bluuebunny/crossref_metadata_2025 huggingface dataset:
Necessity of Temporal Artery Biopsy for Giant Cell Arteritis: A Systematic Review
Authors: Ponich Brett , Hartley Rebecca , Lafreniere Ann-Sophie , Temple-Oberle Claire F.
Published: May 2022

Background:

Temporal artery biopsy (TAB) is currently the gold standard procedure to diagnose giant cell arteritis. Despite low sensitivity, TAB is routinely performed even if a clinical diagnosis has already been made. The objective of this study was to determine the usefulness of TAB for giant cell arteritis management.

Methods:

We performed a systematic review to identify studies that compared steroid treatment between TAB+ and TAB− patients. EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched from inception until April 4, 2020. Titles, abstracts, and full texts were reviewed by two independent reviewers and conflicts resolved by consensus. Studies reporting TAB result and steroid treatment were included. Information pertaining to steroid treatment was compared between TAB+ and TAB− groups. Steroid duration was compared by grouping patients in a less than 6 month group, a 6–24 month group, and a more than 24 month group.

Results:

An estimated 5288 abstracts were screened and 13 studies involving 1355 patients were included. Rate of prebiopsy steroid treatment was higher in TAB+ patients compared with TAB− patients [93% versus 63% (P < 0.001)]. The TAB+ group was more likely to be started on steroids prebiopsy [28% versus 8% (P < 0.001)]. TAB+ and TAB− patients had similar steroid duration for all groups [<6-month group 17% versus 19% (P-0.596), the 6-24-month group 16% versus 19% (P-0.596), and the >24-month group 66% versus 63% (P-0.642)].

Conclusion:

TAB results have minimal impact on treatment, and the utility should be reconsidered when a clinical diagnosis of giant cell arteritis is possible.
Creating a Spaced Repetition Model to Supplement Education in Plastic Surgery
Authors: Koenig Zachary A. , Henderson Joshua T. , Brooke Sebastian M.
Published: May 2022

Plastic surgery encompasses a wide spectrum of material involving comprehensive anatomy, physiology, microbiology, biomaterials, complex surgical techniques, and many nonsurgical interventions. The core disciplines overlap extensively with the foundational knowledge of many other surgical specialties. With the ever-expanding knowledge base required to become a competent plastic surgeon, spaced repetition is a means to optimize learning in plastic surgery and help trainees master new concepts while retaining other facts that are easily forgotten. Platforms for spaced repetition are user-friendly and can be synchronized between devices to streamline progress and make efficient use of the limited free time that exists throughout the workday. Flashcard decks can be imported to these platforms to follow a spaced repetition algorithm. Currently, no publicly available comprehensive deck exists for education in plastic and reconstructive surgery. Creation of flashcard decks covering lectures, textbooks, or old examination questions can reinforce the foundational concepts of our field. Additionally, there is potential to improve resident performance on the Plastic Surgery In-service Training Examination. Once created, this comprehensive flashcard deck can be distributed to plastic surgery residency programs to pave the way for a uniform curriculum.
Staged Surgical Correction of Severe Panfacial and Transverse Nasal Root Asymmetry in Unicoronal Synostosis
Authors: Witherow Helen , Pepper Tom , Naini Farhad B.
Published: May 2022

Nasal asymmetry is widely acknowledged to be one of the most difficult deformities to manage. Most reports in the literature pertain to corrective methods in relation to isolated deformity of the dorsum in the posttraumatic patient. There is a paucity of literature relating to management of nasal radix asymmetry, and still less in the context of severe panfacial asymmetry.
IDAC-Bio, A Software for Internal Dosimetry Based on the New ICRP Biokinetic Models and Specific Absorbed Fractions
Authors: Andersson Martin , Leggett Richard W. , Eckerman Keith , Almén Anja , Mattsson Sören
Published: May 2022

Radiation dosimetry is central to virtually all radiation safety applications, optimization, and research. It relates to various individuals and population groups and to miscellaneous exposure situations—including planned, existing, and emergency situations. The International Commission on Radiological Protection (ICRP) has developed a new computational framework for internal dose estimations. Important components are more detailed and improved anatomical models and more realistic biokinetic models than before. The ICRP is currently producing new organ dose and effective dose coefficients for occupational intakes of radionuclides (OIR) and environmental intakes of radionuclides (EIR), which supersede the earlier dose coefficients in Publication 68 and the Publication 72 series, respectively. However, the ICRP only publishes dose coefficients for a single acute intake of a radionuclide and for an integration period of 50 years for intake by adults and to age 70 years for intakes by pre-adults. The new software, IDAC-Bio, performs committed absorbed dose and effective dose calculations for a selectable intake scenario, e.g., for a continuous intake or an intake during x hours per day and y days per week, and for any selected integration time. The software uses the primary data and models of the ICRP biokinetic models and numerically solves the biokinetic model and calculates the absorbed doses to organs and tissues in the ICRP reference human phantoms. The software calculates absorbed dose using the nuclear decay data in ICRP publication 107. IDAC-Bio is a further development and an important addition to the internal dosimetry program IDAC-Dose2.1. The results generated by the software were validated against published ICRP dose coefficients. The potential of the software is illustrated by dose calculations for a nuclear power plant worker who had been exposed to varying levels of 60Co and who had undergone repeated whole-body measurements, and for a hypothetical member of the public subject to future releases of 148Gd from neutron spallation in tungsten at the European Spallation Source.
Analgosedation in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation Support
Authors: Crow Jessica , Lindsley John , Cho Sung-Min , Wang Jing , Lantry James H. , Kim Bo S. , Tahsili-Fahadan Pouya
Published: May 2022

