bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing institutional pediatric airway emergency readiness: key components and practices
Authors: Siu Jennifer M. , Wolter Nikolaus E. , Propst Evan J.
Published: November 2024

Purpose of review

This contemporary review aims to outline the key components and protocols for assessing emergency readiness in institutional pediatric airway management. Emphasis is placed on identifying essential elements that ensure preparedness and effective response in pediatric airway emergencies within healthcare institutions.

Recent findings

Recent studies highlight several critical components of pediatric airway emergency readiness: dedicated pediatric airway teams, availability of specialized pediatric airway equipment, and simulation-based training to enhance the skills of healthcare providers. Additionally, interdisciplinary team coordination and regular drills have been shown to improve readiness and outcomes in pediatric airway emergencies.

Effective emergency readiness in pediatric airway management requires a multifaceted approach. Key components include availability of appropriate and accessible equipment, adherence to standardized protocols, and ongoing education and training. Regular simulation exercises and interprofessional collaboration are essential for maintaining high levels of preparedness. Implementing these strategies can significantly improve the quality of care and patient outcomes in pediatric airway emergencies.

Level of evidence

Level 3
Efficacy and safety of preoperative intravenous iron versus standard care in colorectal cancer patients with iron deficiency anemia: a systematic review and meta-analysis
Authors: Sydhom Pishoy , Shaaban Abdelgalil Mahmoud , Al-Quraishi Bakr , Shehata Nahla , El-Shawaf Mohamad , Naji Nourhan , Awwad Nouran , Tarek Osman Mohamed , Mahmoud Abdelmonem , Awad Ahmed K.
Published: November 2024

Background:

Anemia, particularly iron deficiency (ID) anemia, is common in colorectal cancer (CRC) patients, affecting up to 58% of individuals. This study aimed to compare the effectiveness and safety of preoperative intravenous iron (IVI) with standard care (no iron or oral iron) in CRC patients with ID anemia.

Methods:

A systematic search across multiple databases identified studies comparing IVI versus no iron or oral iron in CRC patients with ID anemia. Pooled data were analyzed for changes in hemoglobin (Hb) levels, need for red blood cell transfusions (RBCT), overall mean number of transfused RBC units, overall survival (OS), disease-free survival (DFS), and complications.

Results:

The authors analyzed data from 11 studies with 2024 patients and found that IVI significantly increased Hb levels at crucial time points: preoperative (MD=1.17, 95% CI [0.95–1.40], P<0.01), postoperative day one (MD=1.32, 95% CI [0.89–1.76], P<0.01), hospital discharge (MD=0.76, 95% CI [0.28–1.24], P=0.002), and 30 days postoperative (MD=1.57, 95% CI [1.27–1.87], P<0.01). IVI significantly decreased the overall need for RBCT, particularly in the postoperative period (RR=0.69, 95% CI [0.52–0.92], P=0.01). It also reduced the mean number of transfused RBC units, total complications, and wound dehiscence. However, there were no significant differences in total death, hospital stay, infections, paralytic ileus, OS, or DFS.

Conclusion:

Preoperative IVI significantly increased Hb levels at critical time points and markedly reduced the overall need for RBCT, complications, and wound dehiscence. To further validate these findings and ensure robust conclusions, more well-designed randomized controlled trials are warranted.
The Mediating Role of Emotion Regulation Difficulties in the Correlation Between Mindfulness and Psychological Resilience in Patients Diagnosed with Depression
Authors: Arpacı Rabia , Tanrıverdi Derya
Published: November 2024

This study aimed to determine the mediating role of emotion regulation difficulties in the correlation between mindfulness and psychological resilience. This study was conducted with a total of 119 patients diagnosed with major depression. Data were collected with Personal Information Form, Mindfulness Scale, Emotion Regulation Difficulties Scale, and Psychological Resilience Scale. The study participants reported moderate levels of mindfulness and emotion regulation difficulties, and above-average levels of psychological resilience. It was found that there was a moderately negative correlation between mindfulness and emotion regulation difficulties (r = −0.553, p < 0.001), as well as between psychological resilience and emotion regulation difficulties (r = −0.429, p < 0.001). A moderately positive correlation was determined between mindfulness and psychological resilience (r = 0.344, p < 0.001). Emotion regulation difficulties fully mediated the correlation between mindfulness and psychological resilience. These findings will guide the development of interventions aimed at enhancing mindfulness, emotion regulation skills, and psychological resilience in depression treatment.
Extended release of ciprofloxacin from commercial silicone-hydrogel and conventional hydrogel contact lenses containing vitamin E diffusion barriers
Authors: Al Atrach Mehdi , Phan Chau-Minh , Jones Lyndon W.
Published: November 2024

SIGNIFICANCE

Vitamin E could be used as a coating with commercial silicone hydrogel lenses to extend the release of various ophthalmic drugs. This concept could provide a promising approach to improve overall ocular therapeutic outcomes for topical ocular drugs.

PURPOSE

This study aimed to develop a contact lens–based ocular drug delivery system using vitamin E as a diffusion barrier to extend the release duration of ciprofloxacin.

