bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative multi-omics data elucidating the biosynthesis and regulatory mechanisms of furanocoumarins inAngelica dahurica
Authors: Ji Jiaojiao , Han Xiaoxu , Zang Lanlan , Li Yushan , Lin Liqun , Hu Donghua , Sun Shichao , Ren Yonglin , Maker Garth , Lu Zefu , Wang Li
Published: July 2024

Furocoumarins (FCs) are crucial natural products playing a dual role as plant defense molecules and pharmacologically active substances.Angelica dahuricais a renowned herb with diverse and abundant FCs. However, the accumulation pattern over developmental stages, biosynthesis pathway and regulatory mechanisms of FCs inA. dahuricaremain elusive, hindering the production of FCs via synthetic biology approaches. Here, we constructed a chromosome-level reference genome forA. dahuricaand quantified the content dynamics of 17 coumarins across six developmental stages of its medicinal organ, root. It showed a gradual decrease in FC concentration with root enlargement. The combined analyses of transcriptomic and metabolomic data, together with in vivo enzymatic assay, confirmed that CYP71AZ18 was involved in the biosynthesis of bergaptol, whereas CYP71AZ19 and CYP83F95 contributed to the biosynthesis of xanthotoxol. Notably, CYP71AZ19 originated from a proximal duplication event of CYP71AZ18, specific toA. dahurica, subsequently undergoing neofunctionalization. Accessible chromatin regions (ACRs), especially proximal ACRs, are correlated with higher gene expression levels, including the three validated genes involved in FC biosynthesis, showing potential to regulate metabolite biosynthesis. Our findings provide new insights into the biosynthetic pathway of FCs and the epigenetic regulation of metabolite biosynthesis.
Noradrenergic and Dopaminergic Neural Correlates of Trait Anxiety: Unveiling the Impact of Maladaptive Emotion Regulation
Authors: Zareba Michal Rafal , Ariño-Braña Paula , Picó-Pérez Maria , Visser Maya
Published: July 2024

Background

Maladaptive emotion regulation plays a crucial role in the development and maintenance of elevated anxiety levels, both in patients and in individuals with subclinical symptomatology. While pharmacological treatments for anxiety target the emotion dysregulation through dopaminergic, noradrenergic and serotonergic systems, little is known about the underlying mechanisms. Therefore, the current study depicts the association of these neuromodulatory systems’ resting-state functioning with trait-anxiety, investigating the role of maladaptive emotion regulation.

Methods

Amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and whole-brain resting-state functional connectivity (rs-FC) were obtained from the ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe, and correlated with trait-anxiety and self-reported maladaptive emotion regulation (N = 60).

Results

Trait-anxiety was positively associated with LC’s fALFF and negatively with VTA’s whole-brain rs-FC with the left inferior parietal lobule (L-IPL) and the left superior frontal gyrus (L-SFG). Maladaptive emotion regulation was negatively associated with VTA’s rs-FC with these regions, with trait-anxiety fully mediating this association. VTA connectivity with the frontal region, but not parietal, positively predicted its amplitude of neural oscillations, an effect that was paralleled by stronger frontal dopaminergic innervation.

Limitations

Use of external molecular datasets and need for replication in patients.

Conclusions

Noradrenergic and dopaminergic systems appear to contribute differently to subclinical anxiety. While noradrenaline likely acts through a more general mechanism, the dopaminergic dysconnectivity with the frontoparietal control network may act as one of the mechanisms of maladaptive emotion regulation, informing the models on the disorder development.

Highlights

Trait-anxiety shows a positive association with the activity of locus coeruleus

Trait-anxiety and emotional regulation are linked to VTA-frontoparietal connectivity

Trait-anxiety fully mediates emotion regulation’s effect on VTA’s connectivity

Strength of connectivity with VTA is positively linked to the frontal ALFF and fALFF
DNA polymerase λ-driven targeted mutagenesis for directed evolution in human cells
Authors: Aiello Davide , Ciciani Matteo , Marelli Federica , Stancampiano Marta , De Sanctis Veronica , Bertorelli Roberto , Kheir Eyemen Gafar Ali , Maule Giulia , Cereseto Anna , Arosio Daniele
Published: July 2024

