bluuebunny/crossref_metadata_2025 huggingface dataset:
A computational neuroscience framework for quantifying warning signals
Authors: Penacchio O. , Halpin C. G. , Cuthill I. C. , Lovell P. G. , Wheelwright M. , Skelhorn J. , Rowe C. , Harris J. M.
Published: December 2023

Animal warning signals show remarkable diversity, yet subjectively appear to share certain visual features that make defended prey stand out and look different from more cryptic palatable species. For example, many (but far from all) warning signals involve high contrast elements, such as stripes and spots, and often involve the colours yellow and red. How exactly do aposematic species differ from non‐aposematic ones in the eyes (and brains) of their predators?

Here, we develop a novel computational modelling approach, to quantify prey warning signals and establish what visual features they share. First, we develop a model visual system, made of artificial neurons with realistic receptive fields, to provide a quantitative estimate of the neural activity in the first stages of the visual system of a predator in response to a pattern. The system can be tailored to specific species. Second, we build a novel model that defines a ‘neural signature’, comprising quantitative metrics that measure the strength of stimulation of the population of neurons in response to patterns. This framework allows us to test how individual patterns stimulate the model predator visual system.

For the predator–prey system of birds foraging on lepidopteran prey, we compared the strength of stimulation of a modelled avian visual system in response to a novel database of hyperspectral images of aposematic and undefended butterflies and moths. Warning signals generate significantly stronger activity in the model visual system, setting them apart from the patterns of undefended species. The activity was also very different from that seen in response to natural scenes. Therefore, to their predators, lepidopteran warning patterns are distinct from their non‐defended counterparts and stand out against a range of natural backgrounds.

For the first time, we present an objective and quantitative definition of warning signals based on how the pattern generates population activity in a neural model of the brain of the receiver. This opens new perspectives for understanding and testing how warning signals have evolved, and, more generally, how sensory systems constrain signal design.
Nutrition in chronic inflammatory conditions: Bypassing the mucosal block for micronutrients
Authors: Roth‐Walter Franziska , Berni Canani Roberto , O'Mahony Liam , Peroni Diego , Sokolowska Milena , Vassilopoulou Emilia , Venter Carina
Published: December 2023

Nutritional Immunity is one of the most ancient innate immune responses, during which the body can restrict nutrients availability to pathogens and restricts their uptake by the gut mucosa (mucosal block). Though this can be a beneficial strategy during infection, it also is associated with non‐communicable diseases—where the pathogen is missing; leading to increased morbidity and mortality as micronutritional uptake and distribution in the body is hindered. Here, we discuss the acute immune response in respect to nutrients, the opposing nutritional demands of regulatory and inflammatory cells and particularly focus on some nutrients linked with inflammation such as iron, vitamins A, Bs, C, and other antioxidants. We propose that while the absorption of certain micronutrients is hindered during inflammation, the dietary lymph path remains available. As such, several clinical trials investigated the role of the lymphatic system during protein absorption, following a ketogenic diet and an increased intake of antioxidants, vitamins, and minerals, in reducing inflammation and ameliorating disease.
Negative appendectomy rate in the pediatric population: can we reach near‐zero rates? An observational study
Authors: Dreznik Yael , Paran Maya , Sher Carmel , Konen Osnat , Baazov Artur , Nica Adrianna , Kravarusic Dragan
Published: December 2023

Introduction

Correct diagnosis of acute appendicitis may sometimes be challenging. The Negative appendectomy rate (NAR) has declined in the recent years in Europe and USA, in part due to better diagnostic imaging tools. The aim of this study was to examine the rates of negative appendectomy in our institution, investigate trends in its incidence, and identify possible predicting factors.

Methods

A retrospective cohort study, including all patients younger than 18 years of age who underwent an appendectomy between 2007 and 2021 in a single tertiary medical center. Data regarding patient's demographics, laboratory and imaging results, pathological results and clinical outcome were collected.

Results

Between 2007 and 2021, a total of 3937 pediatric patients underwent appendectomy due to a working diagnosis of acute appendicitis. Overall, 143 patients (3.6%) had normal appendix on pathological examination. However, in the last 5 years, the rate of normal appendix was 1.9%, together with an increased rate of pre‐operative imaging (from 40% to nearly 100%).

Conclusion

Low NAR under 2% is an achievable benchmark in the era of accessible pre‐operative imaging. In unequivocal cases, a secondary survey that includes repeated physical examination, blood work and imaging is recommended and may result in near‐zero rates of NAR.
Evidence creation for myelofibrosis: Challenges and opportunities
Authors: Gupta Vikas
Published: December 2023

Evidence‐based guidelines for rare diseases, such as myelofibrosis (MF), continue to prove challenging to develop, and decision‐making for MF is complex. The British Society for Haematology (BSH) has created a pragmatic symptom‐guided risk‐adapted framework on all aspects of management of MF and shared best practices on the use of JAK inhibitors, transplantation and other conventional therapies in the management of myelofibrosis.

