaluation of parturients to the analgesia procedure (9(8,9) vs. 8(8,9), P < .001). However, there was no significant difference in sensory block, motor block, or adverse events between the two groups.

Conclusion

Puncturing through the L2-3 interspace is associated with faster pain relief and a better experience for parturients. These findings present a superior option for anesthesiologists when conducting epidural labor analgesia.

Key messages What is already known on this topic?  Epidural analgesia is an effective way to relieve labor pain. What this study adds?  Puncturing via lumbar 2-3 interspace induces more rapid onset of epidural analgesia. How this study might affect research, practice or policy?  Lumbar 2-3 interspace is a superior option in terms of the speed of pain relief and satisfaction of parturients when conducting epidural labor analgesia.
Three Cases of Complex Eigenvalue/Vector Distributions of Symmetric Order-Three Random Tensors
Authors: Majumder Swastik , Sasakura Naoki
Published: September 2024

Random tensor models have applications in a variety of fields, such as quantum gravity, quantum information theory, mathematics of modern technologies, etc., and studying their statistical properties, e.g. tensor eigenvalue/vector distributions, is interesting and useful. Recently some tensor eigenvalue/vector distributions have been computed by expressing them as partition functions of 0D quantum field theories. In this paper, using this method, we compute three cases of complex eigenvalue/vector distributions of symmetric order-three random tensors, where the three cases can be characterized by the Lie-group invariances, $O(N,\mathbb {R})$, $O(N,\mathbb {C})$, and $U(N,\mathbb {C})$, respectively. Exact closed-form expressions of the distributions are obtained by computing partition functions of four-fermi theories, where the last case is of the “signed” distribution, which counts the distribution with a sign factor coming from a Hessian matrix. As an application, we compute the injective norm of the complex symmetric order-three random tensor in the large-N limit by computing the edge of the last signed distribution, obtaining agreement with an earlier numerical result in the literature.
Assessment of foetal dose and occupational exposure for pregnant workers in nuclear medicine using the Taiwanese pregnancy phantom
Authors: Chang Hao-Ting , Chang Yu-Chen , Hsu Fang-Yuh , Hsu Ching-Han
Published: September 2024

For pregnant workers in nuclear medicine, radiation doses can pose a risk to their foetus. However, foetal radiation doses cannot be measured directly. In this study, a method of estimating foetal radiation doses was developed through simulations and measurements of phantoms of pregnant women in the three trimesters. The uterus and abdominal surface doses for monoenergetic photons (137Cs) and medical diagnostic X-rays were measured, and uterine dose conversion coefficients (UDCCs) were calculated. The accuracy of the UDCC estimates were validated for measurements from thermoluminescent dosemeter (TLD) chips and TLD badges on the abdomen or chest. The foetal effective dose could be estimated using TLD chips and TLD badges on the abdomen or chest, or through literature estimation method. The proposed method can be used to easily and accurately estimate foetal effective doses from chest-worn TLD badges, ensuring accurate estimation in the early stage of pregnancy when a worker may not yet be wearing an abdominal badge. A flowchart for applying the UDCC method to approximate a foetal dose is also provided to ensure that total doses remain below the maximum of 1 mSv recommended in the International Commission on Radiological Protection 103 guidelines.
Implantation of CRT pacemaker during pregnancy: estimated fetal radiation dose
Authors: Manninen Anna-Leena , Järvinen Jukka , Sierpowska Joanna , Mäkelä Timo J , Rissanen Tuomas T
Published: September 2024

The benefits of a cardiac resynchronization therapy (CRT) implantation are known in severe heart failure and its implantation may also be considered during pregnancy to ensure safe pregnancy and delivery for both the mother and the fetus. This study on a patient case aimed to estimate the absorbed dose (AD) to the fetus during the CRT implantation of 21st week of the pregnant woman. AD measurement was done using anthropomorphic phantom, radiophotoluminescence dosemeters and Monte Carlo simulation utilizing kerma area product (KAP) of the procedures. The measured AD for a phantom’s uterus and heart was 0.116 and 14.7 mGy with total KAP of 27.9 Gycm2. The estimated actual AD to the fetus and the mother’s heart was 0.004 and 1.2 mGy, with total KAP of 1.5 Gycm2. The dose to the fetus can be minimized with the optimized procedure.
Radiation exposure to patients undergoing percutaneous transhepatic cholangiography and endoscopic retrograde cholangiography: an advanced phantom study
Authors: Tunçman Duygu , Özgür Eren , Nayci Ali Emre , Günay Osman , Kesmezacar Fahrettin Fatih , Karaçam Songül Çavdar , Üzüm Güngör , Demir Mustafa , Akkuş Baki , Elshami Wiam , Almisned Ghada , Tekin Huseyin Ozan
Published: September 2024