METHODS

Five commercial lenses were soaked for 24 hours in various concentrations of vitamin E dissolved in ethanol (0.0125 to 0.2 g/mL). The lenses were loaded with ciprofloxacin for 24 hours in 3 mL of 3 mg/mL of ciprofloxacin/acetic acid solution. The drug release was evaluated in 3 mL of phosphate-buffered saline solution. At t = 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours, the amount of ciprofloxacin released was measured using a UV-VIS spectrophotometer at 270 nm.

RESULTS

There was a decrease in ciprofloxacin loading with increasing amounts of vitamin E loaded into the silicone hydrogel lenses. For each lens type, there was an optimal amount of vitamin E loaded that extended the release duration of the drug from 1 hour (without vitamin E) to as long as 16 hours. In contrast, vitamin E loaded into hydrogel lenses had no effect on the amounts of drugs loaded or the release duration.

CONCLUSIONS

Vitamin E can be used as a diffusion barrier with commercially available silicone hydrogel lenses to provide sustained release of ciprofloxacin. The results suggest that vitamin E may form blockages in channels within a silicone hydrogel lens material, thereby forcing a longer path for drugs to diffuse into and out of the lens material. There is an optimal amount of vitamin E that needs to be loaded to extend the release duration, and this is lens material dependent.
Identification and Categorization of Technical Errors and Hazard-zones of Robotic versus Laparoscopic total Gastrectomy for Gastric Cancer
Authors: Jia Zhuoyu , Cao Shougen , Wang Daosheng , Tang Changshi , Tan Xiaojie , Liu Shanglong , Liu Xiaodong , Li Zequn , Tian Yulong , Niu Zhaojian , Tang Benjie , Zhou Yanbing
Published: November 2024

Importance:

The current research aimed to conduct a detailed analysis of intraoperative surgical performance, short-term outcomes, identify and categorize technical errors, and hazard-zones enacted during total gastrectomy performed robotically and laparoscopically by surgeons. Prospective research is needed to determine whether the technical advantages of robotic surgery translate to patient outcomes.

Objective:

Identify and process risk areas in robot-assisted total gastrectomy (RTG) and laparoscopic total gastrectomy (LTG) to get the best patient results.

Design:

Patients undergoing RTG and LTG were recruited and randomized into the study. Six consultant/attending surgeons participated in this study and all surgical procedures were recorded. The unedited surgical video-recordings were handed over to third-party experts for granular analysis of the procedures using objective clinical human reliability analysis (OC-HRA) for the quality of intraoperative performance, technical errors, intraoperative complications.

Setting:

This study is a single center prospective randomized controlled trial.

Participants:

82 patients were recruited and participated in this study with 40 cases undergoing RTG and 42 cases for LTG.

Interventions:

RTG vs LTG.

Main Outcomes and Measures:

Determine whether RTG or LTG can provide the better intraoperative technical performance and identify the most hazardous zone (area) during total gastrectomy (TG).

Results:

The technical errors enacted and identified in the RTG and the LTG were (46.11±5.63 VS 58.79±8.45, P＜0.001) respectively. The highest number of technical errors was identified during the dissection of the supra-pancreatic lymph nodes (Task Zones3, TZ3), including No.5, 7, 8a, 9, 11p, and 12a to complete the nodal clearance around the celiac artery and its trifurcation (7.29±1.88 VS 9.43±2.24, P <0.001) in both RTG and LTG. The number of lymph nodes harvested with RTG was higher than LTG (35.36±7.51 VS 30.54±6.95, P=0.016), especially in the upper margin of the pancreas (13.32±4.17 VS 9.36±3.81, P＜0.001). The total cost of hospitalization in the RTG group cost 3% more than LTG group ($15953.41±3533.91 VS $12198.26±2761.27, P＜0.001).

Conclusions:

This study offers compelling OC-HRA evidence demonstrating that RTG facilitates significantly superior technical performance compared to LTG. Whether examining short-term clinical outcomes or intraoperative operations, the robotic surgery system consistently outperforms laparoscopic surgery. Lymph node dissection in the supra-pancreatic region emerged as a major hazard zone in both procedures.

Trial Registration:

chictr.org.cn: ChiCTR2000039193
ExtrAperitoneaL Plasty vs Intraperitoneal oNlay mEsh in ventral hernia repair – a multi-center randomized controlled trial: the ALPINE study protocol
Authors: Süsstrunk Julian , Baur Johannes , Sortino Rosita , Filser Jörg , Herzog Kim , Steinemann Daniel C. , Müller Beat P. , Angehrn Fiorenzo V.
Published: November 2024

Introduction:

Minimally invasive ventral hernia repair (MIVHR) is a frequently performed surgical procedure to address primary or incisional ventral hernias and is recommended by numerous societies. Various techniques are available for MIVHR, including the intraperitoneal onlay mesh (IPOM) procedure and the enhanced view totally extraperitoneal (eTEP) approach.

While both techniques are increasingly applied, they continue to be subject of controversy in literature. Well-designed randomized controlled trials comparing both procedures are lacking. The objective of this study is to investigate whether eTEP is associated with a decreased level of postoperative pain compared to IPOM.

Methods:

This is a prospective, multi-center, randomized, and blinded controlled trial. Patients presenting with primary or incisional epigastric, umbilical, or infraumbilical hernia with a transverse diameter >1 cm and ≤4 cm, or multiple hernias with a cumulative transverse diameter ≤4 cm, will be randomly assigned to undergo either IPOM or eTEP procedures. All patients and assessors of the study outcomes are blinded to the treatment allocation. The trial will be conducted at the St. Clara Hospital Basel, at the University Hospital Basel (Switzerland) and at the Innklinikum Altötting (Germany). It remains open for additional sites to be included. The multi-center design is chosen to minimize environmental bias related to perioperative anesthesiology and nursing care and to enhance participant recruitment.