Commentary on: McLornan et al. The management of myelofibrosis: A British Society for Haematology Guideline. Br J Haematol 2024;204:136–150.
Fact or fiction? Does the position of the end‐to‐end (EEA) stapler spike matter for colorectal anastomoses using a double‐stapled technique?
Authors: Cavallaro Paul , Lee Grace C. , Kanters Arielle , Valente Michael , Holubar Stefan D. , Champagne Bradley , Rosen David , Gorgun Emre , Steele Scott
Published: December 2023

Aim

Surgeons often have strong opinions about how to perform colorectal anastomoses with little data to support variations in technique. The aim of this study was to determine if location of the end‐to‐end (EEA) stapler spike relative to the rectal transection line is associated with anastomotic integrity.

Method

This study was a retrospective analysis of a quality collaborative database at a quaternary centre and regional hospitals. Patients with any left‐sided colon resection with double‐stapled anastomosis were included (December 2019 to August 2022). Our primary endpoint was a composite outcome including positive air insufflation test, incomplete anastomotic donut, or thin/eccentric donut. Our secondary endpoint was clinical leak.

Results

Overall, 633 patients were included and stratified by location of the stapler spike relative to the rectal transection line. Of note, 86 patients had an end‐colon to anterior rectum (“reverse Baker”) anastomosis with no crossing staple lines. The rates of the composite endpoint based on position of the stapler spike were 12.4% (anterior), 8.1% (through), 12.8% (posterior), 5.1% (corner), and 2.3% for the “reverse Baker” (p = 0.03). The overall rate of clinical leak was 3.8% and there were no differences between methods. In a multivariate analysis, the “reverse Baker” anastomosis was associated with decreased odds of poor anastomotic integrity when compared to anastomoses with crossing staple lines (OR 0.20, 95% CI: 0.05–0.87, p = 0.03).

Conclusions

For anastomoses with crossing staple lines, the position of the stapler spike relative to the rectal staple line is not associated with differences in anastomotic integrity. In contrast, anastomoses with no crossing staple lines resulted in significantly lower rates of poor anastomotic integrity, but no difference in clinical leaks.
METTL16‐mediated N6‐methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer
Authors: Li Jimin , Yang Fang , Wang Zeyu , Zheng Siqing , Zhang Shuang , Wang Chen , He Bing , Wang Jia‐Bei , Wang Hao
Published: December 2023

N6‐methyladenosine (m6A) is the most prevalent internal modification in mammalian messenger RNAs and is associated with numerous biological processes. However, its role in chromosomal instability remains to be established. Here, we report that an RNA m6A methyltransferase, METTL16, plays an indispensable role in the progression of chromosome segregation and is required to preserve chromosome stability in colorectal cancer (CRC) cells. Depletion or inhibition of the methyltransferase activity of METTL16 results in abnormal kinetochore‐microtubule attachment during mitosis, leading to delayed mitosis, lagging chromosomes, chromosome mis‐segregation and chromosomal instability. Mechanistically, METTL16 exerts its oncogenic effects by enhancing the expression of suppressor of glucose by autophagy 1 (Soga1) in an m6A‐dependent manner. CDK1 phosphorylates Soga1, thereby triggering its direct interaction with the polo box domain of PLK1. This interaction facilitates PLK1 activation and promotes mitotic progression. Therefore, targeting the METTL16‐Soga1 pathway may provide a potential treatment strategy against CRC because of its essential role in maintaining chromosomal stability.
Induction of CD8+ immune memory and enhanced inflammation in a skin inflammation model through pre‐immunization with inactivated pathogens
Authors: Falkenberg Caroline , Bartholdy Christina , Koch Janne , Toft Martin Fitzner , Skov Søren , Hansen Camilla Hartmann Friis , Hansen Axel Kornerup
Published: December 2023

Laboratory mice live in specific pathogen‐free (SPF) conditions, resulting in an immature immune system comparable to that of newborns rather than adult humans or mice from pet shops. This condition may compromise their translational value. Reintroducing pathogens would lead to the uncontrolled spread of infections and associated diseases, so research facilities should seek safer alternatives. We immunized laboratory mice with a cocktail of pathogens, which were inactivated by ultraviolet irradiation and mixed with the adjuvant AddaVax. This immunization resulted in a higher percentage of CD8+ effector memory T cells compared to untreated mice, although the response was not as robust as in pet shop mice. In a model of skin inflammation, pre‐immunization led to an increased skin inflammatory response compared to non‐immunized mice. All immunized mice seroconverted to the pathogens in the mixture, while none of the non‐immunized mice housed together seroconverted to the pathogens applied to the pre‐immunized mice. In conclusion, pre‐immunization of mice impacts the immune system, which includes increasing the levels of CD8+ effector memory T cells.
SiC actions on characteristics analysis of AZ91D hybrid nanocomposite by liquid state processing
Authors: Yesuraj K. , Ali Mohammed , Venkatesh R. , Kumar S. Chandra
Published: December 2023