Fluoroscopic examinations like Endoscopic Retrograde Cholangiopancreatography (ERCP) and Percutaneous Transhepatic Cholangiography (PTC) are fundamental in diagnosing and treating hepatobiliary diseases. However, these procedures expose patients to significant radiation, highlighting the need for a detailed assessment of the radiation doses received by critical organs. The study’s primary objective is to determine the experimental doses received by critical organs in patients undergoing these procedures. This study utilized an Alderson RANDO phantom outfitted with Thermoluminescent Dosemeters (TLDs) to experimentally measure the radiation doses received by various organs during ERCP and PTC procedures. This method provided direct and accurate data on organ-specific radiation exposure, contrasting with the traditional approach of relying on theoretical simulations. The analysis revealed that PTC generally results in higher radiation doses to organs compared to ERCP. Critical organs, such as the thyroid, spleen, liver, pancreas, ovaries, and uterus, were exposed to varying levels of radiation, with the thyroid and spleen receiving particularly high doses in PTC. The study also demonstrated that the per-minute radiation exposure was consistently higher in PTC across all examined organs. The study’s findings underscore the significant radiation exposure associated with ERCP and PTC, with PTC posing a greater risk. Understanding these exposure levels is crucial for clinical decision-making, particularly when considering patients’ pre-existing conditions and sensitivity to radiation. The study highlights the need for clinicians to carefully weigh the benefits of ERCP and PTC against the potential radiological risks. It suggests a preference for ERCP in situations where radiation exposure needs to be minimized. Furthermore, the findings advocate for ongoing advancements in medical imaging techniques to reduce radiation exposure, emphasizing the importance of patient safety in fluoroscopic examinations. This research contributes significantly to informed clinical decision-making, ensuring that the selection of diagnostic and therapeutic procedures aligns with the best interest of patient health and safety.
Towards sustainable antimicrobial therapies for Staphylococcus aureus skin infections
Authors: Lang Julia C , Shahata Mariam , Melican Keira
Published: September 2024

Skin and soft tissue infections (SSTIs) are a major economic and clinical burden. With the emergence of increasing antimicrobial resistance, novel treatment options, as well as advanced drug delivery systems will be essential to fight these infections and meet the UN Sustainability Development Goals (SDGs). SSTIs are commonly caused by Staphylococcus aureus, including the infamous MRSA (methicillin-resistant S. aureus). In this short review, we discuss new antimicrobial therapies with potential to combat skin infections caused by S. aureus. This includes discussion of antimicrobial strategies originating from both the host and microbiota. Adapting immunotherapy-type approaches to infection is also discussed, giving examples of cellular targets of interest. We examine the difficulties of therapeutic delivery into a barrier tissue such as skin and discuss exciting new developments in interdisciplinary approaches that may help overcome these challenges.
Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease
Authors: Eubanks Elena , VanderSleen Katelyn , Mody Jiya , Patel Neha , Sacks Benjamin , Farahani Mahsa Darestani , Wang Jinying , Elliott Jordan , Jaber Nora , Akçimen Fulya , Bandres-Ciga Sara , Helweh Fadel , Liu Jun , Archakam Sanjana , Kimelman Robert , Sharma Bineet , Socha Philip , Guntur Ananya , Bartels Tim , Dettmer Ulf , Mouradian M. Maral , Bahrami Amir Houshang , Dai Wei , Baum Jean , Shi Zheng , Hardy John , Kara Eleanna
Published: September 2024

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson’s disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of αSyn in Parkinson’s disease is unclear, it is thought that prionoid cell-to-cell propagation of αSyn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates αSyn propagation. Follow up experiments were undertaken for two of those genes,TAX1BP1andADAMTS19, to study the mechanism with which they regulate αSyn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) “3K” αSyn under doxycycline induction. 3K αSyn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed thatTAX1BP1andADAMTS19regulate how αSyn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson’s disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down ofTAX1BP1orADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson’s disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of αSyn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson’s disease: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis, thereby leading to pathology and neurodegeneration.
Revisiting Evidence for Epigenetic Control of Alternative Splicing
Authors: Manz Quirin , List Markus
Published: September 2024