The primary outcome of this study is to evaluate postoperative pain (numeric rating scale and Patient-Reported Outcome Measurement Information System Pain Intensity Short Form 3a) 24 hours after the surgical procedure. Secondary outcomes include the assessment of pain at different times, length of hospital stay, operative time, readmission rate, intraoperative, and postoperative adverse events.
A longitudinal investigation of the acoustic properties of infant-directed speech from 6 to 18 months
Authors: Rosslund Audun , Mayor Julien , Mundry Roger , Singh Arun Prakash , Cristia Alejandrina , Kartushina Natalia
Published: November 2024

Caregivers often modulate their speech when interacting with infants, adapting a register that has been suggested to have attentional, affective and didactic purposes. The present preregistered study examined the longitudinal trajectories of a diverse range of acoustic features of infant-directed speech (IDS) and compared these with adult-directed speech (ADS), in Norwegian parents of 6- to 18-month-old infants. Sixty-nine families participated. Throughout five laboratory visits across one year, parents were recorded reading a picture-book to their infant (IDS) and an experimenter (ADS). The book was designed to tightly control for the linguistic content and context of speech between participants, timepoints and registers. Analyses of a total of 54 594 vowels and 22 958 phrases revealed, first, an overall effect of register: parents used higher pitch, wider pitch range, slower articulation rate, longer vowel duration and more variable and less distinct vowels in IDS than in ADS. Second, significant register-by-age interactions indicated that parents’ IDS, compared with their ADS, featured wider pitch range, larger vowel space and shorter vowel duration in older as compared with younger infants, while pitch, articulation rate and vowel variability and distinctiveness remained relatively stable with age. Results are discussed in the context of the proposed functions of IDS.
Ecological brain: reframing the study of human behaviour and cognition
Authors: Vigliocco Gabriella , Convertino Laura , De Felice Sara , Gregorians Lara , Kewenig Viktor , Mueller Marie A. E. , Veselic Sebastijan , Musolesi Mirco , Hudson-Smith Andrew , Tyler Nicholas , Flouri Eirini , Spiers Hugo J.
Published: November 2024

The last decade has seen substantial advances in the capacity to record behaviour and neural activity in humans in real-world settings, to simulate real-world situations in laboratory settings and to apply sophisticated analyses to large-scale data. Along with these developments, a growing number of groups has begun to advocate for real-world neuroscience and cognitive science. Here, we review the arguments and the available methods for real-world research and outline an overarching framework that embeds key ideas proposed in the literature integrating them into a cyclic process of ‘bringing the lab to the real world’ (recording behavioural and neural activity in real-world settings) and ‘bringing the real-world to the lab’ (manipulating the environments in which behaviours occur in the laboratory) that combines exploratory and confirmatory research and is interdisciplinary (including those sciences concerned with the natural, built or virtual environment). We highlight the benefits brought by this framework emphasizing the greater potential for novel discovery, theory development and human-centred applications to the environment.
Emerging challenge of Linezolid and Vancomycin resistant Enterococci faecium:First case report from Northern Pakistan
Authors: Naeem Afnan , Furqan Warda , Satti Luqman , Usman Javaid , Wattoo Nasir Mehmud
Published: November 2024

Enterococcus faecium are among the most versatile pathogens found to infect hospitalized patients. Resistance against anti-enterococcal antibiotics is gaining access day to day and among them linezolid resistant vancomycin resistant Enterococcus faecium are a nightmare for the clinicians especially in a resource limited country.
A 72year old patient presented with collection of pus and necrosis around the head of pancreases. These pockets of pus resulted as acute postsurgical complication along with surgical site infection. Pus was processed according to clinical guidelines Enterococcus faecium was identified and confirmed by VITEK. Isolate was resistant to vancomycin and linezolid. Tigecyclin was the only option for this patient due to unavailability of quinupristin/dalfopristin as a treatment option. A regular follow up was done and patient was discharged after recovery.
LRVRE is the result of non-implementation of antimicrobial stewardship and it can be followed with further resistance in Enterococcus which can be havoc. Clinicians infection control team and microbiologist should work together to overcome antimicrobial resistance crises.
An Exact and Fast SAT Formulation for the DCJ Distance
Authors: Sarnaik Aaryan M. , Chen Ke , Diaz Austin , Shao Mingfu
Published: November 2024

Reducing into a satisfiability (SAT) formulation has been proven effective in solving certain NP-hard problems. In this work, we extend this research by presenting a novel SAT formulation for computing the double-cut-and-join (DCJ) distance between two genomes with duplicate genes. The DCJ distance serves as a crucial metric in studying genome rearrangement. Previous work achieved an exact solution by transforming it into a maximum cycle decomposition (MCD) problem on the corresponding adjacency graph of two genomes, followed by reducing this problem into an integer linear programming (ILP) formulation. Using both simulated datasets and real genomic datasets, we firmly conclude that the SAT-based method scales much better and runs faster than using ILP, being able to solve a whole new range of instances which the ILP-based method cannot solve in a reasonable amount of time. This underscores the SAT-based approach as a versatile and more powerful alternative to ILP, with promising implications for broader applications in computational biology.
TRPV4 overactivation enhances cellular contractility and drives ocular hypertension in TGFβ2 overexpressing eyes
Authors: Rudzitis Christopher N. , Lakk Monika , Singh Ayushi , Redmon Sarah N. , Kirdajova Denisa , Tseng Yun-Ting , De Ieso Michael L. , Stamer W. Daniel , Herberg Samuel , Križaj David
Published: November 2024