Directed evolution is an efficient strategy to steer protein function to either understand specific biological properties or develop new biotechnology tools. Currently available methods for targeted mutagenesis in human cells rely on deaminases which can only modify specific bases, limiting the region of sequence space explored during evolution. By leveraging CRISPR-Cas9 coupled with an error-prone variant of human DNA polymerase λ, here we developed CRISPR-λ, an unbiased mutagenesis tool for directed evolution in human cells. We evaluated CRISPR-λ by reverting the fluorescence of a mutated EGFP and characterized it using ultra-deep sequencing. The mutagenic activity of CRISPR-λ spans 36-46 nucleotides from the target site, with a mutation frequency as high as 1.4e-4 substitutions per base and with no bias for specific nucleotide substitutions. The versatility of CRISPR-λ extends beyond base substitution, enabling modifications of the target gene through insertions and deletions, thereby broadening its potential for genetic diversification. We validated the efficacy of CRISPR-λ in directed evolution approaches by functionally reverting a mutated blasticidin resistance gene. Furthermore, we demonstrated the sequence diversification power of CRISPR-λ by steering the syncytia formation activity of the SARS-CoV-2 Spike envelope protein in cultured cells.
In vivo–Active Soluble Epoxide Hydrolase–targeting PROTACs with Improved Potency and Stability
Authors: Nakane Keita , Morisseau Christophe , Dowker-Key Presley D. , Benitez Gabrielle , Aguilan Jennifer T. , Nagai Emiko , Sidoli Simone , Hammock Bruce D. , Bettaieb Ahmed , Shinoda Kosaku , Kitamura Seiya
Published: July 2024

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis–targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound8) exhibits a half-maximal degradation concentration in the sub-nM range, is stablein vivo, and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.
Entorhinal cortex represents task-relevant remote locations independent of CA1
Authors: Aery Jones Emily Aster , Low Isabel I. C. , Cho Frances S. , Giocomo Lisa M.
Published: July 2024

Neurons can collectively represent the current sensory experience while an animal is exploring its environment or remote experiences while the animal is immobile. These remote representations can reflect learned associations and be required for learning. Neurons in the medial entorhinal cortex (MEC) reflect the animal's current location during movement, but little is known about what MEC neurons collectively represent during immobility. Here, we recorded thousands of neurons in superficial MEC and dorsal CA1 as mice learned to associate two pairs of rewarded locations. We found that during immobility, the MEC neural population frequently represented positions far from the animal's location, which we defined as 'non-local coding'. Cells with spatial firing fields at remote locations drove non-local coding, even as cells representing the current position remained active. While MEC non-local coding has been reported during sharp-wave ripples in downstream CA1, we observed non-local coding more often outside of ripples. In fact, CA1 activity was less coordinated with MEC during non-local coding. We further observed that non-local coding was pertinent to the task, as MEC preferentially represented remote task-relevant locations at appropriate times, while rarely representing task-irrelevant locations. Together, this work raises the possibility that MEC non-local coding could strengthen associations between locations independently from CA1.
Anthropogenic climate change will likely outpace coral range expansion
Authors: Vogt-Vincent Noam S. , Pringle James M. , Cornwall Christopher E. , McManus Lisa C.
Published: July 2024

Past coral range expansions suggest that high-latitude environments may serve as refugia, potentially buffering tropical biodiversity loss due to climate change. We explore this possibility for corals globally, using a dynamical metacommunity model incorporating temperature, light intensity, pH, and four distinct, interacting coral assemblages. This model reasonably reproduces the observed distribution and recent decline of corals across the Indo-Pacific and Caribbean. Our simulations suggest that there is a mismatch between the timescales of coral reef decline and range expansion under future predicted climate change. Whereas the most severe declines in coral cover will likely occur within 60–80 years, significant tropical coral range expansion requires centuries. The absence of large-scale coral refugia in the face of rapid anthropogenic climate change emphasises the urgent need to reduce greenhouse gas emissions, and mitigate non-thermal stressors for corals, both in the tropics and high-latitudes.
Solid state NMR spectral editing of histidine, arginine and lysine using Hadamard encoding
Authors: Gopinath Tata , Kraft Alyssa , Shin Kyungsoo , Wood Nicholas A. , Marassi Francesca M.
Published: July 2024

The NMR signals from protein sidechains are rich in information about intra- and inter-molecular interactions, but their detection can be complicated due to spectral overlap as well as conformational and hydrogen exchange. In this work, we demonstrate a protocol for multi-dimensional solid-state NMR spectral editing of signals from basic sidechains based on Hadamard matrix encoding. The Hadamard method acquires multi-dimensional experiments in such a way that both the backbone and under-sampled sidechain signals can be decoded for unambiguous editing in the15N spectral frequency dimension. All multi-dimensional15N-edited solid-state NMR experiments can be acquired using this strategy, thereby accelerating the acquisition of spectra spanning broad frequency bandwidth. Application of these methods to the ferritin nanocage, reveals signals from N atoms from His, Arg, Lys and Trp sidechains, as well as their tightly bound, ordered water molecules. The Hadamard approach adds to the arsenal of spectroscopic approaches for protein NMR signal detection.
Waning immunity drives respiratory virus evolution and reinfection
Authors: Bull James J , Koelle Katia , Antia Rustom
Published: July 2024

Reinfections with respiratory viruses such as influenza viruses and coronaviruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with a heterologous, antigenically different strain. As such, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect fully immune hosts. Invasion can occur even when the variant’s immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should replace the wild-type, and as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.
Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation
Authors: Liu Huanhuan , Binoy Anupama , Ren Siqi , Martino Thomas C. , Miller Anna E. , Willis Craig R. G. , Veerabhadraiah Shivakumar R. , Sukul Abhijit , Bons Joanna , Rose Jacob P. , Schilling Birgit , Jurynec Michael J. , Zhu Shouan
Published: July 2024

Objectives

Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development.