Alternative splicing is crucial for increasing eukaryotic cell transcriptome and proteome diversity Changes in alternative splicing play a key role in cell differentiation and tissue development, and aberrations in this process have been associated with diseases Despite its importance, the exact mechanisms for regulating alternative splicing are poorly understood Several epigenetic marks, such as histone modification H3K36me3, have previously been associated with changes in alternative splicing Here, we leverage the EpiATLAS data set to systematically re-evaluate evidence for epigenetic control of alternative splicing. We used SUPPA2 to calculate percentage spliced-in (PSI) values for skipped exons and retained introns and integrated this information with histone ChIP-seq and DNA methylation data In addition to genome-wide association analysis with partial correlation and machine learning, we perform locus-specific PSI modeling on individual alternative splicing events The latter represents a new contribution enabled by the unprecedented number of uniformly processed datasets in EpiATLAS. Our results confirm previously reported global associations of DNAm and H3K36me3 for exon inclusion and emphasize the importance of intrinsic features for genome-wide associations. On an event-specific level, trying to identify co-transcriptionally spliced events with epigenetic influence, we show that overall gene expression biases locus-specific analyses Further, we show that epigenetic signal can predict PSI value in cis and trans, indicating sample-specific epigenetic fingerprints that distort across-sample analyses Specifically, generalized linear models select epigenetic features predictive for PSI values not only in their genomic vicinity but also on different chromosomes. Our study demonstrates that epigenetic marks are associated with the alternative inclusion of exons and introns Without a mechanistic explanation for these associations, our work emphasizes the need for more detailed research into the relationship between epigenetic changes and transcriptome diversity.
Ultrastructural and transcriptional changes during a giant virus infection of a green alga
Authors: Gajigan Andrian P. , Schvarcz Christopher R. , Conaco Cecilia , Edwards Kyle F. , Steward Grieg F.
Published: September 2024

The complete genome sequence of theOceanusvirus kaneohensestrain (Tetraselmis virus 1; TetV-1) was previously reported, but little is known about the virus infection cycle. Using a permissiveTetraselmisisolate (UHM1315), we estimated the eclipse period (4–8 hours), latent period (16 hrs), and burst size (800–1000) of the virus and documented ultrastructural and transcriptional changes in the host during infection. Putative viral factories and electron-dense inclusion bodies appeared in the cytoplasm of infected cells by 8 and 16 h post-infection, respectively. The nucleus and chloroplasts appeared to remain intact but reduced in size after 8 h. Transcriptome sequencing suggests that the viral genome codes for 830 transcripts. Those expressed early in infection (eclipse period at 0.25 and 4 hr) were related to the initiation of transcription, DNA synthesis, translation, and host immune repression. During the later, post-eclipse period (8, 12, 16 hr), virus structural genes were expressed. For the algal host, transcripts related to lipid metabolism and endocytosis were upregulated during the early phase, while those for protein modification/ turnover/ transport were downregulated. In the later period, host transcripts associated with basic cellular processes were upregulated, while genes related to morphogenesis/development were downregulated. Many of the most highly expressed virus and host genes were of unknown function, highlighting a need for additional functional studies.
Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling
Authors: Kigar Stacey L. , Lynall Mary-Ellen , DePuyt Allison E. , Atkinson Robert , Sun Virginia H. , Samuels Joshua D. , Eassa Nicole E. , Poffenberger Chelsie N. , Lehmann Michael L. , Listwak Samuel J. , Livak Ferenc , Elkahloun Abdel G. , Clatworthy Menna R. , Bullmore Edward T. , Herkenham Miles
Published: September 2024

Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice. We find that chronic, but not acute, stress causes meningeal neutrophil accumulation, and CSD increases neutrophil trafficking in vascular channels emanating from skull bone marrow (BM). Transcriptional analysis suggested CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protected against the anhedonic and anxiogenic effects of CSD stress, potentially through reduced infiltration of IFNAR+neutrophils into the meninges from skull BM. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitate development of new therapies for stress-related disorders.