The risk for developing primary open-angle glaucoma (POAG) correlates with the magnitude of ocular hypertension (OHT) and the concentration of transforming growth factor-β2 (TGFβ2) in the aqueous humor. Effective treatment of POAG requires detailed understanding of interaction between pressure sensing mechanisms in the trabecular meshwork (TM) and biochemical risk factors. Here, we employed molecular, optical, electrophysiological and tonometric strategies to establish the role of TGFβ2 in transcription and functional expression of mechanosensitive channel isoforms alongside studies of TM contractility in biomimetic hydrogels, and intraocular pressure (IOP) regulation in a mouse model of TGFβ2 -induced OHT. TGFβ2 upregulated expression ofTRPV4andPIEZO1transcripts and time-dependently augmented functional TRPV4 activation. TRPV4 activation induced TM contractility whereas pharmacological inhibition suppressed TGFβ2-induced hypercontractility and abrogated OHT in eyes overexpressing TGFβ2.Trpv4-deficient mice resisted TGFβ2-driven increases in IOP. Nocturnal OHT was not additive to TGFβ- evoked OHT. Our study establishes the fundamental role of TGFβ as a modulator of mechanosensing in nonexcitable cells, identifies TRPV4 channel as the final common mechanism for TM contractility and circadian and pathological OHT and offers insights future treatments that can lower IOP in the sizeable cohort of hypertensive glaucoma patients that resist current treatments.
The Trade-Off Between Torque and Power with Speed: A Study of Shoulder Performance During an Isokinetic and Multiplanar Task
Authors: Lee Kayla D.L , Lee Erin C.S , Rainbow Michael J.
Published: November 2024

The human shoulder likely evolved under selective pressures favouring diverse tasks that require high mobility, speed, and torque. For example, humans are uniquely adept at high-speed and accurate throwing. Prior work has aimed to quantify the kinematics and kinetics of upper limb movements in isometric or uniplanar motions. However, we still do not fully understand the trade-offs of shoulder torque and power with angular velocity during functional tasks that are reflective of demands that may be relevant to the shoulder’s evolution. We developed a novel approach for upper limb 3D inverse dynamic calculations by integrating motion capture with an instrumented cable machine. Twenty-five participants performed a crossbody, isokinetic upper limb motion at various cable speeds in a rigid and free torso condition (self-imposed). Shoulder torque decreased significantly (p < 0.05) with increasing angular velocity in 19 and 16 participants for the constrained and unconstrained conditions, respectively. Shoulder power increased significantly (p < 0.05) with angular velocity for 6 and 11 participants for constrained and unconstrained, respectively. T-tests revealed no statistical difference between the torso conditions for torque and power against angular velocity. Our findings suggest that despite having a trade-off in torque and velocity, the shoulder may be tuned to produce power over a wide range of velocities independent of energy transfer from the lower extremities.
A Multi-Modal Deep Learning Framework with Both Sequence and Structure for Tumor Antigens Prediction
Authors: Jin Ruofan , Ge Jingxuan , Zhang Guanqiao , Deng Ziyan , Hsieh Kim , Hou Tingjun , Zhou Ruhong
Published: November 2024

Tumor antigens are key targets in cancer immunotherapies that can be recognized by T cell receptor and induce immune responses. However, precision screening of immunogenic tumor antigens remains a great challenge due to human leukocyte antigen (HLA) restriction and tumor antigen escape. Here, we introduce MultiTAP (Multi-modal Tumor Antigen Predictor), a pioneering multi-modal framework with TCR-peptide-HLA sequence and structure features incorporating an attention mechanism designed to accurately identify tumor antigens with immunogenic properties. By constructing the multi-modal TCR-peptide-HLA Dataset (TPHD) and integrating its sequence and structure, we perform antigen feature enhancement using peptide-HLA (pHLA) structural features at the residue level, achieving interpretable prediction of immunogenicity for tumor antigens. Relative to existing baseline models, the MultiTAP framework has exhibited superior efficacy in predicting the immunogenicity of tumor antigens. Through comprehensive out-of-distribution (OOD) assessments, MultiTAP has maintained predictive robustness across diverse HLA phenotypes and the continuously evolving landscape of epitope distributions. Overall, MultiTAP presents a brand-new and promising approach for cancer immunotherapies that target tumor antigens.
A Contribution To The Anatomy Of Two Rare Cetacean Species: The Hourglass Dolphin (Lagenorhynchus Cruciger) And The Spectacled Porpoise (Phocoena dioptrica)
Authors: Graïc Jean-Marie , Gerussi Tommaso , Cozzi Bruno , Kot Brian Chin Wing , Boys Rebecca M. , Perrott Matthew R. , Fleury Kane , Burns Emma , Webster Trudi , Betty Emma L. , Howarth Odette , Loch Carolina , White Sophie , Dawson Steve , Rayment William , Hunter Stuart , Cole Ros , Cox Derek , Young Melanie , Roberts Joseph , Waterhouse Tom , Smith Robin , Ogle Mike , Fyfe Jim , Hendriks Hannah , van Helden Anton , Johnstone Muriel , Stewart Ramari Oliphant , Fordyce R. Ewan , Stockin Karen A.
Published: November 2024