Extracorporeal membrane oxygenation (ECMO) is an increasingly utilized intervention for cardiopulmonary failure. Analgosedation during ECMO support is essential to ensure adequate pain and agitation control and ventilator synchrony, optimize ECMO support, facilitate patient assessment, and minimize adverse events. Although the principles of analgosedation are likely similar for all critically ill patients, ECMO circuitry alters medication pharmacodynamics and pharmacokinetics. The lack of clinical guidelines for analgosedation during ECMO, especially at times of medication shortage, can affect patient management. Here, we review pharmacological considerations, protocols, and special considerations for analgosedation in critically ill adults receiving ECMO support.
A Case of Opsoclonus-Myoclonus-Ataxia With Neuronal Intermediate Filament IgG Detected in Cerebrospinal Fluid
Authors: Merati Melody , Rucker Janet C. , McKeon Andrew , Frucht Steven J. , Hu Jessica , Balcer Laura J. , Galetta Steven L.
Published: May 2022

A 62-year-old man presented with headache, fever, and malaise. He was diagnosed with Anaplasma phagocytophilum, confirmed by serum polymerase chain reaction, and started on oral doxycycline. After 5 days of treatment, the patient began to experience gait imbalance with frequent falls, as well as myoclonus, and confusion. Examination was notable for opsoclonus-myoclonus-ataxia (OMA) and hypometric saccades. Cerebrospinal fluid (CSF) autoimmune encephalitis panel demonstrated a markedly elevated neuronal intermediate filament (NIF) immunoglobulin G antibody titer of 1:16, with positive neurofilament light- and heavy-chain antibodies. These antibodies were suspected to have been triggered by the Anaplasma infection. Repeat CSF examination 8 days later still showed a positive immunofluorescence assay for NIF antibodies, but the CSF titer was now less than 1:2. Body computed tomography imaging was unrevealing for an underlying cancer. Our patient illustrates a postinfectious mechanism for OMA and saccadic hypometria after Anaplasma infection.
Quercitrin improved cognitive impairment through inhibiting inflammation induced by microglia in Alzheimer’s disease mice
Authors: Wang Lixin , Sun Jinxia , Miao Zhulei , Jiang Xin , Zheng Yuejuan , Yang Guizhen
Published: May 2022

Objective

Diets rich in quercitrin show a neuroprotective effect, but the mechanism is not very clear at present. The objective of this study is to explore the effect and mechanism of quercitrin in the treatment of alzheimer’s disease (AD).

Methods

5XFAD transgenic mice were fed with a diet supplemented with quercitrin for three consecutive months. Behavioral experiments were conducted to assess the cognitive ability, luminex liquid chip technology was used to assess the production of proinflammatory cytokines and immunohistochemistry was used to elucidate the activation of microglia.

Results

Quercitrin increased the frequency in exploring new objects, shortened the escape latency and increased the frequency crossing the platform in AD model mice. Quercitrin inhibited the activation and proliferation of microglia, inhibited the secretion of inflammatory cytokines and chemokines and reduced the accumulation of amyloid-β plaques in AD model mice.

Conclusion

Quercitrin improved mice cognitive impairment through alleviating the intensity of inflammatory response and is a promising medicinal plant extract in the treatment of AD.
The activated synaptic terminals beyond the light illumination range affect the results of optogenetics
Authors: Ji Xuying , Liu Wenhui , Xiao Haoran , Xiao Zhongju
Published: May 2022

Objectives

Optogenetics is widely applied to study complex brain networks. However, recent studies have found that light alone can produce effects that are unrelated to optogenetics, and it is still unclear whether this can affect the results of optogenetic experiments.

Methods

We explored the characteristics of projection of interneurons to excitatory neurons in the auditory cortex with optogenetics, transgenic mice and patch-clamp recording.

Results

We discovered that postsynaptic responses can be induced when we stimulated a blank area adjacent to the edge of brain slice. Similar results can be observed after blocking the polysynaptic responses by drugs. Together with the results of control experiments, we found that the false response is caused by activating the synaptic terminals beyond the range of the blue light (470 nm). Also, there was a linear relationship between the response and the stimulus distance for all data, which suggested that these false responses may be related to other factors, such as light scattering.