With an inherent lowest density and distinct solubility with enhanced mechanical behavior reason, the magnesium alloy composite is extensively used in the auto and aero sectors. The processing of magnesium alloy found micro‐cracks and voids between the oxidation spot, which fails properties. Through the sulfur hexafluoride (SF6) atmosphere, the AZ91D alloy hybrid nanocomposites are synthesized with 10 wt% alumina (Al2O3) and 0, 3, 6, and 9 wt% of silicon carbide (SiC) nanoparticles via a liquid state process with 400 rpm stir speed followed by vacuum die casting. The effect of SiC actions on physical behavior, microstructural formation, and mechanical properties of AZ91D/10 wt%Al2O3, AZ91D/10 wt%Al2O3/3 wt% SiC, AZ91D/10 wt% Al2O3/6 wt% SiC, and AZ91D/10 wt% Al2O3/9 wt% SiC composites are studied and its results compared with cast AZ91D alloy. Due to the actions of SiC in AZ91D/10 wt%Al2O3, the composite density conforms to the rule of mixture, and the void and micro‐cracks are limited (less than 1%) by the impact of the casting process, as evidenced in the microstructural illustration. An effect of 10 wt% Al2O3 and 9 wt% SiC contents in AZ91D facilitates maximum tensile strength of 181 MPa, improved elongation percentage of 2.2%, optimum hardness of 85HV, and superior impact toughness of 21.8 J/mm2, which is higher than the all other compositions.
A meta‐analysis evaluating wound infections and other complications following distal versus complete gastrectomy for gastric cancer
Authors: Imam Mohamed S. , Abdel‐Sattar Randa M. , Alotaibi Ghadah Rashed , Alotaibi Khalid Sinhat , Almuthaybiri Nasser Mutiq , Alshahrani Shahad Abdullah , Alghamdi Mohammed Abdulaziz , Abdelrahim Mohamed E. A.
Published: December 2023

A meta‐analysis investigation was carried out to measure the wound infections (WIs) and other postoperative problems (PPs) of distal gastrectomy (DG) compared with total gastrectomy (TG) for gastric cancer (GC). A comprehensive literature investigation till February 2023 was used and 1247 interrelated investigations were reviewed. The 12 chosen investigations enclosed 2896 individuals with GC in the chosen investigations' starting point, 1375 of them were TG, and 1521 were DG. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were utilized to compute the value of the WIs and other PPs of DG compared with TG for GC by the dichotomous approaches and a fixed or random model. TG had significantly higher overall PP (OR, 1.58; 95% CI, 1.15–2.18, p = 0.005), WIs (OR, 1.69; 95% CI, 1.07–2.67, p = 0.02), peritoneal abscess (PA) (OR, 2.99; 95% CI, 1.67–5.36, p < 0.001), anastomotic leakage (AL) (OR, 1.90; 95% CI, 1.21–2.97, p = 0.005) and death (OR, 2.26; 95% CI, 1.17–4.37, p = 0.02) compared to those with DG in individuals with GC. TG had significantly higher overall PP, WIs, PA, AL and death compared to those with DG in individuals with GC. However, care must be exercised when dealing with its values because of the low sample size of some of the nominated investigations for the meta‐analysis.
The cantilever contact‐point resin bonded bridge; adhesion 2.0
Authors: Gresnigt Marco M. M. , Jonker Joyce A. , van der Made Stephan A. M.
Published: December 2023

Aim

When young patients are congenitally missing anterior teeth, different treatment modalities can be used to complement the dental arch. This article proposes a new treatment modality for the replacement of anterior teeth, the cantilever contact‐point resin bonded bridge (CCP‐RBB).

Materials and Methods

In this proof of principle study, CCP‐RBB's delivered by one operator were clinically assessed. Patients who were missing maxillary incisors and had suitable intra‐oral conditions for a contact‐point cantilever RBB were included. Three cases are presented to describe all adhesive steps. This proof of principle clinical study is presented with up to 60 months follow‐up of the cantilever contact resin bonded bridges.

Results

A total of 19 CCP‐RBB's were evaluated after a mean period of 29.8 months. None of the restorations exhibited failure, carious lesions or fractures during the follow‐up periods, demonstrating an absence of restoration debonding or the need for repair.

Conclusion

The new cantilever contact‐point resin bonded bridge exhibited an excellent treatment modality without failure or debonding up to 5 years. More and extended duration in vivo studies are needed to evaluate this new treatment modality.

Clinical Significance

In this proof of principle the new cantilever contact‐point resin bonded bridge obtained excellent results up to 5 years of clinical follow‐up.
Utilizing non‐human primate models to combat recent COVID‐19/SARS‐CoV‐2 and viral infectious disease outbreaks
Authors: Kwon Taeho
Published: December 2023