The anatomical description of the hourglass dolphin (Lagenorhynchus cruciger) and the spectacled porpoise (Phocoena dioptrica) remains largely unexplored, due to limited specimen availability and preservation challenges. This study employed digital imaging techniques, conventional histology and computed tomography to provide three-dimensional visualisation of anatomical structures for detailed volumetric analysis prior to necropsy. We present a comprehensive analysis of the gross macroscopical and microscopical morphology of two hourglass dolphins and four spectacled porpoises. The hourglass dolphins were characterised by their distinctive black and white pigmentation and a hooked dorsal fin, while the spectacled porpoises were distinguished for their large dorsal fin and unique eye markings. Morphometric measurements and skeletal characteristics were similar to those present in literature, while the anatomy and topography of internal organs and systems were similar to those found in other odontocetes. The respiratory systems showed an absence of lobation and a rightbronchus trachealis. Although precise lung measurements were challenging, qualitative assessments indicate relatively large lungs for their body size, supporting the “short dive, big lung” hypothesis and suggesting that these species are not deep divers. The spectacled porpoise dorsal fin is uniquely large accompanied by a developed blood supply. This organ is hypothesised to act as a thermoregulatory window, helping to manage body heat. Overall, this study provides new data on the anatomy of the hourglass dolphin and spectacled porpoise, providing insights that may influence future research on these rare species. The findings highlighted the importance of anatomical studies in explaining in detail the evolutionary relationships within cetaceans and their ecological roles in the Southern Ocean ecosystems.
Are we serologically prepared against an avian influenza pandemic and could seasonal flu vaccines help us?
Authors: Sanz-Muñoz Iván , Sánchez-Martínez Javier , Rodríguez-Crespo Carla , Concha-Santos Corina S. , Hernández Marta , Rojo-Rello Silvia , Domínguez-Gil Marta , Mostafa Ahmed , Martinez-Sobrido Luis , Eiros Jose M. , Nogales Aitor
Published: November 2024

The current situation with H5N1 highly pathogenic avian influenza virus (HPAI) is causing a worldwide concern due to multiple outbreaks in wild birds, poultry, and mammals. Moreover, multiple zoonotic infections in humans have been reported. Importantly, HPAI H5N1 viruses with genetic markers of adaptation to mammals have been detected. Together with HPAI H5N1, avian influenza viruses H7N9 (high and low pathogenic) stand out due to their high mortality rates in humans. This raises the question of how prepared we are serologically and whether seasonal vaccines are capable of inducing protective immunity against these influenza subtypes. An observational study was conducted in which sera from people born between years 1925-1967, 1968-1977, and 1978-1997 were collected before or after 28 days or 6 months post-vaccination with an inactivated seasonal influenza vaccine. Then, haemagglutination inhibition, viral neutralization, and immunoassays were performed to assess the basal protective immunity of the population as well as the ability of seasonal influenza vaccines to induce protective responses. Our results indicate that subtype-specific serological protection against H5N1 and H7N9 in the representative Spanish population evaluated was limited or nonexistent. However, seasonal vaccination was able to increase the antibody titers to protective levels in a moderate percentage of people, probably due to cross-reactive responses. These findings demonstrate the importance of vaccination and suggest that seasonal influenza vaccines could be used as a first line of defense against an eventual pandemic caused by avian influenza viruses, to be followed immediately by the use of more specific pandemic vaccines.

Importance

Influenza A viruses (IAV) can infect and replicate in multiple mammalian and avian species. Avian influenza virus (AIV) is a highly contagious viral disease that occurs primarily in poultry and wild water birds. Due to the lack of population immunity in humans and ongoing evolution of AIV, there is a continuing risk that new IAV could emerge and rapidly spread worldwide causing a pandemic, if the ability to transmit efficiently among humans was gained. The aim of this study is to analyze the basal protection and presence of antibodies against IAV H5N1, and H7N9 subtypes in the population from different ages. Moreover, we have evaluated the h humoral response after immunization with a seasonal influenza vaccine. This study is strategically important to evaluate the level of population immunity that is a major factor when assessing the impact that an emerging IAV strain would have, and the role of seasonal vaccines to mitigate the effects of a pandemic.
Unsupervised Deep Disentangled Representation of Single-Cell Omics
Authors: Moinfar Amir Ali , Theis Fabian J.
Published: November 2024