Conclusions

The LED-light-evoked response cannot reflect microcircuit of the recorded neuron and the activated neurons within the illumination range accurately. Together, these results confirm that light alone can affect neural activity, but this can be unrelated to the genuine ‘optogenetic effect’.
Loss of GBA in zebrafish leads to dopaminergic neurodegeneration, but overexpression of α-synuclein does not further worsen degeneration
Authors: Kodera Kazuki , Matsui Noriko , Saitoh Akihiko , Matsui Hideaki
Published: May 2022

Objectives

Parkinson’s disease is a neurodegenerative disorder that causes motor and nonmotor symptoms due to the loss of dopaminergic nerves and is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein. Glucosylceramidase beta (GBA), which is a causative gene of autosomal recessive Gaucher disease, is also known to be a risk gene for Parkinson’s disease. In this study, we tried to detect synergistic effects of α-synuclein accumulation and gba depletion on dopaminergic neurodegeneration in zebrafish.

Methods

We generated a transgenic line of zebrafish overexpressing the A53T α-synuclein and gba mutant fish, and analyzed pathologies of α-synuclein aggregation and neurodegeneration.

Results

Zebrafish overexpressing the A53T α-synuclein did not exhibit α-synuclein aggregate formation. After the loss of gba function in this mutant α-synuclein transgenic line, we observed the marked presence of α-synuclein aggregates. Loss of gba function in zebrafish resulted in dopaminergic and noradrenergic neurodegeneration but this level of neurodegeneration was not exacerbated by overexpression of mutant α-synuclein.

Conclusions

These results indicate that loss of gba function was sufficient to generate a neurodegenerative phenotype in zebrafish regardless of the expression of α-synuclein.
Biologic vs Synthetic Mesh for Parastomal Hernia Repair: Post Hoc Analysis of a Multicenter Randomized Controlled Trial
Authors: Miller Benjamin T , Krpata David M , Petro Clayton C , Beffa Lucas R A , Carbonell Alfredo M , Warren Jeremy A , Poulose Benjamin K , Tu Chao , Prabhu Ajita S , Rosen Michael J
Published: May 2022

BACKGROUND:

Parastomal hernias are often repaired with mesh to reduce recurrences, but the presence of an ostomy increases the wound class from clean to clean-contaminated/contaminated and makes the choice of mesh more controversial than in a strictly clean case. We aimed to compare the outcomes of biologic and synthetic mesh for parastomal hernia repair.

STUDY DESIGN:

This is a post hoc analysis of parastomal hernia repairs in a randomized trial comparing biologic and synthetic mesh in contaminated ventral hernia repairs. Outcomes included rates of surgical site occurrences requiring procedural intervention (SSOPI), reoperations, stoma/mesh-related adverse events, parastomal hernia recurrence rates (clinical, patient-reported, and radiographic) at 2 years, quality of life (EQ-5D, EQ-5D Visual Analog Scale, and Hernia-Related Quality of Life Survey), and hospital costs up to 30 days.

RESULTS:

A total of 108 patients underwent parastomal hernia repair (57 biologic [53%] and 51 synthetic [47%]). Demographic and hernia characteristics were similar between the two groups. No significant differences in SSOPI rates or reoperations were observed between mesh types. Four mesh erosions into an ostomy requiring reoperations (2 biologic vs 2 synthetic) occurred. At 2 years, parastomal hernia recurrence rates were similar for biologic and synthetic mesh (17 [29.8%] vs 13 [25.5%], respectively; p = .77). Overall and hernia-related quality of life improved from baseline and were similar between the two groups at 2 years. Median total hospital cost and median mesh cost were higher for biologic compared with synthetic mesh.

CONCLUSION:

Biologic and synthetic mesh have similar wound morbidity, reoperations, 2-year hernia recurrence rates, and quality of life in parastomal hernia repairs. Cost should be considered in mesh choice for parastomal hernia repairs.
Quality characteristics and antioxidant activity of stick jelly prepared with aronia juice
Authors: Hwang Eun-Sun , Shon EunMyeong
Published: May 2022

The study was conducted to investigate quality characteristics and antioxidant activities of stick jelly prepared using 0, 25, 50, and 100% aronia juice instead of water. The moisture content of stick jelly was 81.88 to 88.22%, with the highest moisture content in jelly without the addition of aronia juice. The addition of aronia juice tended to decrease the moisture content of stick jelly compared to the control group. The ash and crude fat contents of the jelly increased with an increasing aronia juice content. The sugar content, total acidity, and hardness of the jelly increased, while the pH tended to decrease, with and increased aronia juice content. Regarding chromaticity, L* and b* values decreased, and a* values increased with an increasing aronia juice content. The total polyphenol and total flavonoid contents increased with an increasing aronia juice content. The antioxidant activity, measured based on the DPPH and ABTS radical-scavenging activities, and reducing powder were significantly higher in jelly containing the aronia juice than those in the control, and proportionally increased with an increasing aronia juice content. Overall, these findings suggest that aronia juice can be used for stick jelly making.
Synergistic protection against secondary pneumococcal infection by human monoclonal antibodies targeting distinct epitopes
Authors: Gingerich Aaron D. , Royer Fredejah , McCormick Anna L. , Scasny Anna , Vidal Jorge E. , Mousa Jarrod J.
Published: May 2022