Methods

Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed inSirt5-/-and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB).

Results

We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK’s predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation inSIRT5that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe–F) to leucine (Leu–L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes.

Conclusions

We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.
Longevity or Well-being? A Dual-Dimension Structure of Neuroticism
Authors: He Yini , Xiao Jing , Hu Ke , Gao Tian , Yan Yan , Wang Lei , Li Kaixin , Lei Wenkun , Zhao Kun , Dong Changsheng , Tian Xiaohan , Ding Chaoyue , Peng Yingjie , Xian Junxing , Huang Shangzheng , Liu Xiya , Li Long , Zhang Peng , Zhang Zhanjun , He Sheng , Li Ang , Liu Bing
Published: July 2024

The development of personality traits is often viewed as evolutionarily adaptive. Current neuroticism research, however, predominantly highlights its negative health impacts, neglecting its potential evolutionary advantages. We propose that neuroticism’s inter-individual variability can be structured into two distinct geometric dimensions. One, named the Emotional Reactivity-Instability/Distress Spectrum (ERIS), correlates strongly with longevity and is associated with chronic diseases and risk-averse lifestyle. This dimension is underpinned by evolutionarily conserved subcortical brain regions and genes. The other, resembling the overall neuroticism score, is primarily linked to mental and stress-related disorders, as well as life satisfaction. It involves higher-order emotional brain regions and is genetically enriched in human-accelerated regions. Collectively, these dimensions represent a dual-strategy personality framework that optimizes survival and well-being, with the former being evolutionarily conservative and the latter potentially a unique human adaptation.
Bidimensional Perfectionism and Psychological Distress: The Roles of Self-Esteem and Self-Compassion
Authors: Chung Cheuk Hei Peony , Lee Antoinette Marie
Published: July 2024

Perfectionism as a personality trait can be seen as having both adaptive and maladaptive dimensions. Nevertheless, their relationships with psychological distress remain mixed in the current literature. Previous studies were also limited by the use of impure measurements and the failure to statistically control for the effects of the other dimension. By addressing these major limitations and exploring the mediating and moderating roles of self-esteem and self-compassion, the current study provides an in-depth examination of the relationships between bidimensional perfectionism and psychological distress. In a community sample of 503 adults, results supported a bidimensional view of perfectionism, with maladaptive perfectionism positively predicting psychological distress and adaptive perfectionism being unrelated to psychological distress. Self-esteem was found to mediate the relationships between both dimensions of perfectionism and psychological distress. Self-compassion was only found to moderate the relationship between maladaptive perfectionism and self-esteem. Whilst the maladaptive nature of maladaptive perfectionism was supported in this study, findings suggested that adaptive perfectionism remains a more complicated construct. Future studies should aim at clarifying the nature and psychological outcomes of adaptive perfectionism.
The cellular hierarchy of acute myeloid leukemia informs personalized treatment
Authors: Severin Yannik , Festl Yasmin , Benoit Tobias M. , Wegmann Rebekka , Hale Benjamin D. , Roiss Michael , Kienzler Anne-Kathrin , Pabst Thomas , Scharl Michael , Sunagawa Shinichi , Manz Markus G. , Müller Antonia M.S. , Snijder Berend
Published: July 2024

Acute myeloid leukemia (AML) is characterized by malignant myeloid precursors that span a cellular hierarchy from dedifferentiated leukemic stem cells to mature blasts. While the diagnostic and prognostic importance of AML blast maturation is increasingly recognized, personalized therapies are currently not tailored to a patients individual makeup of this cellular hierarchy. In this study, we use multiplexed image-basedex vivodrug screening (pharmacoscopy) to systematically quantify the drug sensitivity across the cellular hierarchy of AML patients. We analyzed 174 prospective and longitudinal patient samples from 44 newly diagnosed AML patients, which indicated that differences in the AML hierarchy significantly identified poor responses to first-line therapy, outperforming European LeukemiaNet (ELN) criteria. Critically, drug response profiling across the AML hierarchy of each patient improved the accuracy of predicting patient response to first-line therapy (AUC 0.91), and revealed alternative individualized treatment options targeting the complete AML hierarchy of non-responding patients. We confirmed these findings in an independent cohort of 26 relapsed/refractory AML patients, for whom pan-hierarchy response profiling improved response predictionspost hoc. Overall, our results quantify the clinical importance of therapeutically targeting the complete cellular hierarchy of newly diagnosed AML, and identify multiplexed image-basedex vivodrug screening to enable quantification and targeting of the AML maturation hierarchy for improved personalized treatment.
Application of Urinary Peptide-Biomarkers in Trauma Patients as a Predictive Tool for Prognostic Assessment, Treatment Interventions, and Intervention Timing: Prospective Nonrandomized Pilot Study
Authors: Aktas Gökmen , Keller Felix , Siwy Justyna , Latosinska Agnieszka , Mischak Harald , Mayor Jorge , Clausen Jan , Wilhelmi Michaela , Brauckmann Vesta , Sehmisch Stephan , Omar Pacha Tarek
Published: July 2024