Single-cell genomics allows for the unbiased exploration of cellular heterogeneity. Representation learning methods summarize high-dimensional single-cell data into a manageable latent space in a typically nonlinear fashion, allowing cross-sample integration or generative modeling. However, these methods often produce entangled representations, limiting interpretability and downstream analyses. Existing disentanglement methods instead either require supervised information or impose sparsity and linearity, which may not capture the complexity of biological data. We, therefore, introduce Disentangled Representation Variational Inference (DRVI), an unsupervised deep generative model that learns nonlinear, disentangled representations of single-cell omics. This is achieved by combining recently introduced additive decoders with nonlinear pooling, for which we theoretically prove disentanglement under reasonable assumptions. We validate DRVI’s disentanglement capabilities across diverse relevant biological problems, from development to perturbational studies and cell atlases, decomposing, for example, the Human Lung Cell Atlas into meaningful, interpretable latent dimensions. Moreover, we demonstrate that if applied to batch integration, DRVI’s integration quality does not suffer from the disentanglement constraints and instead is on par with entangled integration methods. With its disentangled latent space, DRVI is inherently interpretable and facilitates the identification of rare cell types, provides novel insights into cellular heterogeneity beyond traditional cell types, and highlights developmental stages.
Ophiostomatalean fungi associated withCyrtogenius luteusinfestedPinus massoniana, including characterization ofMasuyamyces qingyuanensissp. nov. in China
Authors: Liu Kun , Gao Xiang , Wang Ya-Jie , Yin Ming-Liang
Published: November 2024

Ophiostomatalean fungi refers to the species in the order Ophiostomatales of Ascomycota. This group of fungi comprises wood blue-stain agents and some species that are important pathogens of trees, nematodes, or humans. Most species in the Ophiostomatales have beneficial relationships with wood-boring insects such as bark beetles. Recent surveys were conducted to investigate the diversity of Ophiostomatoid fungi associated withCyrtogenius luteusinfestingPinus massonianain some areas of Guangdong, China. This study, 382 fungal strains were obtained, and 224 were identified as belonging to the Ophiostomatales order. Identification of these strains revealed that they spanned seven distinct genera. A new species,Masuyamyces qingyuanensis sp. nov., was discovered and identified through a combination of morphological and phylogenetic analyses across four gene regions: beta-tubulin (TUBB), internal transcribed spacer (ITS), large subunit ribosomal RNA (LSU), and translation elongation factor 1 alpha (EF1A).
Multiplexed perturbation of yew reveals cryptic proteins that enable a total biosynthesis of baccatin III and Taxol precursors
Authors: McClune Conor James , Liu Jack Chun-Ting , Wick Chloe , De La Peña Ricardo , Lange Bernd Markus , Fordyce Polly M. , Sattely Elizabeth S.
Published: November 2024

Plants make complex and potent therapeutic molecules, but difficulties in sourcing from natural producers or chemical synthesis can challenge their use in the clinic. A prominent example is the anti-cancer therapeutic paclitaxel (Taxol®). Identification of the full paclitaxel biosynthetic pathway would enable heterologous drug production, but it has eluded discovery despite a half century of intensive research. Within the search space ofTaxus’large, enzyme-rich genome, we suspected the complex paclitaxel pathway would be difficult to resolve using conventional gene co-expression analysis and small sample sets. To improve the resolution of gene set identification, we developed a multiplexed perturbation strategy to transcriptionally profile cell states spanning tissues, cell types, developmental stages, and elicitation conditions. This approach revealed a set of paclitaxel biosynthetic genes that segregate into expression modules that suggest consecutive biosynthetic sub-pathways. These modules resolved seven new genes that, when combined with previously known enzymes, are sufficient for thede novobiosynthesis and isolation of baccatin III, an industrial precursor for Taxol, inNicotiana benthamianaleaves at levels comparable to the natural abundance inTaxusneedles. Included are taxane 1β-hydroxylase (T1βH), taxane 9α-hydroxylase (T9αH), taxane 7β-O-acyltransferase (T7ΑΤ), taxane 7β-O-deacetylase (T7dA), taxane 9α-O-deacetylase (T9dA), and taxane 9-oxidase (T9ox). Importantly, the T9αH we discovered is distinct and independently evolved from those recently reported, which failed to yield baccatin III with downstream enzymes. Unexpectedly, we also found a nuclear transport factor 2 (NTF2)-like protein (FoTO1) crucial for high yields of taxanes; this gene promotes the formation of the desired product during the first taxane oxidation step, resolving a longstanding bottleneck in paclitaxel pathway reconstitution. Together with a new β-phenylalanine-CoA-ligase, the eight genes discovered in this study enables the complete reconstitution of 3’-N-debenzoyl-2’-deoxy-paclitaxel with a 20-enzyme pathway inNicotianaplants. More broadly, we establish a generalizable approach for pathway discovery that scales the power of co-expression studies to match the complexity of specialized metabolism, enabling discovery of gene sets responsible for high-value biological functions.
Mitomycin C eliminates cyanobacterial transcription without detectable lysogen induction in aMicrocystis-dominated bloom in Lake Erie
Authors: Martin Robbie M. , Denison Elizabeth R. , Pound Helena L. , Barnes Ellen A. , Chaffin Justin D. , Wilhelm Steven W.
Published: November 2024

Although evidence indicates that viruses are important in the ecology ofMicrocystisspp., many questions remain. For example, how doesMicrocystisexist at high, bloom-associated cell concentrations in the presence of viruses that infect it? The phenomenon of lysogeny and associated homoimmunity offer possible explanations to this question. Virtually nothing is known about lysogeny inMicrocystis, but a metatranscriptomic study suggests that widespread, transient lysogeny is active during blooms. These observations lead us to posit that lysogeny is important in modulatingMicrocystisblooms. Using a classic mitomycin C-based induction study, we tested for lysogeny in aMicrocystis-dominated community in Lake Erie in 2019. Treated communities were incubated with 1 mg L-1mitomycin C for 48 h alongside unamended controls. We compared direct counts of virus-like-particles (VLPs) and examined community transcription for active infection by cyanophage. Mitomycin C treatment did not increase VLP count. Mitomycin C effectively eliminated transcription in the cyanobacterial community, while we detected no evidence of induction. Metatranscriptomic analysis demonstrated that the standard protocol of 1 mg L-1was highly-toxic to the cyanobacterial population, which likely inhibited induction of any prophage present. Follow-up lab studies indicated that 0.1 mg L-1may be more appropriate for use in freshwater cyanobacterial studies. These findings will guide future efforts to detect lysogeny inMicrocystisblooms.