Streptococcus pneumoniae persists as a leading cause of bacterial pneumonia despite the widespread use of polysaccharide-based vaccines. The limited serotype coverage of current vaccines has led to increased incidence of non-vaccine serotypes, as well as an increase in antibiotic resistance among these serotypes. Pneumococcal infection often follows a primary viral infection such as influenza virus, which hinders host defense and results in bacterial spread to the lungs. We previously isolated human monoclonal antibodies (mAbs) against the conserved surface antigen pneumococcal histidine triad protein D (PhtD), and we demonstrated that mAbs to this antigen are protective against lethal pneumococcal challenge prophylactically and therapeutically. In this study, we elucidated the mechanism of protection of a protective anti- pneumococcal human mAb, PhtD3, which is mediated by the presence of complement and macrophages in a mouse model of pneumococcal infection. Treatment with mAb PhtD3 reduced blood and lung bacterial burden in mice, and mAb PhtD3 is able to bind to bacteria in the presence of the capsular polysaccharide, indicating exposure of surface PhtD on encapsulated bacteria. In a mouse model of secondary pneumococcal infection, protection mediated by mAb PhtD3 and another mAb targeting a different epitope, PhtD7, was reduced, however, robust protection was restored by combining mAb PhtD3 with mAb PhtD7, indicating a synergistic effect. Overall, these studies provide new insights into anti-pneumococcal mAb protection and demonstrate for the first time that mAbs to pneumococcal surface proteins can protect against secondary pneumococcal infection in the mouse model.

Author Summary

The persistence of Streptococcus pneumoniae as a leading cause of bacterial pneumonia despite numerous approved pneumococcal vaccines is a serious threat to public health globally. Currently, prophylactic and therapeutic options for Streptococcus pneumoniae are constrained by the limited serotype coverage of vaccines and the emergence of antibiotic resistant strains. An additional hurdle to overcome is the incidence of secondary pneumococcal infection following a viral infection, which leads to increased mortality. Here, we determined the mechanism of action of a monoclonal antibody (mAb) that targets Streptococcus pneumoniae. We found that mAb PhtD3 operates through macrophage and complement mediated functions. mAb PhtD3 was also discovered to reduce bacterial titers in the lungs and blood and bind to a related antigen PhtE. We also tested additional mAbs and discovered that two unique mAbs to the antigen PhtD conferred protection in a pneumococcal-influenza virus co-infection model. Our study provides new insights into the mechanisms and therapeutic potential of mAbs targeting conserved proteins of Streptococcus pneumoniae.
Effectiveness of the neutralizing antibody sotrovimab among high-risk patients with mild to moderate SARS-CoV-2 in Qatar
Authors: Zaqout Ahmed , Almaslamani Muna A. , Chemaitelly Hiam , Hashim Samar A. , Ittaman Ajithkumar , Alimam Abeir , Rustom Fatma , Daghfal Joanne , Abukhattab Mohammed , AlMukdad Sawsan , Kaleeckal Anvar Hassan , Latif Ali Nizar , Butt Adeel A. , Bertollini Roberto , Al-Khal Abdullatif , Omrani Ali S. , Abu-Raddad Laith J.
Published: May 2022

Effectiveness of sotrovimab against severe, critical, or fatal COVID-19 was investigated in Qatar using a case-control study design at a time when BA.2 Omicron subvariant dominated incidence. Adjusted odds ratio of progression to severe, critical, or fatal COVID-19, comparing those sotrovimab-treated to those untreated, was 2.67-fold higher (95% CI: 0.60-11.91).
Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
Authors: Ma Qing , Yang Liuyi , Tolentino Karen , Zhao Yang , Lizenburger Ulrike M , Shi Quanming , Zhu Lin , Tsai Miao-Chih , Chen Jun-An , Lai Ian , Zeng Hong , Li Lingjie , Chang Howard Y.
Published: May 2022

HOTAIR is a 2.2 kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted epithelial to mesenchymal transition. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.
Organization of the corticotropin-releasing hormone and corticotropin-releasing hormone-binding protein systems in the central nervous system of the sea lamprey Petromyzon marinus
Authors: Sobrido-Cameán Daniel , González-Llera Laura , Anadón Ramón , Barreiro-Iglesias Antón
Published: May 2022