One sentence summary

Type I interferon sensing neutrophils accumulate in meninges of psychosocially stressed mice via skull bone marrow channels and are associated with the negative behavioral sequelae of stress; blockade of this pathway inhibits neutrophil trafficking and improves behavioral outcomes.
LexicMap: efficient sequence alignment against millions of prokaryotic genomes
Authors: Shen Wei , Iqbal Zamin
Published: September 2024

Alignment against a database of genomes is a fundamental operation in bioinformatics, popularized by BLAST. However, the rate at which microbial genomes are sequenced has continued to increase, and there are now datasets in the millions, far beyond the abilities of existing alignment tools. We introduce LexicMap, a nucleotide sequence alignment tool for efficiently querying moderate length sequences (> 500 bp) such as a gene, plasmid or long read against up to millions of prokaryotic genomes. A key innovation is to construct a small set of probek-mers (e.g. n = 40,000) which “window-cover” the entire database to be indexed, in the sense that every 500 bp window of every database genome contains multiple seedk-mers each with a shared prefix with one of the probes. Storing these seeds, indexed by the probes with which they agree, in a hierarchical index enables fast and low-memory variable-length seed matching, pseudoalignment, and then full alignment. We show that LexicMap is able to align with higher sensitivity than Blastn as the query divergence drops from 90% to 80% for queries ≥ 1 kb, and then benchmark on small (GTDB) and large (AllTheBacteria and Genbank+RefSeq) databases. We show that LexicMap achieves higher sensitivity and speed and lower memory compared to the state-of-the-art approaches. Alignment of a single gene against 2.34 million prokaryotic genomes from GenBank and RefSeq takes 36 seconds (rare gene) to 15 minutes (16S rRNA gene). LexicMap produces output in standard formats including that of BLAST and is available under MIT license athttps://github.com/shenwei356/LexicMap.
Insulin-Independent Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2
Authors: Lee Jeongmin , Ustione Alessandro , Wilkerson Emily M , Balakrishnan Rekha , Thurmond Debbie C. , Goldfarb Dennis , Piston David W.
Published: September 2024

Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT), independent of insulin. The large molecular weight secreted fraction mediates insulin receptor-dependent recovery of euglycemia in a T1D animal model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction also promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. From this fraction, we identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. These findings confirm that BAT transplants affect physiology and demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.

HIGHLIGHTS

The large molecular weight brown adipocyte-secreted protein fraction suppresses glucagon secretion and normalizes glycemia in mouse models of type 1 diabetes (T1D), independent of insulin, offering a novel therapeutic strategy for disease management.

Nidogen-2, a critical component of this fraction, is identified as an inhibitor of glucagon secretion in pancreatic α-cells by regulating intracellular messenger activities.

The large-secreted protein fraction prevents T1D-related whitening of brown adipose tissue, promotes adipocyte differentiation, and enhances browning of inguinal white adipose tissue.

This fraction enhances glucose uptake in adipose tissue, skeletal muscle, and liver through an insulin receptor-dependent pathway.
Developing Biosensors for Specific Assessment ofTrans-translation inPseudomonas aeruginosa
Authors: L’Hermitte Bastien , Chauvet Thomas , Georgeault-Daguenet Sylvie , Yondre Nicolas Le , Jehan Philippe , Gillet Reynald , Baysse Christine
Published: September 2024

Trans-translation is a crucial bacterial process and a target for new antibiotics. We developed twoPseudomonas aeruginosabiosensor strains that detecttrans-translation inhibitors by exploiting the bacterium’s natural red fluorescence, linked to protoporphyrin IX accumulation. The first biosensor monitors tmRNA-SmpB-mediated tagging, while the second serves as control for biosensor 1 by keeping track of ClpP1-related proteolysis and porphyrin biosynthesis. Validation through gene deletions and complementation confirmed their specificity. These biosensors were effective in screening antibiotics and designed inhibitors, demonstrating their potential for high-throughput identification oftrans-translation inhibitors in drug-resistantP. aeruginosa.
Population-level age effects on the white matter structure subserving cognitive flexibility in the human brain
Authors: Wolfe Tatiana , Gassel Alexandra , Calvert Maegan L. , Isaac Lee , James G. Andrew , Kosick Timothy R. , Kilts Clint D.
Published: September 2024