Background

Treatment of severely injured patients represents a major challenge, in part due to the unpredictable risk of major adverse events, including death. Preemptive personalized treatment aimed at preventing these events is a key objective of patient management; however, the currently available scoring systems provide only moderate guidance. Molecular biomarkers from proteomics/peptidomics studies hold promise for improving the current situation, ultimately enabling precision medicine based on individual molecular profiles.

Methods

To test the hypothesis that proteomics biomarkers could predict patient outcomes in severely injured patients, we initiated a pilot study involving consecutive urine sampling (on days 0, 2, 5, 10, and 14) and subsequent peptidome analysis using capillary electrophoresis coupled to mass spectrometry (CE-MS) of 14 severely injured patients and two additional ICU patients. The urine peptidomes of these patients were compared to the urine peptidomes of age- and sex-matched controls. Previously established urinary peptide-based classifiers, CKD274, AKI204, and CoV50, were applied to the obtained peptidome data, and the association of the scores with a combined endpoint (death and/or kidney failure and/or respiratory insufficiency) was investigated.

Results

CE-MS peptidome analysis identified 281 peptides that were significantly altered in severely injured patients. Consistent upregulation was observed for peptides from A1AT, FETUA, and MYG, while peptides derived from CD99, PIGR and UROM were consistently reduced. Most of the significant peptides were from different collagens, and the majority were reduced in abundance. Two of the predefined peptidomic classifiers, CKD273 and AKI204, showed significant associations with the combined endpoint, which was not observed for the routine scores generally applied in the clinics.

Conclusions

This prospective pilot study confirmed the hypothesis that urinary peptides provide information on patient outcomes and may guide personalized interventions based on individual molecular changes. The results obtained allow the planning of a well-powered prospective trial investigating the value of urinary peptides in this context in more detail.
Effectiveness Over Time of a Primary Series of the Original Monovalent COVID-19 Vaccines in Adults in the United States
Authors: Layton J. Bradley , Lloyd Patricia C , Peetluk Lauren S , Jiao Yixin , Djibo Djeneba Audrey , Gruber Joann F , Deng Jie , Bui Christine , Lo An-Chi , Ogilvie Rachel P , Parambi Ron , Miller Michael E , Song Jennifer , Weatherby Lisa B , Cho Sylvia , Wong Hui Lee , Clarke Tainya C , Hervol Jessica Rose , Illei Dóra , Bell Elizabeth J , Yang Grace Wenya , Seeger John D , Wernecke Michael , Richey Morgan M , Forshee Richard A , Anderson Steven A , Chillarige Yoganand , McMahill-Walraven Cheryl N , Amend Kandace L , Anthony Mary S , Shoaibi Azadeh
Published: July 2024

With data from 2 US claims databases (Optum, CVS Health) supplemented with Immunization Information System COVID 19 vaccine records, we evaluated overall and time-specific vaccine effectiveness (VE) of an initial primary series for 3 monovalent COVID 19 vaccines—BNT162b2, mRNA-1273, and JNJ-7836735—in adults (18-64 years). Vaccinated individuals were matched to unvaccinated comparators, and we estimated VE against any medically diagnosed COVID 19 and hospital/emergency department (ED)-diagnosed COVID 19. Additionally, we estimated VE by era of predominant variants, in subgroups, and compared across vaccine brands. The cohorts consisted of 341,097 (Optum) and 1,151,775 (CVS Health) matched pairs for BNT162b2; 201,604 (Optum) and 651,545 (CVS Health) for mRNA-1273; and 49,285 (Optum) and 149,813 (CVS Health) for JNJ-7836735. Summary VE estimates from meta-analysis against hospital/ED-diagnosed COVID 19 were: BNT162b2, 77% (95% CI, 76%-78%); mRNA-1273, 84% (95% CI, 83%-85%), JNJ-7836735 66% (95% CI, 63%-68%). VE estimates were higher for hospital/ED-diagnosed COVID 19 than for medically diagnosed COVID-19, and VE estimates were highest in adults receiving mRNA-1273 for both outcomes. VE was sustained for approximately 7 months for medically-diagnosed and up to 9 months for hospital/ED-diagnosed COVID 19. VE differed by brand and variant era. Additional real-world research is needed as new variants and recommendations for updated vaccines have evolved.
Resource Considerations for Acute Ischemic Stroke Intervention in Nonagenarians
Authors: Gandhi Sani , Hollender Kimberly , Chukwuneke Florence , Mehta Deviyani , Cheng Roger
Published: July 2024

Background

While there is evidence to support the viability of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) as treatments for acute ischemic stroke (AIS) even in the very elderly, there are practical considerations to be made regarding triage and resource allocation, particularly in a hub-and-spoke system of stroke intervention.