In recent times, global viral outbreaks and diseases, such as COVID‐19 (SARS‐CoV‐2), Zika (ZIKV), monkeypox (MPOX), Ebola (EBOV), and Marburg (MARV), have been extensively documented. Swiftly deciphering the mechanisms underlying disease pathogenesis and devising vaccines or therapeutic interventions to curtail these outbreaks stand as paramount imperatives. Amidst these endeavors, animal models emerge as pivotal tools. Among these models, non‐human primates (NHPs) hold a position of particular importance. Their proximity in evolutionary lineage and physiological resemblances to humans render them a primary model for comprehending human viral infections. This review encapsulates the pivotal role of various NHP species—such as rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), african green monkeys (Chlorocebus sabaeus/aethiops), pigtailed macaques (Macaca nemestrina/Macaca leonina), baboons (Papio hamadryas/Papio anubis), and common marmosets (Callithrix jacchus)—in investigations pertaining to the abovementioned viral outbreaks. These NHP models play a pivotal role in illuminating key aspects of disease dynamics, facilitating the development of effective countermeasures, and contributing significantly to our overall understanding of viral pathogenesis.
Women with elevated blood pressure and stage 1 hypertension are at high risk for preeclampsia. A retrospective study at a tertiary facility in Japan
Authors: Shindo Ryosuke , Aoki Shigeru , Nakanishi Sayuri , Obata Soichiro , Miyagi Etsuko
Published: December 2023

Aim

In 2017, the American College of Cardiology (ACC) re‐defined hypertension (HT) as follows: elevated blood pressure (EBP), systolic blood pressure (SBP) 120–129 mmHg and diastolic blood pressure (DBP) <80 mmHg; stage 1 HT, SBP 130–139 mmHg or DBP 80–89 mmHg; and stage 2 HT: SBP ≥140 mmHg or DBP ≥90 mmHg. It is well known that women with stage 2 HT are at higher risk of preeclampsia and have poorer pregnancy and delivery outcomes. While there are few reports on the risk in women with EBP and stage 1 HT, and none from Japan. This study aimed to determine whether women in Japan with EBP and stage 1 HT are at risk of preeclampsia.

Methods

In this single‐center retrospective study conducted in Japan, subjects were classified into stage 2 HT, stage 1 HT, EBP, and normal groups based on blood pressure measurements at the time of the first visit before 20 weeks of gestation. Women with a diagnosis of hypertension made before pregnancy were classified into the stage 2 HT group. We compared pregnancy and delivery outcomes, such as preeclampsia, between groups.

Results

A total of 5129 cases (normal, n = 4283; EBP, n = 427; stage 1 HT, n = 303; stage 2 HT, n = 116) were included. Preeclampsia incidence rates were 2.7%, 5.6%, 10.6%, and 21.6%, respectively. The adjusted OR (95% CI) for preeclampsia incidence were 2.90 (1.81–4.66), 5.90 (3.87–9.20), and 13.80 (7.97–24.0), respectively.

Conclusions

Women with EBP and stage 1 HT are at high risk of preeclampsia, similar to those with stage 2 HT.
Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved
Authors: Cardinali Daniel P.
Published: December 2023

Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c‐peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1–1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.
Zonated iron deposition in the periportal zone of the liver is associated with selectively enhanced lipid synthesis
Authors: Yang Qiuyuan , Wu Yue , Liu Wei , Ou Xiaojuan , Zhang Wei , Wang Jianning , Chang Yanzhong , Wang Fudi , Gao Ming , Liu Sijin
Published: December 2023

Background and Aims

Disorders in liver lipid metabolism have been implicated in a range of metabolic conditions, including fatty liver and liver cancer. Altered lipid distribution within the liver, shifting from the pericentral to the periportal zone under pathological circumstances, has been observed; however, the underlying mechanism remains elusive. Iron, an essential metal, exhibits a zonal distribution in the liver similar to that of lipids. Nevertheless, the precise relationship between iron and lipid distribution, especially in the pericentral and periportal zones, remains poorly understood.

Methods

We conducted comprehensive in vitro and in vivo experiments, combining with in situ analysis and RNA sequencing, aiming for a detailed exploration of the causal relationship between iron accumulation and lipid metabolism.

Results

Our research suggests that iron overload can disrupt the normal distribution of lipids within the liver, particularly in the periportal zone. Through meticulous gene expression profiling in both the pericentral and periportal zones, we identified pyruvate carboxylase (PC) as a pivotal regulator in iron overload‐induced lipid accumulation. Additionally, we revealed that the activation of cyclic adenosine monophosphate response element binding protein (CREB) was indispensable for Pc gene expression when in response to iron overload.

Conclusions

In summary, our investigation unveils the crucial involvement of iron overload in fostering hepatic lipid accumulation in the periportal zone, at least partly mediated by the modulation of Pc expression. These insights offer new perspectives for understanding the pathogenesis of fatty liver diseases and their progression.
A focused review of visible light therapies for vitiligo
Authors: Winkie Mitchell J. , Sakunchotpanit Goranit , Salazar Carlos E. , Gunasekera Nicole S. , Buzney Elizabeth A. , Nambudiri Vinod E.
Published: December 2023

Background

Vitiligo can be challenging to treat and exhibit an unpredictable clinical course. Phototherapy in the form of visible light can achieve both repigmentation and depigmentation outcomes in vitiligo, with minimal associated adverse events. This review focuses on the mechanistic understandings and clinical outcomes of visible light‐based treatments for vitiligo.

Methods

Articles were retrieved from PubMed starting from May 1965 until August 2023, yielding 496 unique articles. We conducted title, abstract, and full‐text screening to identify articles describing the use of visible light (380–750 nm), either as part of combination therapy or as monotherapy, for repigmentation or depigmentation treatment in vitiligo.