Cognitive flexibility, a cognition crucial for adaptive behavior, involves multi-scale functioning across several neuronal organization levels. While the neural underpinnings of flexibility have been studied for decades, limited knowledge exist about the structure and differentiation of the white matter subserving brain regions implicated in cognitive flexibility. Neural changes that occur over the lifespan have an impact in the brain’s white matter organization and, thereby, may alter cognitive flexibility abilities. This study investigates the population-level relationship between cognitive flexibility and macromolecular properties of white matter across two periods of adulthood, aiming to discern how these associations vary over different life stages and brain tracts. A novel method to study age-effects in the brain’s structure-function associations is proposed. First, the white matter structure implicated in cognitive flexibility was delineated by tracing in the Human Connectome Project tractography template the pathways subserving neural regions derived via meta-analysis of set-shifting. Then, a cohort analysis was performed to characterize related brain features using a subset of the UKBiobank MRI data which has a companion functional/behavioral dataset.1We found that (1)the wiring of cognitive flexibility is defined by specialized tracts, which present undifferentiated features early in adulthood, and significantly differentiated types in later life. (2)These MRI-derived properties are correlated with individual subprocesses of cognition which intimately relate to the latent construct of cognitive flexibility function (switch, inhibition, and updating).2(3)In late life, myelin-related homogeneity of specific white matter tracts implicated in cognitive flexibility declines as a function of chronological age—a phenomenon not observed in early life. Our findings support the age-related differentiation of white matter tracts implicated in cognitive flexibility as a natural substrate of brain adaptive function.

Significance Statement

Cognitive flexibility, a cognition that facilitates adaptation to environmental demands, involves complex brain processes. During the lifespan, brain changes affecting the brain’s structural organization are theorized to impact cognitive flexibility. This study characterizes how the brain’s connectivity is correlated with cognitive flexibility throughout adulthood. By analyzing macromolecular properties of white matter, this study found that certain parts of the brain’s wiring related to cognitive flexibility become more distinct with advanced age. This age-related distinction of the wiring implicated in cognitive flexibility appears as a natural, underlying characteristic of the human brain which may impact specific aspects of thinking, like shifting between tasks or updating information.
An alveolus lung-on-a-chip model ofMycobacterium fortuitumlung infection
Authors: Ektnitphong Victoria , Dias Beatriz R.S. , Campos Priscila C. , Shiloh Michael U.
Published: September 2024

Lung disease due to non-tuberculous mycobacteria (NTM) is rising in incidence. While both two dimensional cell culture and animal models exist for NTM infections, a major knowledge gap is the early responses of human alveolar and innate immune cells to NTM within the human alveolar microenvironment. Here we describe development of a humanized, three-dimensional, alveolus lung-on-a-chip (ALoC) model ofMycobacterium fortuitumlung infection that incorporates only primary human cells such as pulmonary vascular endothelial cells in a vascular channel, and type I and II alveolar cells and monocyte-derived macrophages in an alveolar channel along an air-liquid interface.M. fortuitumintroduced into the alveolar channel primarily infected macrophages, with rare bacteria inside alveolar cells. Bulk-RNA sequencing of infected chips revealed marked upregulation of transcripts for cytokines, chemokines and secreted protease inhibitors (SERPINs). Our results demonstrate how a humanized ALoC system can identify critical early immune and epithelial responses toM. fortuituminfection. We envision potential application of the ALoC to other NTM and for studies of new antibiotics.
Unraveling tumor heterogeneity: Quantitative insights from scRNA-seq analysis in breast cancer subtypes
Authors: Senra Daniela , Guisoni Nara , Diambra Luis
Published: September 2024

Tumors are complex systems characterized by genetic, transcriptomic, phenotypic, and microenvironmental variations. The complexity of this heterogeneity plays a crucial role in metastasis, tumor progression, and recurrence. In this work, we utilized publicly available single-cell transcriptomics data from human breast cancer samples (ER+, HER2+, and triple-negative) to evaluate key concepts pertinent to cancer biology. Quantitative assessments included measures based on copy number alterations (CNAs), entropy, transcriptomic heterogeneity, and different protein-protein interaction networks (PPINs).