Importance

Harmful algal blooms dominated byMicrocystisspp. occur throughout the world’s freshwater ecosystems leading to detrimental effects on ecosystem services that are well documented. After decades of research, the scientific community continues to struggle to understand the ecology ofMicrocystisblooms. The phenomenon of lysogeny offers an attractive, potential explanation to several ecological questions surrounding blooms. However, almost nothing is known about lysogeny inMicrocystis. We attempted to investigate lysogeny in aMicrocystisbloom in Lake Erie and found that the standard protocols used to study lysogeny in aquatic communities are inappropriate for use inMicrocystisstudies, and perhaps freshwater cyanobacterial studies more broadly. This work can be used to design better methods to study the viral ecology ofMicrocystisblooms.
Microbiome impact of ibezapolstat and otherClostridioides difficileinfection relevant antibiotics using humanized mice
Authors: Wolfe Trenton M. , Jo Jinhee , Pinkham Nick V. , Garey Kevin W. , Walk Seth T.
Published: November 2024

Background

Ibezapolstat (IBZ) is a competitive inhibitor of the bacterial Pol IIIC enzyme in clinical development for treatment ofClostridioides difficileinfection (CDI). Previous studies demonstrated IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN). However, head-to-head comparisons with other CDI antibiotics have not been done. The purpose of this study was to compare microbiome changes associated with IBZ to other clinically used CDI antibiotics.

Methods

Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control). 16S rRNA encoding gene sequencing of temporally collected stool samples was used to compare gut microbiome perturbation between treatment and no-drug control groups.

Results

Among the tested antibiotics, the most significant change in microbiome diversity was observed in MET-treated mice. Each antibiotic had a unique effect, but changes in alpha and beta diversity following FDX- and IBZ-treated groups were less pronounced compared to those observed in VAN-or MET-treated groups. By the end of therapy, both IBZ and FDZ increased the relative abundance of Bacteroidota (phylum), with IBZ additionally increasing the relative abundance of Actinomycetota (phylum).

Conclusion

In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity compared to VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies.
Impact of Paraben on Uterine Collagen: An Integrated and Targeted Correlative Approach Using Second Harmonic Generation Microscopy, Nanoindentation, and Atomic Force Microscopy
Authors: Arshee Mahmuda R. , Shukla Ritwik , Li Jie , Bagchi Indrani C. , Ziv-Gal Ayelet , Johnson A. J. Wagoner
Published: November 2024

This study investigates the structural and mechanical changes in uterine collagen following exposure to propylparaben (PP), using a combined methodology of Second Harmonic Generation (SHG) microscopy, Nanoindentation (NI), and Atomic Force Microscopy (AFM). SHG analysis identified significant disorganization in collagen fibril orientation in the circumferential layer and heterogeneous distribution of regions with elevated forward to backward ratios (F/B) across all uterine layers due to PP exposure. High F/B can indicate multiple potential fibril-level changes like thickened fibrils, higher crosslinking, fibril disorganization - changes not fully decipherable by SHG alone. Recognizing this limitation, the study employs NI and AFM to provide complementary mechanical and nanoscale insights. NI revealed increased indentation modulus in the exposed uteri, suggesting increased stiffness. Co-registration of the indentation response with SHG parameters uncovered that elevated F/B regions show enhanced mechanical stiffness, suggesting a fibrotic transformation following PP exposure. AFM was specifically performed on regions identified by SHG as having low or high F/B, providing the necessary nanoscale resolution to elucidate the structural changes in fibrils that are likely responsible for the observed alterations. This approach confirmed the presence of disordered and entangled collagen fibrils in the circumferential layer in all regions and an increase in fibril diameter in the high F/B regions in the exposed uteri. Together, these findings demonstrate significant alterations in collagen architecture due to PP exposure, revealing disruptions at both the fiber and fibril levels and highlighting the potential for broader applications of the multi-scale, multi-modal approach in collagenous tissue studies.
LUMIC: Latent diffUsion for Multiplexed Images of Cells
Authors: Hung Albert , Zhang Charles J. , Sexton Jonathan Z. , O’Meara Matthew J. , Welch Joshua D.
Published: November 2024