The expression of the corticotropin-releasing hormone (PmCRH) and the CRH-binding protein (PmCRHBP) mRNAs was studied by in situ hybridization in the brain of prolarvae, larvae and adults of the sea lamprey Petromyzon marinus. We also generated an antibody against the PmCRH mature peptide to study the distribution of PmCRH-immunoreactive cells and fibers. PmCRH immunohistochemistry was combined with anti-tyrosine hydroxylase immunohistochemistry, PmCRHBP in situ hybridization or neurobiotin transport from the spinal cord. The most numerous PmCRH-expressing cells were observed in the magnocellular preoptic nucleus-paraventricular nucleus and in the superior and medial rhombencephalic reticular formation. PmCRH expression was more extended in adults than in larvae, and some cell populations were mainly (olfactory bulb) or only (striatum, ventral hypothalamus, prethalamus) observed in adults. The preopto-paraventricular fibers form conspicuous tracts coursing towards the neurohypophysis, but many immunoreactive fibers were also observed coursing in many other brain regions. Brain descending fibers in the spinal cord come from cells located in the isthmus and in the medial rhombencephalic reticular nucleus. The distribution of PmCRHBP-expressing neurons was different from that of PmCRH cells, with cells mainly present in the septum, striatum, preoptic region, tuberal hypothalamus, pretectum, pineal complex, isthmus, reticular formation, and spinal cord. Again, expression in adults was more extended than in larvae. PmCRH- and PmCRHBP-expressing cells are different, excluding colocalization of these substances in the same neuron. Present findings reveal a complex CRH/CRHBP system in the brain of the oldest extant vertebrate group, the agnathans, which shows similarities but important divergences with that of mammals.
Mapping the risks of China’s global coastal development to marine socio-ecological systems
Authors: Simmons B. Alexander , Butt Nathalie , O’Hara Casey C. , Ray Rebecca , Ma Yaxiong , Gallagher Kevin P.
Published: May 2022

Rapid coastal development continues to jeopardize the integrity of marine socio-ecological systems. China is now the largest bilateral creditor in the world, committing nearly half a trillion US dollars to overseas development finance since 2008. Meanwhile, there are growing concerns over the impacts of this boom in Chinese development finance on marine systems. Here, we quantify the risks of coastal development projects financed by China to marine biodiversity and coastal Indigenous communities. Ports present the greatest impact risks to marine systems, in terms of both magnitude and area at risk, with power plants, roads, and other facilities presenting relatively high localized risks. Risks are most prominent in Africa and the Caribbean, with coastal Indigenous communities in Western and Central Africa particularly vulnerable to the potential negative impacts of development. All projects present some risk to threatened marine species and potential critical habitats, but few present high risks to nearby marine protected areas. Most projects present additional risks to ecosystems that are already under increasing human pressures, but some are likely to introduce new risks to relatively intact ecosystems. “Bluing” future coastal development projects in China’s overseas development finance portfolio will require more social and environmental safeguards, higher standards for host-country impact assessments, and greater integration of land-sea risk mitigation and management approaches.
ALDH2 DEFICIENCY INCREASES SUSCEPTIBILITY TO BINGE ALCOHOL-INDUCED GUT LEAKINESS, ENDOTOXEMIA, AND ACUTE LIVER INJURY IN MICE THROUGH THE GUT-LIVER AXIS
Authors: Rungratanawanich Wiramon , Wang Xin , Kawamoto Toshihiro , Chidambaram Saravana Babu , Song Byoung-Joon
Published: May 2022

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol used disorder (AUD), including alcoholic liver disease (ALD), and elevated oxidative stress. We hypothesized thatAldh2-knockout (KO) mice are susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposingAldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency inAldh2-KO mice increases their sensitivity to alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia inAldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and/or bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury, indicating the disruption in the gut-liver axis. Furthermore, treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colonic cells. These changes were reversed by Alda-1, an ALDH2 activator, indicating a crucial role of ALDH2 in protecting against alcohol-induced epithelial barrier dysfunction. All these findings suggest thatALDH2deficiency or gene mutation in humans is a risk factor to alcohol-mediated gut and liver injury, and ALDH2 could be an important therapeutic target against alcohol-associated tissue/organ damage.

Highlights

Binge alcohol increases oxidative and nitrative stress in the intestine and liver.

Binge alcohol causes gut leakiness, endotoxemia, and acute liver injury.

Leaky gut is caused by elevated degradation of nitrated intestinal TJ/AJ proteins.

Aldh2-KO mice are susceptible to binge-alcohol-induced leaky gut and liver injury.