We found that entropy and PPIN activity related to the cell cycle delineate cell clusters with notably elevated mitotic activity, particularly elevated in aggressive breast cancer subtypes. Additionally, CNA distributions differentiate between ER+ and HER2+/TN subtypes. Further, we identified positive correlations among the CNA score, entropy, and the activities of PPINs associated with the cell cycle, as well as basal and mesenchymal cell lines. These scores reveal associations with tumor characteristics, reflecting the known malignancy spectrum across breast cancer subtypes.

By bridging the gap between existing literature and a comprehensive quantitative approach, we present a novel framework for quantifying cancer traits from scRNA-seq data by establishing several scores. This approach highlights the potential for deeper insights into tumor biology compared to conventional marker-based approaches.
Wirelessly-Powered Ingestible Electronic Capsule for Non-invasive Gastrointestinal Optogenetics
Authors: Elsherif Mohamed , El-Din Rawan Badr , Makhambetova Zhansaya , Naser Heba , Boitet Maylis , Singh Rahul , Oh Keonghwan , Sukesan Revathi , Ha Sohmyung , Ramadi Khalil B.
Published: September 2024

Optogenetics enables the activation and inhibition of neurons with cell specificity. The gut harbors intricate networks of enteric and central neurons. Uncovering these neuronal pathways in vivo is challenging with traditional neuroscience probes due to the highly motile and harsh gut environment. Here we report the development of an ingestible electronic capsule for non-invasive optical gut stimulation (ICOPS) in rodents. ICOPS is powered wirelessly via a transmitter coil, dosed via oral gavage, and safely excreted without causing obstruction. ICOPS permits modular interchangeability of onboard light-emitting diodes (LEDs) for illumination. We exemplify this with optical irradiance at 470 nm, a commonly-used wavelength in optogenetics for activating channelrhodopsin2. ICOPS features a micro-LED (µLED), a 460-turn coil wound around a ferrite core, and a resonating capacitor. We optimized the transmitting and receiving circuits to achieve maximum power transfer at low operating frequencies (45-140 kHz), overcoming challenges like loose coupling and misalignment. The capsule operates effectively at a distance up to 12 cm longitudinally, 9 cm laterally, and 75° rotational angle relative to the magnetic field. Specific absorption rate (SAR) calculations indicate transmitter-induced SAR levels within safe limits for the occupational environment at 6 Armsand 45 and 63 kHz frequencies ICOPS is robust and transits through the rat gastrointestinal (GI) tract in under 20 hours intact. We demonstrate in vivo functionality and viability of ICOPS using IVIS micro-computed tomography (µCT). ICOPS could pave the way for non-invasive optogenetic interfacing of enteric neural circuits towards their use to regulate motility, visceral pain, and other gastrointestinal disorders.
Differential coding of fruit, leaf, and microbial odours in the brains ofDrosophila suzukiiandDrosophila melanogaster
Authors: Dumenil Claire , Yildirim Gülsüm , Haase Albrecht
Published: September 2024

The flyDrosophila suzukii, a close relative ofD. melanogasterseverely damages the production of berry and stone fruits in large parts of the world. UnlikeD. melanogaster, which reproduces on overripe and fermenting fruits on the ground,D. suzukiiprefers to lay its eggs in ripening fruits still on the plants. Flies locate fruit hosts by their odorant volatiles, which are detected and encoded by a highly specialized olfactory system before being translated into behaviour. The exact information processing pathway is not yet fully understood, especially the evaluation of odour attractiveness. It is also unclear what differentiates the brains ofD. suzukiiandD. melanogasterto cause the crucial difference in host selection. We hypothesized that the basis for different behaviours is already formed at the level of the antennal lobe ofD. suzukiiandD. melanogaster,by different neuronal responses to volatiles associated with ripe and fermenting fruit. We thus investigated by 3Din vivotwo-photon calcium imaging how both species encoded odours from ripe fruits, leaves, fermented fruits, bacteria, and their mixtures in the antennal lobe. We then assessed their behavioural responses to mixtures of ripe and fermenting odours. The neural responses reflect species-dependent shifts in the odour code. In addition to this, morphological differences were also observed. Yet this was not directly reflected in different behavioural responses to the odours tested.
Chronic mitochondrial fragmentation elicits a neuroprotective Warburg-like effect inDrosophilaneurons
Authors: Richhariya Shlesha , Shin Daniel , Schlichting Matthias , Rosbash Michael
Published: September 2024