Results

Twenty‐seven articles met inclusion criteria, offering preclinical and clinical data regarding the utilization of helium‐neon laser (red light) and blue light‐emitting diodes (LEDs) as methods of repigmentation therapy in vitiligo. Preclinical and clinical data on the utilization of Q‐switched ruby laser (694 nm) and frequency‐doubled (FD) Nd:YAG laser (532 nm) for vitiligo depigmentation therapy were also identified.

Conclusion

While limited by small studies and a lack of standardized administration of phototherapy, the evidence for visible light's effectiveness in managing vitiligo is encouraging. Red light therapy using He–Ne lasers and blue light therapy via LEDs can stimulate repigmentation in patients with vitiligo with minimal adverse events. Q‐switched ruby and FD Nd:YAG lasers provide viable, visible light depigmentation options, either alone or with topical agents. With limited clinical data, larger studies are needed to validate the efficacy of visible light therapy in treating vitiligo and to better understand its long‐term outcomes.
Designing cross‐sector collaboration to foster technological innovation: Empirical insights from eHealth partnerships in five countries
Authors: Verhoest Koen , Callens Chesney , Klijn Erik Hans , Brogaard Lena , García‐Rayado Jaime , Nõmmik Steven
Published: December 2023

This article examines the impact of partnership design on technological innovation in public‐private innovation partnerships. It develops two competing hypotheses on how specific partnership characteristics lead to innovation in health care services. The study compares 19 eHealth partnerships across five European countries and uses fuzzy‐set qualitative comparative analysis to test the hypotheses. The findings show that small, centralized, and homogeneous partnerships are most successful at achieving technological innovation. The study highlights the importance of partnership design in spurring innovation and calls for a reconsideration of some of the underlying assumptions of collaborative innovation theory.
Overcoming barriers to reef restoration: field‐based method for approximate genotyping of Acropora cervicornis
Authors: Blanco‐Pimentel Macarena , Kenkel Carly D. , Kitchen Sheila A. , Calle‐Triviño Johanna , Baums Iliana B. , Cortés‐Useche Camilo , Morikawa Megan K.
Published: December 2023

Reef restoration efforts aim to enhance resilience by safeguarding the genetic diversity of coral populations. This could be facilitated by genotyping methods that are relatively inexpensive, and field‐based. A potential method for assessing coral genotypic diversity arises from self‐recognition phenomena. Past studies have shown that contact between tissues from the same genet (isogeneic) will fuse whereas tissue from different genets (allogeneic) will result in rejection. However, the accuracy of this method has been questioned. Here, we revisit the grafting method as a tool to estimate genotypic diversity in a Caribbean coral restoration target, Acropora cervicornis. Ten ramets of unknown genetic relation were arranged in 82 grafting tests consisting of 5‐fragment bundles that replicated all possible combinations between ramets. After 10 weeks, we found that outcomes of acceptance and rejection were highly consistent (96.7% across all combinations and replicates). The proposed existence of 4 genets across the 10 ramets based on response outcomes was confirmed by two SNP‐based genotyping methods. Both genet pairing (isogeneic or allogeneic pairs) and genetic distance significantly affected the odds of acceptance or rejection responses. Moreover, a significant correlation was found between the degree of fusion between fragments and their genetic distance, supporting that the most related ramets are accepted more strongly compared to those that are more unrelated. This field‐based contact method can be a powerful tool to estimate genotypic diversity in coral nurseries, facilitating the management of genetic diversity within the nursery and genotype‐level tracking of key traits like disease and bleaching resistance.
Dynamics of 2D fluid in bounded domain via conformal variables
Authors: Chernyavsky Alexander , Dyachenko Sergey
Published: December 2023

In the present work, we compute numerical solutions of an integro‐differential equation for traveling waves on the boundary of a 2D blob of an ideal fluid in the presence of surface tension. We find that solutions with multiple lobes tend to approach Crapper capillary waves in the limit of many lobes. Solutions with a few lobes become elongated as they become more nonlinear. It is unclear whether there is a limiting solution for small number of lobes, and what are its properties. Solutions are found from solving a nonlinear pseudodifferential equation by means of the Newton conjugate‐residual method. We use Fourier basis to approximate the solution with the number of Fourier modes up to .
Comparing a point‐of‐care urine tenofovir lateral flow assay to self‐reported adherence and their associations with viral load suppression among adults on antiretroviral therapy
Authors: Phillips Tamsin , Gomba Yolanda , Myer Landon
Published: December 2023

Background

Point‐of‐care (POC) lateral flow assays (LFA) to detect tenofovir (TFV) in urine have been developed to measure short‐term ART adherence. Limited data exist from people living with HIV in routine care.

Methods

Adults on TFV‐containing regimens, having a routine viral load (VL) at an HIV clinic in Cape Town, South Africa were enrolled in a cross‐sectional study. Patients recalled missed ART doses in the past three and 7 days and urine was tested using a POC TFV LFA. VL on the day was abstracted from medical records.