ALDH2 inhibition increases alcohol-induced T84 colonic epithelial cell permeability.
Regulation of metabolic health by dietary histidine in mice
Authors: Flores Victoria , Spicer Alexandra B. , Sonsalla Michelle , Richardson Nicole E. , Yu Deyang , Sheridan Grace E. , Trautman Michaela E. , Babygirija Reji , Cheng Eunhae P. , Rojas Jennifer M. , Yang Shany E. , Wakai Matthew H. , Hubbell Ryan , Kasza Ildiko , Tomasiewicz Jay L. , Green Cara L. , Dantoin Claudia , Alexander Caroline M. , Baur Joseph A. , Malecki Kristen C. , Lamming Dudley W.
Published: May 2022

Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. While the effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched- chain amino acids (BCAAs), we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean male mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. We find that the effects of histidine restriction surprisingly does not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity.

Key Points

Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan.

Restriction of specific individual essential amino acids can recapitulate the benefits of PR.

Reduced histidine promotes leanness and increased energy expenditure in mice.

Reduced histidine does not extend the lifespan of mice when begun in mid-life.

Dietary levels of histidine are positively associated with BMI in humans.
Immune Checkpoint Activity Regulates Polycystic Kidney Disease Progression
Authors: Kleczko Emily K. , Nguyen Dustin T. , Marsh Kenneth H. , Bauer Colin D. , Li Amy S. , Furgeson Seth B. , Gitomer Berenice Y. , Chonchol Michel B. , Clambey Eric T. , Zimmerman Kurt A. , Nemenoff Raphael A. , Hopp Katharina
Published: May 2022

Innate and adaptive immune cells modulate Autosomal Dominant Polycystic Kidney Disease (ADPKD) severity, a common kidney disease with inadequate treatment options. ADPKD shares parallels with cancer where immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have shown that, in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of PD-1 on CD8+ T cells and PD-L1 on macrophages and epithelial cells in Pkd1RC/RC mice versus wildtypes, paralleling disease severity. PD-L1 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking two immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers. Together, our data suggests that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.
Legacy of past exposure to hypoxia and warming regulates ecosystem service provided by oysters
Authors: Donelan Sarah C. , Ogburn Matthew B. , Breitburg Denise
Published: May 2022

Climate change is having substantial impacts on organism fitness and ability to deliver critical ecosystem services, but these effects are often examined only in response to current environments. Past exposure to stress can also affect individuals via carryover effects, and whether these effects scale from individuals to influence ecosystem function and services is unclear. We explored carryover effects of two coastal climate change stressors – hypoxia and warming – on oyster (Crassostrea virginica) growth and nitrogen bioassimilation, an important ecosystem service. Oysters were exposed to a factorial combination of two temperature and two diel-cycling dissolved oxygen treatments at three-months-old and again one year later. Carryover effects of hypoxia and warming influenced oyster growth and nitrogen storage, with early life stress generally reducing nitrogen storage and relative tissue growth, particularly in warm environments. When extrapolated to the reef scale, carryover effects reduced estimated nitrogen storage by a restored oyster reef by as much as 41%, a substantial decline in a critical ecosystem service. Even brief exposure to climate change stressors early in life has persistent, negative effects on an ecosystem service one year later. Carryover effects on individuals impact processes at the ecological scale and must be considered in assessments of and management plans for species and ecosystems threatened by anthropogenic change.

Significance Statement

Anthropogenic change threatens organisms’ ability to provide ecosystem services through effects on individual phenotypes. Past experiences with anthropogenic stress can have delayed, persistent impacts on organisms via carryover effects, but how carryover effects scale to influence ecosystem function and services is not yet established. In marine systems, foundation species such as oysters mitigate effects of eutrophication by storing nutrients like nitrogen in their tissue and shell. We show that past exposure to two interacting climate change stressors (hypoxia and warming) reduces nitrogen stored by oysters by as much as 41% one year after initial exposure. Our results reveal carryover effects as a novel pathway through which climate change affects ecosystem processes that should be incorporated into conservation and management plans.
Rapid biomechanical imaging at low irradiation level via dual line-scanning Brillouin microscopy
Authors: Zhang Jitao , Nikolic Milos , Tanner Kandice , Scarcelli Giuliano
Published: May 2022

Brillouin microscopy is a promising all-optical technique for biomechanics but is limited by slow acquisition speed and/or large irradiation doses. Here, we introduce multiplexed Brillouin microscopy that overcomes both these limits by over one order of magnitude with selective illumination and single-shot analysis of hundreds of points along the incident beam axis. We demonstrate the enabling capabilities of this method probing rapid response to perturbations and long-term mechanical evolution of tumor spheroids.
Reverse engineering environmental metatranscriptomes clarifies best practices for eukaryotic assembly
Authors: Krinos Arianna I. , Cohen Natalie R. , Follows Michael J. , Alexander Harriet
Published: May 2022