Methods

This is a cross-sectional study using stroke quality registry data from 2017-2021 at a comprehensive stroke center serving as the primary hub for an associated healthcare system. We identified patients aged 90 or above who received acute stroke treatment with IVT and/or MT. NIHSS, modified Rankin Score (mRS), transfer status, length of stay (LOS), and discharge disposition were examined.

Results

Out of 268 total nonagenarians admitted for AIS, 60 received an acute intervention (37 IVT, 14 MT, 9 both). All MT attempts resulted in successful reperfusion (>TICI2b). Median initial and discharge mRS were 2 and 5 respectively; only 3.3% were discharged home, with 46.7% of patients either deceased or discharged to hospice. Median LOS was 5 days (range 0-77), but prolonged LOS was common, with 11 patients having LOS >14 days. Comparing the groups who received MT vs. IVT alone, the median initial NIHSS was 17 vs. 15 (p=0.23); the MT group had better baseline mRS (1 vs 3, p=0.005), but despite this, there were no significant differences in mortality (57% vs 41%) or discharge mRS (5 vs. 5). Median LOS was not significantly different (6 vs. 5 days). Mortality in MT was 75% for transfers vs. 53% for local arrivals (p=0.36).

Conclusion

Despite safe and technically successful treatment, outcomes were poor overall in the nonagenarian population after both MT +/- IVT, with very high morbidity and mortality.
RetroTest unravels LINE-1 retrotransposition in Head and Neck Squamous Cell Carcinoma
Authors: Brea-Iglesias Jenifer , Oitabén Ana , Zumalave Sonia , Rodriguez-Martin Bernardo , Gallardo-Gómez María , Santamarina Martín , Pequeño-Valtierra Ana , Juaneda-Magdalena Laura , García-Escudero Ramón , López-Cedrún José Luis , Fraga Máximo , Tubio José MC , Martínez-Fernández Mónica
Published: July 2024

The relevant role of LINE-1 (L1) retrotransposition in cancer has been recurrently demonstrated in recent years. However, their repetitive nature hampers their identification and detection, hence remaining inaccessible for clinical practice. Also, its clinical relevance for cancer patients is still limited. Here, we develop a new method to quantify L1 activation, called RetroTest, based on targeted sequencing and a sophisticated bioinformatic pipeline, allowing its application in tumor biopsies. First, we performed the benchmarking of the method and confirmed its high specificity and reliability. Then, we unravel the L1 activation in HNSCC according to a more extensive cohort including all the HNSCC tumor stages. Our results confirm that RetroTest is remarkably efficient for L1 detection in tumor biopsies, reaching a high sensitivity and specificity. In addition, L1 retrotransposition estimation reveals a surprisingly early activation in HNSCC progression, contrary to its classical association with advanced tumor stages. This early activation together with the genomic mutational profiling of normal adjacent tissues supports field cancerization process in this tumor. These results underline the importance of estimating L1 retrotransposition in clinical practice towards an earlier and more efficient diagnosis in HNSCC.

Highlights

RetroTest represents the first method to determine LINE-1 retrotransposition from tumor biopsies in real clinical settings.

RetroTest not only offers global LINE-1 retrotransposition ratios but also identifies the active LINE-1 source elements.

RetroTest elucidates a really early LINE-1 activation in early tumor stages of Head and Neck Squamous Cell Carcinoma.

Whole Genome Analysis and LINE-1 retrotransposition demonstrates processes of field cancerization in Head and Neck Squamous Cell Carcinoma.

LINE-1 retrotransposition favors an earlier and more efficient Head and Neck Squamous Cell Carcinoma diagnosis.
Insight and Suicidality in First Episode Psychosis: The Mediating Role of Depression
Authors: Tayfur Sumeyra N. , Song Zhiqian , Li Fangyong , Hazan Hadar , Gibbs-Dean Toni , Purushothaman Deepa , Karmani Sneha , Ponce Terashima Javier , Tek Cenk , Srihari Vinod
Published: July 2024