Results

Among 314 participants, 293 (93%) had VL <1000 copies/mL, 20 (6%) had no TFV detected and 24 (8%) reported ≥1 missed dose in the past 3 days. Agreement between VL ≥1000 and undetectable TFV was higher compared to 3‐day recall of ≥1 missed dose (Kappa 0.504 vs. 0.163, p = 0.015). The AUC to detect VL ≥1000 was 0.747 (95% CI 0.637–0.856) for undetectable TFV. This was statistically significantly better than for 7‐day recall (0.571 95% CI 0.476–0.666, p = 0.040) but not for 3‐day recall (0.587 95% CI 0.492–0.681, p = 0.071) of ≥1 missed dose.

Conclusion

In this largely virally suppressed cohort, TFV in urine had better agreement with VL than self‐reported adherence and was a better predictor of viraemia on two of three self‐report measures. Used in combination with VL, the POC urine TFV LFA could flag patients with viraemia in the presence of ART. Further research is needed to understand the potential application in different populations on ART, including pregnant women.
Evaluation of the impact of repeated intravenous phage doses on mammalian host–phage interactions
Authors: Tan Xin , Chen Kai , Jiang Zhihuan , Liu Ziqiang , Wang Siyun , Ying Yong , Zhang Jieqiong , Yuan Shengjian , Huang Zhipeng , Gao Ruyue , Zhao Min , Weng Aoting , Yang Yongqing , Luo Huilong , Zhang Daizhou , Ma Yingfei
Published: December 2023

Phage therapy has shown great promise for the treatment of multidrug-resistant bacterial infections. However, the lack of a thorough and organized understanding of phage–body interactions has limited its clinical application. Here, we administered different purified phages (
Salmonella
phage SE_SZW1,
Acinetobacter
phage AB_SZ6, and
Pseudomonas
phage PA_LZ7) intravenously to healthy animals (rats and monkeys) to evaluate the phage-induced host responses and phage pharmacokinetics with different intravenous (IV) doses in healthy animals. The plasma and the organs were sampled after different IV doses to determine the phage biodistribution, phage-induced cytokines, and antibodies. The potential side effects of phages on animals were assessed. A non-compartment model revealed that the plasma phage titer gradually decreased over time following a single dose. Repeated doses resulted in a 2–3 Log
10
decline of the plasma phage titer at 5 min compared to the first dose, regardless of the type of phage administered in rats. Host innate immune responses were activated including splenic enlargement following repeated doses. Phage-specific neutralization antibodies in animals receiving phages were detected. Similar results were obtained from monkeys. In conclusion, the mammalian bodies were well-tolerant to the administered phages. The animal responses to the phages and the phage biodistribution profiles could have a significant impact on the efficacy of phage therapy.

IMPORTANCE

Phage therapy has demonstrated potential in addressing multidrug-resistant bacterial infections. However, an insufficient understanding of phage–host interactions has impeded its broader clinical application. In our study, specific phages were administered intravenously (IV) to both rats and monkeys to elucidate phage–host interactions and evaluate phage pharmacokinetics (PK). Results revealed that with successive IV administrations, there was a decrease in plasma phage concentrations. Concurrently, these administrations elicited both innate and adaptive immune responses in the subjects. Notably, the observed immune responses and PK profiles exhibited variation contingent upon the phage type and the mammalian host. Despite these variations, the tested mammals exhibited a favorable tolerance to the IV-administered phages. This underscores the significance of comprehending these interactions for the optimization of phage therapy outcomes.
Development of LIBRA-seq for the guinea pig model system as a tool for the evaluation of antibody responses to multivalent HIV-1 vaccines
Authors: Vukovich Matthew J. , Raju Nagarajan , Kgagudi Prudence , Manamela Nelia P. , Abu-Shmais Alexandra A. , Gripenstraw Kathryn R. , Wasdin Perry T. , Shen Xiaoying , Dwyer Bridget , Akoad Jumana , Lynch Rebecca M. , Montefiori David C. , Richardson Simone I. , Moore Penny L. , Georgiev Ivelin S.
Published: December 2023

Consistent elicitation of serum antibody responses that neutralize diverse clades of HIV-1 remains a primary goal of HIV-1 vaccine research. Prior work has defined key features of soluble HIV-1 Envelope (Env) immunogen cocktails that influence the neutralization breadth and potency of multivalent vaccine-elicited antibody responses including the number of Env strains in the regimen. We designed immunization groups that consisted of different numbers of SOSIP Env strains to be used in a cocktail immunization strategy: the smallest cocktail (group 2) consisted of a set of two Env strains, which were a subset of the three Env strains that made up group 3, which, in turn, were a subset of the six Env strains that made up group 4. Serum neutralizing titers were modestly broader in guinea pigs that were immunized with a cocktail of three Envs compared to cocktails of two and six, suggesting that multivalent Env immunization could provide a benefit but may be detrimental when the cocktail size is too large. We then adapted the LIBRA-seq platform for antibody discovery to be compatible with guinea pigs, and isolated several tier 2 neutralizing monoclonal antibodies. Three antibodies isolated from two separate guinea pigs were similar in their gene usage and CDR3s, establishing evidence for a guinea pig public clonotype elicited through vaccination. Taken together, this work investigated multivalent HIV-1 Env immunization strategies and provides a novel methodology for screening guinea pig B cell receptor antigen specificity at a high-throughput level using LIBRA-seq.