Diverse communities of microbial eukaryotes in the global ocean provide a variety of essential ecosystem services, from primary production and carbon flow through trophic transfer to cooperation via symbioses. Increasingly, these communities are being understood through the lens of omics tools, which enable high-throughput processing of communities of multiple species. Metatranscriptomics in particular offers an understanding of real-time gene expression in microbial eukaryotic communities, providing a window into community metabolic activity. However, these approaches are rarely validated. A systematic validation of metatranscriptome assembly and annotation methods is necessary to appropriately assess (1) the fidelity of our community composition measurements and (2) the confidence of novel taxonomic and functional content discovered with metatranscriptomics. Here, we presenteukrhythmic, an automated and customizable multi-assembler workflow for eukaryotic metatranscriptome assembly, annotation, and analysis, and validate the ability of the pipeline to recapitulate simulated eukaryotic community-level expression data treated as a gold standard. Finally, we apply this pipeline to two previously published metatranscriptomic datasets, showing both recapitulation of previous results as well as enhanced taxonomic and functional gene discovery.
SOCS3 limits endotoxin-induced endothelial dysfunction by blocking a required autocrine interleukin 6 signal in human umbilical vein endothelial cells
Authors: Martino Nina , Ramos Ramon Bossardi , Chuy Dareen , Tomaszek Lindsay , Adam Alejandro P
Published: May 2022

Increased circulating levels of soluble interleukin (IL)-6 receptor α (sIL-6Rα) are commonly observed during inflammatory responses, allowing for IL-6 signaling to occur in cells that express the ubiquitous receptor subunit gp130 but not IL-6Rα, such as endothelial cells. Activation of Toll-like receptor (TLR)-4 or the tumor necrosis factor (TNF) receptor leads to NF-κB-dependent increases in endothelial IL-6 expression. Thus, we hypothesize that danger signals may induce autocrine IL-6 signaling within the endothelium via sIL-6Rα-mediated trans-signaling. In support of this hypothesis, we recently demonstrated that conditional deletion in the endothelium of the IL-6 signaling inhibitor SOCS3 leads to rapid mortality in mice challenged with the TLR-4 agonist endotoxin through increases in vascular leakage, thrombosis, leukocyte adhesion, and a type I-like interferon response. Here, we sought to directly test a role for sIL-6Rα in LPS-treated human umbilical vein endothelial cells. We show that cotreatment with sIL-6Rα dramatically increases the loss of barrier function and the expression of COX2 and tissue factor mRNA levels induced by LPS. This co-treatment led to a strong activation of STAT1 and STAT3 while not affecting LPS-induced activation of p38 and NF-κB signaling. Similar results were obtained when sIL-6Rα was added to a TNF challenge. JAK inhibition by pretreatment with ruxolitinib or by SOCS3 overexpression blunted LPS and sIL-6R synergistic effects, while SOCS3 knockdown further increased the response. Together, these findings demonstrate that IL-6 signaling downstream of NF-kB activation leads to a strong endothelial activation and may explain the acute endotheliopathy observed during critical illness.
Unravelling the mechanisms of adaptation to high pressure in proteins
Authors: Caliò Antonino , Koza Michael Marek , Fontanay Stephane , Oger Philippe , Peters Judith
Published: May 2022

Life is thought to have appeared in the depth of the sea, under high hydrostatic pressure. Nowadays, it is known that the deep biosphere hosts a myriad of life forms thriving under high pressure conditions. However, the evolutionary mechanisms leading to their adaptation are still not known. Here we show the molecular bases of these mechanisms through a neutron scattering study of two orthologous proteins. We observed that pressure adaptation involves the decoupling of protein-water dynamics and the elimination of cavities in the protein core. This is achieved by an enrichment of acidic residues on the protein surface and by the use of bulkier hydrophobic residues in the core. These findings will be the starting point in the search of a complete genomic model explaining high pressure adaptation.
Linkage mapping reveals loci that underlie differences in C. elegans growth
Authors: Nyaanga Joy , Andersen Erik C.
Published: May 2022

Growth rate and body size are complex traits that contribute to the fitness of organisms. The identification of loci that underlie differences in these traits provides insights into the genetic contributions to development. Leveraging Caenorhabditis elegans as a tractable metazoan model for quantitative genetics, we can identify genomic regions that underlie differences in growth. We measured post-embryonic growth of the laboratory-adapted wild-type strain (N2) and a wild strain from Hawaii (CB4856), and found differences in body size. Using linkage mapping, we identified three distinct quantitative trait loci (QTL) on chromosomes IV, V, and X that are associated with variation in body size. We further examined these size-associated QTL using chromosome substitution strains and near-isogenic lines, and validated the chromosome X QTL. Additionally, we generated a list of candidate genes for the chromosome X QTL. These genes could potentially contribute to differences in animal growth and should be evaluated in subsequent studies. Our work reveals the genetic architecture underlying animal growth variation and highlights the genetic complexity of body size in C. elegans natural populations.
Targeted genomic sequencing with probe capture for discovery and surveillance of coronaviruses in bats
Authors: Kuchinski Kevin S. , Loos Kara D. , Suchan Danae M. , Russell Jennifer N. , Sies Ashton N. , Kumakamba Charles , Muyembe Francisca , Kingebeni Placide Mbala , Lukusa Ipos Ngay , N’Kawa Frida , Losoma Joseph Atibu , Makuwa Maria , Gillis Amethyst , LeBreton Matthew , Ayukekbong James A. , Monagin Corina , Joly Damien O. , Saylors Karen , Wolfe Nathan D. , Rubin Edward M. , Tamfum Jean J. Muyembe , Prystajecky Natalie A. , McIver David J. , Lange Christian E. , Cameron Andrew D.S.
Published: May 2022