Understanding the relationship between insight, depression, and suicidality in first-episode psychosis (FEP) is crucial for improving clinical outcomes and preventing suicide during early treatment stages. This longitudinal cohort study examined 264 participants enrolled in coordinated specialty care (CSC) services for FEP to investigate how insight and depression at admission impact suicidality at 6 and 12 months, assess depression's mediating role between insight and suicidality, and evaluate the persistence of depression over time. Regression analyses assessed the relationships among these variables, while mediation analyses explored depression's mediating effect. Significant predictors of suicidality at 6 months included insight (OR 0.71, 95% CI: 0.53 - 0.94), depression (OR 5.40, 95% CI: 2.45 - 12.61), and previous suicide attempts (OR 2.91, 95% CI: 1.21 - 7.00). At 12 months, insight (OR 0.70, 95% CI: 0.52 - 0.92) and depression (OR 2.82, 95% CI: 1.26 - 6.50) remained significant. Depression mediated 27.32% of the effect of insight on suicidality at 6 months and 19.76% at 12 months. Despite a general decrease in depressive symptoms, a subset of participants remained persistently depressed. The study highlights the significant mediating role of depression in the relationship between insight and suicidality, with depression emerging as the strongest predictor of suicidality. Early detection and treatment of depression in FEP should be prioritized, and further research should focus on targeted interventions within CSC.
Prospective Registration of Trials: Where we are, why, and how we could get better
Authors: Mongin Denis , Buitrago-Garcia Diana , Capderou Sami , Agoritsas Thomas , Gabay Cem , Courvoisier Delphine Shophie , Iudici Michele
Published: July 2024

Objectives: Transparent trial conduct requires prospective registration of a randomized controlled trial before the enrolment of the first participant. Registration aims to minimize potential biases through unjustified or hidden modification of trial design. We aimed to (1) estimate the proportion of randomized controlled trials that are prospectively registered and determine the time trends and the factors associated with prospective registration; (2) evaluate the reasons for non-adherence with prospective registration and explore potential mechanisms to enhance adherence with prospective registration. We studied trials published in rheumatology as a case study. Design and setting: We searched for reports of trials in rheumatology published between January 2009 and December 2022 using MEDLINE-PubMed. We retrieved trial registration numbers using metadata and reviewed full texts. We conducted a multivariable logistic regression to identify factors associated with prospective trial registration. We sent an online survey to authors of trials that were not prospectively registered. We inquired about possible reasons for non-adherence with prospective registration and asked about potential solutions. Results: We identified 1093 primary reports of randomized controlled trials; 453 (41.4%) were not prospectively registered. Of these, 130 (11.9%) were not registered, and 323 (29.5%) were retrospectively registered. Prospective registration increased over time at a rate of 3% per year (p<0.001), with only 13.3% (2/15) trials prospectively registered in 2009 to 73.2% (112/153) trials in 2022. Even among journals publicly supporting ICMJE recommendation, 16% of the trials published in 2022 were not prospectively registered. In the multivariable model, prospective registration was associated with a larger sample size, recruitment conducted across countries, and publication in a journal with a higher impact factor. Trial evaluating non pharmaceutical intervention, especially education, delivery of health care or wellness, had a lower rate of prospective registration. Investigators reported lack of knowledge, or organizational problems as the main reasons for retrospective registration. Authors also suggested linking ethical approval to trial registration as the best option to ensure prospective registration. Conclusions: Despite significant improvement, adherence to prospective registration remains unsatisfactory in rheumatology. Different strategies targeting journal editors, healthcare professionals, and researchers may improve trial registration.
Life without sex: Large-scale study links sexlessness to physical, cognitive, and personality traits, socioecological factors, and DNA
Authors: Abdellaoui Abdel , Wesseldijk Laura W. , Gordon Scott D. , Pasman Joëlle A. , Smit Dirk J.A. , Androvičová Renáta , Martin Nicholas G. , Ullén Fredrik , Mosing Miriam A. , Zietsch Brendan P. , Verweij Karin J.H.
Published: July 2024

Romantic (typically sexual) relationships are important to personal, physical, mental, social, and economic wellbeing, and to human evolution. Yet little is known about factors contributing to long-term lack of intimate relationships. We investigated phenotypic and genetic correlates of never having had sex in ∼400,000 UK residents aged 39 to 73 and ∼13,500 Australian residents aged 18 to 89. The strongest associations revealed that sexless individuals were more educated, less likely to use alcohol and smoke, more nervous, lonelier, and unhappier. Sexlessness was more strongly associated with physical characteristics (e.g. upper body strength) in men than in women. Sexless men tended to live in regions with fewer women, and sexlessness was more prevalent in regions with more income inequality. Common genetic variants explained 17% and 14% of variation in sexlessness in men and women, with a genetic correlation between sexes of 0.56. Polygenic scores predicted a range of related outcomes in the Australian dataset. Our findings uncover multifaceted correlates of human intimacy of evolutionary significance.
Haptoglobin and glutamine synthetase may biomark cachexia induced by anti-acute myeloid leukemia chemotherapy
Authors: Campelj Dean G. , Timpani Cara A. , Spiesberger Guinevere , Formosa Luke E. , Steele Joel R. , Zhang Haijian , Schittenhelm Ralf B. , Leow Lewis , Goodman Craig A. , Rybalka Emma
Published: July 2024

Background

Anti-cancer chemotherapy is an underappreciated contributor to cancer cachexia, an often irreversible body-wasting condition that causes 20-30% of cancer-related deaths. An obstacle to predicting, monitoring and understanding the mechanisms underlying chemotherapy cachexia is that each cancer (and sub-type) is assigned different chemotherapeutic compounds, typically in multi-agent regimens. Here, we investigate the chemotherapy induction regimen (CIR) used in the haematological cancer, acute myeloid leukemia (AML). We hypothesized that the AML CIR would induce cachexia, including loss of lean tissue mass and skeletal muscle atrophy.