IMPORTANCE

Multivalent vaccination with soluble Env immunogens is at the forefront of HIV-1 vaccination strategies but little is known about the influence of the number of Env strains included in vaccine cocktails. Our results suggest that adding more strains is sometimes beneficial but may be detrimental when the number of strains is too high. In addition, we adapted the LIBRA-seq platform to be compatible with guinea pig samples and isolated several tier 2 neutralizing monoclonal antibodies, some of which share V and J gene usage and >70% CDR3 identity, thus establishing the existence of public clonotypes in guinea pigs elicited through vaccination.
A widespread methylotroph acyl-homoserine lactone synthase produces a new quorum sensing signal that regulates swarming in
Methylobacterium fujisawaense
Authors: Wallace Mike , Cummings, Jr. Dale A. , Roberts Andrew G. , Puri Aaron W.
Published: December 2023

Pink-pigmented facultative methylotrophs of the genera
Methylorubrum
and
Methylobacterium
are metabolically versatile bacteria that colonize many diverse environments on earth. Despite their widespread occurrence, the molecular details of how these organisms interact with each other and their environment remain understudied. We analyzed genes encoding
N
-acylhomoserine lactone (acyl-HSL) quorum sensing signal synthases in the published genomes of these bacteria and determined that the product of the largest family of signal synthases had not been characterized. We identified 3
R
-OH-5
Z
-C
12:1
-HSL as a novel signal produced by these synthases using inverse stable isotopic labeling and structural characterization by mass spectrometry, nuclear magnetic resonance spectroscopy, and chemical synthesis. We show that in the methylotroph
Methylobacterium fujisawaense
DSM5686, this signal activates its cognate LuxR-family transcription factor and is produced in a positive feedback loop. We also discover that in this strain, quorum sensing negatively regulates swarming motility by activating the expression of a small protein that binds a predicted transcription factor. These results characterize a previously undescribed, yet widespread quorum sensing system used by pink-pigmented facultative methylotrophs, which helps us understand the chemical ecology of these important bacteria.

IMPORTANCE

Bacteria known as pink-pigmented facultative methylotrophs colonize many diverse environments on earth, play an important role in the carbon cycle, and in some cases promote plant growth. However, little is known about how these organisms interact with each other and their environment. In this work, we identify one of the chemical signals commonly used by these bacteria and discover that this signal controls swarming motility in the pink-pigmented facultative methylotroph
Methylobacterium fujisawaense
DSM5686. This work provides new molecular details about interactions between these important bacteria and will help scientists predict these interactions and the group behaviors they regulate from genomic sequencing information.
Viscosity-dependent determinants of
Campylobacter jejuni
impacting the velocity of flagellar motility
Authors: Ribardo Deborah A. , Johnson Jeremiah J. , Hendrixson David R.
Published: December 2023

Campylobacter jejuni
colonizes the thick mucus layer lining the lower intestinal epithelium of hosts to promote commensalism in birds and animals or diarrheal disease in humans.
C. jejuni
displays higher swimming velocity as external viscosity increases, which likely benefits colonization and persistence in the intestinal mucus layer of hosts.
C. jejuni
produces one of the most structurally complex bacterial flagellar motors, which has been proposed to generate high torque for high swimming velocity. However, it is unknown how this flagellar motor alters output to impact swimming velocities in a viscosity-dependent manner. In this work, we identified
vi
scosity-dependent
d
eterminant
A
(VidA) (
Cjj81176_0996
) and VidB (
Cjj81176_1107
) in modulating swimming velocity primarily in low-viscosity environments.
C. jejuni
Δ
vidA
cells were non-motile or swam slowly in low-viscosity media, but swam with high velocity similar to wild-type cells in both Newtonian and non-Newtonian media with high viscosity. These data indicate that VidA is required for swimming in low-viscosity environments. Suppressor mutants suggested that the lower swimming velocity of Δ
vidA
in low viscosity was due to unregulated activity of VidB, which we propose has a brake- or clutch-like activity to reduce swimming velocity in low viscosity. Unlike other bacterial flagellar brakes or clutches, we found no evidence for cyclic diguanylate monophosphate influencing VidB activity. Our analyses suggest that the mechanics of the
C. jejuni
flagellar motor has naturally evolved for high-velocity swimming in milieus with high viscosity and requires the unique combination of VidA and VidB to modulate its activity to slow swimming velocity in low-viscosity environments.