Public health emergencies like SARS, MERS, and COVID-19 have prioritized surveillance of zoonotic coronaviruses, resulting in extensive genomic characterization of coronavirus diversity in bats. Sequencing viral genomes directly from animal specimens remains a laboratory challenge, however, and most bat coronaviruses have been characterized solely by PCR amplification of small regions from the best-conserved gene. This has resulted in limited phylogenetic resolution and left viral genetic factors relevant to threat assessment undescribed.

In this study, we evaluated whether a technique called hybridization probe capture can achieve more extensive genome recovery from surveillance specimens. Using a custom panel of 20,000 probes, we captured and sequenced coronavirus genomic material in 21 swab specimens collected from bats in the Democratic Republic of the Congo. For 15 of these specimens, probe capture recovered more genome sequence than had been previously generated with standard amplicon sequencing protocols, providing a median 6.1-fold improvement (ranging up to 69.1-fold). Probe capture data also identified five novel alpha- and betacoronaviruses in these specimens, and their full genomes were recovered with additional deep sequencing. Based on these experiences, we discuss how probe capture could be effectively operationalized alongside other sequencing technologies for high-throughput, genomics-based discovery and surveillance of bat coronaviruses.
Secondary metabolites produced during Aspergillus fumigatus and Pseudomonas aeruginosa biofilm formation
Authors: Bastos Rafael Wesley , Akiyama Daniel , Fernanda dos Reis Thaila , Colabardini Ana Cristina , Luperini Rafael Sanchez , Alves de Castro Patrícia , Baldini Regina Lúcia , Fill Taícia , Goldman Gustavo H.
Published: May 2022

In Cystic Fibrosis (CF), mucus plaques are formed in the patient’s lung, creating a hypoxic condition and a propitious environment for colonization and persistence of many microorganisms. There is clinical evidence showing that Aspergillus fumigatus can co-colonize CF patients with Pseudomonas aeruginosa, which has been associated with lung function decline. P. aeruginosa produces several compounds with inhibitory and anti-biofilm effects against A. fumigatus in vitro; however, little is known about the fungal compounds produced in counterattack. Here, we annotated fungal and bacterial secondary metabolites (SM) produced in mixed biofilms in normoxia and hypoxia conditions. We detected nine SMs produced by P. aeruginosa. Phenazines and different analogs of pyoverdin were the main compounds produced by P. aeruginosa, and their secretion were increased by the fungal presence. The roles of the two operons responsible for phenazines production (phzA1 and phzA2) were also investigated showing both mutants are able to produce partial sets of phenazines. We detected a total of 20 SMs secreted by A. fumigatus either in monoculture or in co-culture with P. aeruginosa. All these compounds are secreted during biofilm formation either in normoxia or hypoxia. However, only eight compounds (demethoxyfumitremorgin C, fumitremorgin, ferrichrome, ferricrocin, tricetylfusigen, gliotoxin, gliotoxin E, and pyripyropene A) were detected during the biofilm formation by the co-culture of A. fumigatus and P. aeruginosa upon both normoxia and hypoxia conditions. Overall, we showed how diverse is SM secretion during A. fumigatus and P. aeruginosa mixed culture and how this can affect biofilm formation both in normoxia and hypoxia.

Author Summary

The interaction between Pseudomonas aeruginosa and Aspergillus fumigatus has been well-characterized in vitro. In this scenario, the bacterium exerts a strong inhibitory effect against the fungus. However, little is known about the metabolites produced by the fungus to counterattack the bacteria. Our work aimed to annotate secondary metabolites (SM) secreted during co-culture between P. aeruginosa and A. fumigatus during biofilm formation in both normoxia and hypoxia. The bacterium produces several different types of phenazines and pyoverdins, in response to the fungus presence. In contrast, we were able to annotate 29 metabolites produced during A. fumigatus biofilm formation but only eight compounds were detected during biofilm formation by the co-culture of A. fumigatus and P. aeruginosa upon both normoxia and hypoxia. In conclusion, we have detected many SMs secreted during A. fumigatus and P. aeruginosa biofilm formation. This analysis can provide several opportunities to understand the interaction between these two species.