Methods

Using an unbiased proteomics approach we interrogated the underlying molecular mechanisms. 3-month-old male Balb/c mice were treated with the AML CIR via intraperitoneal injections of daunorubicin (1.7 mg/kg) on days 1-3, and cytarabine (33.2 mg/kg) administered on days 1-7 or vehicle. Mice were assessed 24 hours after the last treatment, on day 8, or allowed to recover for 2 weeks and assessed on day 22. A third cohort was given access to running wheels in cages. We assessed body composition, whole body metabolism and assessed the muscle proteome using quantitative tandem mass tag labelling LC-MS/MS analysis.

Results

The AML CIR-induced acute cachexia involved a ∼10% loss of body mass, ∼10% loss of lean mass and ∼20% reduction in skeletal muscle fibre size. Whole body metabolism and ambulatory activity declined. This cachexic phenotype did not recover over the 2-week post-CIR period (lean mass loss post-CIR: 1 week ∼7% vs 2 weeks ∼9%). In voluntarily active CIR-treated mice, body wasting was exacerbated due to unchecked loss of fat mass (CIR sedentary: ∼31% vs CIR active: ∼51%). Muscle proteome studies revealed upregulation of haptoglobin (Hp) and glutamine synthetase (Glul), which were positively correlated with body and lean mass loss. Hp was sensitive to the conditional induction, recovery and exacerbation of AML CIR-mediated cachexia, suggestive of biomarker potential.

Conclusions

The AML CIR induces an acute reduction of body, lean and fat mass underpinned by skeletal muscle atrophy, hypermetabolism and catabolism. Our data uncovered a conditionally sensitive muscle biomarker in Hp, which may be useful as a prognostic tool across other scenarios of chemotherapy-induced myopathy and cachexia or as a target for therapeutic discovery in follow-up studies.
Overcoming the challenges of cascade reactions and complex substrates in natural product biocatalysis: Immobilization of a cyclodipeptide synthase
Authors: Alvarado-Ramírez Lynette , Sutherland Emmajay , Melchor-Martínez Elda M. , Parra-Saldívar Roberto , Bonaccorso Alfredo D. , Czekster Clarissa Melo
Published: July 2024

Cyclodipeptide synthases (CDPSs) use aminoacylated tRNAs to produce cyclic dipeptide natural products which can have anticancer and neuroprotective activity. Despite their potential, applications involving CDPSs are hindered by enzyme instability and challenges in producing aminoacylated tRNAs. Immobilizing enzymes can enhance stability and recyclability, yet studies on immobilized enzymes using aminoacylated tRNAs are lacking. Here, we immobilized the CDPS enzyme fromParcubacteria bacteriumRAAC4_OD1_1 (PbCDPS) using three sustainable supports: biochar from waste materials, calcium-alginate beads, and chitosan beads. Active PbCDPS immobilization led to production of the cyclodipeptide cyclo (His-Glu) (cHE). Notably, following activation with glutaraldehyde, a five-fold increase in cHE production was observed, while the immobilized enzyme remained active for seven consecutive cycles. Furthermore, we co-immobilized three enzymes required for the cascade reaction yielding cHE, all of which require aminoacyl-tRNA substrates (PbCDPS, histidyl-tRNA synthetase, and glutamyl-tRNA synthetase). This enzymatic cascade successfully generated the cyclic dipeptide of interest, showcasing the potential of immobilizing complex enzymes operating in cascade on a single support. We demonstrated that tRNAs remained free in solution without adsorption onto beads. This work paves the way for the immobilization of enzymes utilizing tRNAs and potentially other complex substrates, expanding the spectrum of reactions exploitable with this technology.

Graphical Abstract

For Table of Contents Only
PrePR-CT: Predicting Perturbation Responses in Unseen Cell Types Using Cell-Type-Specific Graphs
Authors: Alsulami Reem , Lehmann Robert , Khan Sumeer A. , Lagani Vincenzo , Gómez-Cabrero David , Kiani Narsis A. , Tegner Jesper
Published: July 2024