The rapid advancement of high-content, single-cell technologies like robotic confocal microscopy with multiplexed dyes (morphological profiling) can be leveraged to reveal fundamental biology, ranging from microbial and abiotic stress to organ development. Specifically, heterogeneous cell systems can be perturbed genetically or with chemical treatments to allow for inference of causal mechanisms. An exciting strategy to navigate the high-dimensional space of possible perturbation and cell type combinations is to use generative models as priors to anticipate high-content outcomes in order to design informative experiments. Towards this goal, we present the Latent diffUsion for Multiplexed Images of Cells (LUMIC) framework that can generate high quality and high fidelity images of cells. LUMIC combines diffusion models with DINO (self-Distillation with NO labels), a vision-transformer based, self-supervised method that can be trained on images to learn feature embeddings, and HGraph2Graph, a hierarchical graph encoder-decoder to represent chemicals. To demonstrate the ability of LUMIC to generalize across cell lines and treatments, we apply it to a dataset of∼27,000 images of two cell lines treated with 306 chemicals and stained with three dyes from the JUMP Pilot dataset and a newly-generated dataset of∼3,000 images of five cell lines treated with 61 chemicals and stained with three dyes. To quantify prediction quality, we evaluate the DINO embeddings, Kernel Inception Distance (KID) score, and recovery of morphological feature distributions. LUMIC significantly outperforms previous methods and generates realistic out-of-sample images of cells across unseen compounds and cell types.
scHiCcompare: an R package for differential analysis of single-cell Hi-C data
Authors: Nguyen My , Wall Brydon P. G. , Harrell J. Chuck , Dozmorov Mikhail G.
Published: November 2024

Changes in the three-dimensional (3D) structure of the human genome are key indicators of cancer and developmental disorders. Techniques like chromatin conformation capture (Hi-C) have been developed to study these global 3D structures, typically requiring millions of cells and an extremely high sequencing depth (around 1 billion reads per sample) for bulk Hi-C. In contrast, single-cell Hi-C (scHi-C) captures 3D structures at the individual cell level but faces significant data sparsity, marked by a high proportion of zeros. While differential analysis methods exist for bulk Hi-C data, they are limited for scHi-C data. To address this, we developed a method for differential scHi-C analysis, building on existing techniques in the HiCcompare R package. Our approach imputes sparse scHi-C data by considering genomic distances and creates pseudo-bulk Hi-C matrices by summing condition-specific data. The data are normalized using LOESS regression, and differential chromatin interactions are detected via Gaussian Mixture Model (GMM) clustering. Our workflow outperforms existing methods in identifying differential chromatin interactions across various genomic distances, fold changes, resolutions, and sample sizes in both simulated and experimental contexts. This allows for effective detection of cell type-specific differences in chromatin structure, which has meaningful associations with biological and epigenetic features. Our method is implemented in the scHiCcompare R package, available athttps://github.com/dozmorovlab/scHiCcompare.

Graphical abstract
Ultrastructural expansion microscopy (U-ExM) visualization of malaria parasite dense granules using RESA as a representative marker protein
Authors: Fukumoto Junpei , Tsuboi Takafumi , Takashima Eizo
Published: November 2024

Dense granules (DG) are understudied apical organelles in merozoites, the malaria parasite stage that invades erythrocytes. Only six proteins have been identified which localize to DGs, despite that DG proteins play crucial roles in multiple steps of intraerythrocytic parasite development. To develop a tool for investigating DG structure and function, this study applied ultrastructural expansion microscopy (U-ExM) to visualize the ring-infected erythrocyte surface antigen (RESA) inPlasmodium falciparummerozoites. Merozoites were expanded to approximately four times their original size, allowing the identification of DGs without the need for electron microscopy. RESA localization in merozoite DGs was confirmed by staining with a combination of anti-RESA mAb and protein staining by NHS-ester. The translocation of RESA to the infected erythrocyte membrane was also observed in early ring-stage parasites. These results are in good agreement with the RESA localization reported using immunoelectron microscopy (IEM). By using U-ExM, the identification of novel DG proteins will be facilitated without time-consuming IEM, thereby contributing to describing erythrocyte parasitism byP. falciparum.
Image-based DNA Sequencing Encoding for Detecting Low-Mosaicism Somatic Mobile Element Insertions
Authors: Tan Miaomiao , Lin Zhinan , Chen Zhuofu , Park Junseok , He Ziting , Zhou Haonan , Lee Eunjung A. , Gao Zhipeng , Zhu Xiaowei
Published: November 2024

Active LINE-1 (L1),Alu, and SVA mobile elements in the human genome are capable of retrotransposition, resulting in novel mobile element insertions (MEIs) in both germline and somatic tissues. Detecting MEIs through DNA sequencing relies on supporting reads overlapping MEI junctions; however, artifacts from DNA amplification, sequencing, and alignment errors produce numerous false positives. Systematic detection of somatic MEIs, particularly those with low mosaicism, remains a significant challenge. Previous methods had required a high number of supporting reads which limits the detection sensitivity, or human inspections that are susceptible to biases. Here, we developed RetroNet, an algorithm that encodes MEI-supporting sequencing reads into images, and employs a deep neural network to identify somatic MEIs with as few as two reads. Trained on extensive and diverse datasets and benchmarked across various conditions, RetroNet surpasses previous methods and eliminates the need for extensive manual examinations. When applied to bulk whole genome sequencing of a cancer cell line, RetroNet achieved an average precision of 0.885 and recall of 0.845 for detecting somatic L1 insertions, including four true mutations with only two supporting reads. RetroNet is applicable to the rapidly generated short-read sequencing data and has the potential to provide further insights into the functional and pathological implications of somatic retrotranspositions.