Mitochondrial fission and fusion are dynamic and important cellular processes, but the roles of these two very different mitochondrial forms – predominantly spherical and tubular - are not well-characterized in neurons of animals and especially in aging neurons. This is important because neurons are long-lived and mitochondrial dynamics is associated with neurodegenerative diseases. We used here an efficient cell type-specific CRISPR approach to knockout key fission-fusion genes and disrupt mitochondrial dynamics within the inessential clock neurons ofDrosophila. Surprisingly, fusion is much more important than fission for maintaining long-term neuronal function. Neurons survive chronic mitochondrial fragmentation due to loss of fusion by triggering a cancer-like transcriptomic response. This Warburg effect includes ATF4-mediated upregulation of the aerobic glycolysis geneLactate dehydrogenase(Ldh), and LDH is essential to prevent neurodegeneration of neurons deficient in the fusion geneOpa1. These results and others provide insights into the intersection of neuronal metabolism, aging and neurodegeneration.
Leveraging Multi-Modal Feature Learning for Predictions of Antibody Viscosity
Authors: Anapindi Krishna D. B. , Liu Kai , Wang Willie , Yu Yao , He Yan , Hsieh Edward J. , Huang Ying , Tomazela Daniela
Published: September 2024

The shift towards the subcutaneous administration route for biologics therapeutics has gained momentum due to its patient-friendly nature, convenience, reduced healthcare burden, and improved compliance compared to traditional intravenous infusions. However, one of the potentially significant challenges with this transition is managing the viscosity of the administered solutions. High viscosity can pose substantial development and manufacturability challenges, directly impacting the patient by increasing injection time and pain at the injection site. Moreover, high viscosity formulations can prolong residence time at the injection site, affecting absorption kinetics and potentially altering the intended pharmacological profile and therapeutic efficacy of the biologic candidate. This publication explores the application of a multimodal feature learning workflow for predicting the viscosity of antibodies in therapeutics discovery, integrating multiple data sources such as sequence, structural, physicochemical properties, and embeddings from a language model. This approach enables the model to learn from various underlying rules, including physicochemical rules from molecular simulations and molecular protein evolutionary rules by large, pre-trained deep learning foundation models. By comparing the effectiveness of this approach against other selected published viscosity prediction methods, this study offers insights on their intrinsic viscosity predictive potential and usability in therapeutics antibody early development pipelines.
Velamins: the first green-light emitting class of wild-type Ca2+-regulated photoproteins isolated from the ctenophoreVelamen parallelum
Authors: Soares Douglas M. M. , Galeazzo Gabriela A. , Sgro Germán G. , de Moraes Gabriela V. , Kronenberg Leora , Borukh Emmanuella , Migotto Alvaro E. , Gruber David F. , Sparks John S. , Pieribone Vincent A. , Stevani Cassius V. , Oliveira Anderson G.
Published: September 2024

Ca2+-regulated photoproteins (CaPhs) consist of single-chain globular proteins to which coelenterazine, a widely distributed marine luminogenic substrate (the luciferin), binds along with molecular oxygen, producing a stable peroxide. Upon Ca2+addition, CaPhs undergo conformational changes leading to the cyclization of the peroxide and the formation of a high-energy intermediate. Subsequently, its decomposition yields coelenteramide in an excited state and results in the emission of a flash of light. To date, all CaPhs reported produce blue light (λmax465-495 nm). Here, we report the cloning and functional characterization of a novel class of wild-type CaPhs capable of emitting green light: velamins, isolated from the bioluminescent ctenophoreVelamen parallelum. Ten unique photoprotein-like sequences were recovered and grouped in three main clusters. Representative sequences were cloned, expressed, purified, and regenerated into the active His-tagged α-, β-, and γ-velamins. Upon injection of a calcium-containing buffer into the velamin, a flash of green light (λmax500-508 nm) was observed across pH values ranging from 7 to 9. Whilst α-velamin isoforms exhibited the highest light emission activity, β- and γ-velamins were found to be more thermostable at higher temperatures. Velamins are the only known wild-type Ca2+-regulated photoproteins that exhibit the longest wavelength in light emission, making them a promising model for studying spectral modulation. As a result, velamins hold potential for enhancing the sensitivity of signal detection in analytical systems, particularly when dealing with complex biological matrices.
Directed evolution of a sequence-specific covalent protein tag for RNA labeling
Authors: Huang Rongbing , Ting Alice Y.
Published: September 2024