Predicting the transcriptional response of chemical perturbations is crucial to understanding gene function and developing drug candidates, promising a streamlined drug development process. Single-cell sequencing has provided an ideal data basis for training machine learning models for this task. Recent advances in deep learning have led to significant improvements in predictions of chemical as well as genetic perturbations at the single cell level. Experiments have shown that different cell types exhibit distinct transcriptional patterns and responses to perturbation. This poses a fundamental problem for predicting transcriptional responses of drugs or cell types outside the training data. Accordingly, existing methods lack cell-type-specific modeling or do not explicitly provide an interpretable mechanism for the gene features. In this study, we introduce a novel approach that employs a network representation of various cell types as an inductive bias, improving prediction performance in scenarios with limited data while acknowledging cellular differences. We applied our framework to four small-scale single-cell perturbation datasets and one large-scale screening experiment, demonstrating that this representation can inherently generalize to previously unseen cell types. Furthermore, our method outperforms the state-of-the-art methods in predicting the post-perturbation response in unobserved cell types.
Meta-analysis of spatial genetic patterns among European saproxylic beetles - the influence of history and contemporary forest quality
Authors: Krovi Rama Sarvani , Amer Nermeen , Oczkowicz Maria , Kajtoch Łukasz
Published: July 2024

The phylogeography of forest-dwelling species in Europe is well understood, although our knowledge regarding the genetics of saproxylic beetles remains insufficient. This knowledge gap extends to understanding the influence of both quaternary history and contemporary forest dynamics on population genetics. To fill this gap, we conducted a systematic review and meta-analysis of recent literature concerning saproxylic beetle taxa with available genetic data. We include both threatened and common species in our study which enabled us to generalize our findings to the whole saproxylic community. Results suggest a latitudinal decrease in diversity in most species, likely influenced by Pleistocene glaciation and subsequent population expansions from southern refugia. Additionally, we observed an east-west gradient in diversity, with threatened species exhibiting higher diversity towards the east. This may reflect historical forest dynamics and anthropogenic pressures, such as heavy wood logging in Western Europe. Similarly, we found a pattern along altitude, with populations in higher elevation forests, which are often more natural, exhibiting higher diversity. Furthermore, we identified distinct phylogenetic units or genetic clusters in southern Europe reflecting the distribution of glacial refugia. For some taxa, distinct units were also reported in eastern Europe where populations spread from Asian refugia. Central Europe showed a high number of phylogenetic units, although unique (private) clades or clusters were absent. Most likely it is an effect of the presence of beetles that originated from various refugia belonging to different phylogenetic units.

This study brings insights into general phylogeographic patterns, which have previously been examined only for single representatives of saproxylic beetles. It should also help in the proper planning of conservation and management efforts of wood-dwelling beetles.
A comprehensive guide through the fold and stability of cytochrome c with implications for disease
Authors: Yousaf Muhammad Abrar , Meli Massimiliano , Colombo Giorgio , Savoia Anna , Pastore Annalisa
Published: July 2024

Cytochrome c (Cyt-c), encoded byCYCSgene, is crucial for electron transport, peroxidase activity, and apoptosis. Mutations inCYCScan cause thrombocytopenia 4 (THC4), a disorder with low platelet counts. We have, for instance, recently described six Italian families with five different heterozygous missenseCYCSvariants. These mutations likely enhance peroxidase and apoptotic activities, yet mechanisms causing reduced platelet production and increased apoptosis are unclear. This study investigates all clinically important Cyt-c variants using an integrated bioinformatics approach. Our findings reveal that all variants are at evolutionarily conserved sites, potentially disrupting Cyt-c function and contributing to disease phenotypes. Specific variants are predicted to affect phosphorylation (T20I, V21G, Y49H), and ubiquitination (G42S, A52T, A52V, T103I). Cyt-c variants may influence the function of interacting genes and proteins involved in apoptosis and mitochondrial function. Molecular dynamics simulations (500 ns) reveal significant structural differences from the wild-type protein, with mutants showing reduced stability and increased unfolding and flexibility, particularly in the Ω-loop regions. These changes result in the displacement of the Ω-loops away from the heme iron, weakening critical hydrogen bonds and consequently opening the heme active site. This open conformation may enhance accessibility to small molecules such as H₂O₂, thereby promoting peroxidase activity, which may enhance apoptosis and likely impact megakaryopoiesis and platelet homeostasis in THC4.
Different RNA recognition by ProQ and FinO depends on the sequence surrounding intrinsic terminator hairpins
Authors: Mamońska Maria D. , Basczok Maciej M. , Stein Ewa M. , Olejniczak Mikołaj
Published: July 2024

Escherichia coliProQ and FinO proteins both have RNA-binding FinO domains, which bind to intrinsic transcription terminators, but each protein recognizes distinct RNAs. To explore how ProQ and FinO discriminate between RNAs we transplanted sequences surrounding terminator hairpins between RNAs specific for each protein, and compared their binding to ProQ, the isolated FinO domain of ProQ (ProQNTD), and FinO. The results showed that the binding specificity of chimeric RNAs towards ProQ, ProQNTD, or FinO was determined by the origin of the transplanted sequence. Further analysis showed that the sequence surrounding the terminator hairpin, including a purine-purine mismatch, in natural RNA ligands of FinO and in chimeric RNAs weakened their binding by ProQNTD. Overall, our studies suggest that the discrimination between RNAs by ProQ and FinO is determined by RNA sequence elements surrounding the intrinsic terminator hairpin.