IMPORTANCE

Bacteria can adapt flagellar motor output in response to the load that the extracellular milieu imparts on the flagellar filament to enable propulsion. Bacteria can adapt flagellar motor output in response to the load that the extracellular milieu imparts on the flagellar filament to enable propulsion through diverse environments. These changes may involve increasing power and torque in high-viscosity environments or reducing power and flagellar rotation upon contact with a surface.
C. jejuni
swimming velocity in low-viscosity environments is comparable to other bacterial flagellates and increases significantly as external viscosity increases. In this work, we provide evidence that the mechanics of the
C. jejuni
flagellar motor has evolved to naturally promote high swimming velocity in high-viscosity environments. We found that
C. jejuni
produces VidA and VidB as auxiliary proteins to specifically affect flagellar motor activity in low viscosity to reduce swimming velocity. Our findings provide some of the first insights into different mechanisms that exist in bacteria to alter the mechanics of a flagellar motor, depending on the viscosity of extracellular environments.
Supplemental Material: Mechanisms of nitrogen isotope fractionation at an ancient black smoker in the 2.7 Ga Abitibi greenstone belt, Canada
Authors: Martin Ashley N. , al. et
Published: December 2023

Additional details regarding samples, core locations, petrographic descriptions, thin-section images, analytical procedures, and data tables.  
Supplemental Material: Elastic stresses can form metamorphic fabrics
Authors: Gilgannon James , al. et
Published: December 2023

Details about the apparatus, data acquisition, experimental conditions, segmentation workflow, and kinematic model.  
Varicella-zoster virus vasculopathy in a patient with multiple sclerosis receiving natalizumab
Authors: Elmståhl Anna , Buchwald Fredrik , Ilinca Andreea
Published: December 2023

We present a case of a woman in her 30s with relapsing-remitting multiple sclerosis, treated with natalizumab, who developed ophthalmic varicella zoster virus (VZV) infection, with subsequent vasculopathy causing cerebral ischaemic lesions. She was treated with acyclovir, prednisolone and acetylsalicylic acid and fully recovered. VZV vasculopathy is associated with stroke and immunomodulating treatments may increase the risks of these adverse events. To date, nine VZV-related vasculopathy cases in patients treated with natalizumab have been reported in English literature and are summarised in this paper. Although rare, VZV intracerebral vasculopathy is an important differential diagnosis in patients with unexplained new-onset neurological symptoms after a herpes zoster infection. Treatment guidelines for VZV vasculopathy and for continuing treatment of multiple sclerosis after such an event are currently not established.
Delayed healing of rectal mucosa after endoscopic submucosal dissection (ESD) with nintedanib use
Authors: Yalamarthi Niveditha , Alipouriani Ali , Savage Erica , Gorgun Emre
Published: December 2023

Nintedanib is a novel antifibrotic agent used in the treatment of interstitial lung diseases. It has been associated with delayed wound healing and wound dehiscence in case reports after major surgeries when used perioperatively. This report presents an unprecedented case of a non-healing ulcer following an endorobotic submucosal dissection of a recurrent, adenomatous rectal polyp, likely due to nintedanib use. In this article, key components of the case were described with the aim to highlight a noteworthy differential diagnosis when suspecting recurrent rectal polyps as well as the need for further research on the effects of nintedanib on healing of polypectomy sites postoperatively.
Autologous blood products: Leucocyte and Platelets Rich Fibrin (L-PRF) and Platelets Rich Plasma (PRP) gel to promote cutaneous ulcer healing – a systematic review
Authors: Napit Indra B , Shrestha Dilip , Neupane Karuna , Adhikari Anju , Dhital Rolina , Koirala Rachita , Gopali Lovin , Ilozumba Onaedo , Gill Paramjit , Watson Samuel I , Choudhury Sopna , Lilford Richard J
Published: December 2023

Objective

To summarise evidence on the effectiveness of Platelet-Rich Plasma (PRP) gel and Leucocyte and Platelet Rich Fibrin (L-PRF) gel as agents promoting ulcer healing compared with the standard wound dressing techniques alone.

Design

Systematic review.

Eligibility criteria

Individual patient randomised controlled trials on skin ulcers of all types excluding traumatic lesions.

Intervention group: treatment with topical application of L-PRF gel or PRP gel to the wound surface.

Control group: treatment with standard skin ulcer care using normal saline, normgel or hydrogel dressings.

Information sources

Medline (Ovid), Excerpta Medica Database (EMBASE), Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science and manual search of studies from previous systematic reviews and meta-analyses. The papers published from 1946 to 2022 with no restriction on geography and language were included. The last date of the search was performed on 29 August 2022.

Data extraction and synthesis

Independent reviewers identified eligible studies, extracted data, assessed risk of bias using V.2 of the Cochrane risk-of-bias tool for randomised trials tool and assessed certainty of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Main outcome measures

Time to complete healing, proportion healed at a given time and rate of healing.

Results

Seven studies met the inclusion criteria, five using PRP gel and two using L-PRF gel. One study showed a better proportion of complete healing, three reported reduced meantime to complete healing and five showed improved rate of healing per unit of time in the intervention group. The risk of bias was high across all studies with one exception and the GRADE showed very low certainty of evidence.

Conclusion

The findings show potential for better outcomes in the intervention; however, the evidence remains inconclusive highlighting a large research gap in ulcer treatment and warrant better-designed clinical trials.

PROSPERO registration number

CRD42022352418.