Efficient methods for conjugating proteins to RNA are needed for RNA delivery, imaging, editing, interactome mapping, as well as for barcoding applications. Non-covalent coupling strategies using viral RNA binding proteins such as MCP have been applied extensively but are limited by tag size, sensitivity, and dissociation over time. We took inspiration from a sequence-specific, covalent protein-DNA conjugation method based on the Rep nickase of a porcine circovirus called “HUH tag”. Though wild-type HUH protein has no detectable activity towards an RNA probe, we engineered an RNA-reactive variant, called rHUH, through 7 generations of yeast display-based directed evolution. Our 13.4 kD rHUH has 12 mutations relative to HUH, and forms a covalent tyrosine-phosphate ester linkage with a 10-nucleotide RNA recognition sequence (“rRS”) within minutes. We engineered the sensitivity down to 1 nM of target RNA, shifted the metal ion requirement from Mn2+towards Mg2+, and demonstrated efficient labeling in mammalian cell lysate. This work paves the way toward a new methodology for sequence-specific covalent protein-RNA conjugation in biological systems.
Blanking on Blanks: Few Insect Microbiota Studies Control for Contaminants - A Systematic Review
Authors: Williamson Elisabeth , Hammer Tobin , Hogendoorn Katja , Eisenhofer Raphael
Published: September 2024

Research on insect-microbe relationships is booming, with DNA sequencing being the most commonly used method to describe insect microbiota. However, sequencing is vulnerable to contamination, especially when the sample has low microbial biomass. Such low-biomass samples are common across insect taxa, developmental stages, and tissue types. Identifying putative contaminants is essential to distinguish between true microbiota and introduced contaminant DNA. It is therefore important that studies control for contamination, but how often this is done is unknown. To investigate the status quo of contamination control, we undertook a systematic literature review to quantify the prevalence of negative control usage and contamination control across the literature on insect microbiota (specifically bacterial communities) over the past 20 years. Two-thirds of the 243 insect microbiota studies evaluated did not include blanks (negative controls), and only 13.6% of the studies sequenced these blanks to control for contamination in their samples. Our findings highlight a major lack of contamination control in the field of insect microbiota research. This result suggests that a large number of microbes reported in the literature may be contaminants as opposed to insect-associated microbiota, and that more rigorous contamination control is needed to improve research reliability, validity and reproducibility. Based on our findings, we recommend a modified version of the guidelines outlined in the RIDES checklist: Report methodology, Include negative controls, Determine the level of contamination, Explore contamination downstream, and State the amount of off-target amplification.

IMPORTANCE

Our systematic review reveals a major lack of methodological rigour within the field of research on insect-associated microbiota. The small percentage of studies that control for contamination suggests that a considerable proportion of bacteria reported in the literature could be contaminants. The implication of this finding is that true microbiota may be masked or misrepresented, especially in insects with low microbial biomass.
TNF⍺-driven Aβ aggregation, synaptic dysfunction and hypermetabolism in human iPSC-derived cortical neurons
Authors: Díaz Alicia González , Belli Elisa , Mannini Benedetta , Urrutia Gustavo Antonio , Vendruscolo Michele
Published: September 2024

Alzheimer’s disease (AD) patients exhibit an increased load of Aβ aggregates in the brain parenchyma. The neurotoxic nature of these aggregates has been underscored by recent advances in therapies aimed at reducing their load. To make further progress towards the development of increasingly effective treatments, there is a still largely unmet need for reliable cell models that comprehensively recapitulate aggregate-driven AD pathology. Here, we report a robust and scalable pipeline for generating human iPSC-derived cortical neurons that display Aβ aggregates in their axonal projections. This phenotype is caused by a repeated dosage of tumour necrosis factor-alpha (TNFα) to simulate the chronic inflammatory environment characteristic of AD and enhanced in neurons carrying the Swedish mutation. In association with the increased Aβ deposits in the cell bodies, this cell model exhibits other key hallmarks of AD, including structural alterations of synapses, electrophysiological asynchronous hyperactivity, and hypermetabolism. Overall, these results illustrate how repeated TNFα treatment models central aspects of AD pathology, and provides a platform that could be used for facilitating the translation of potential drugs to clinical applications.