bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic Profiling of Hypoplastic Lungs Suggests an Underlying Inflammatory Response in the Pathogenesis of Abnormal Lung Development in Congenital Diaphragmatic Hernia
Authors: Wagner Richard , Lieckfeldt Paula , Piyadasa Hadeesha , Markel Moritz , Riedel Jan , Stefanovici Camelia , Peukert Nicole , Patel Daywin , Derraugh Gabrielle , Min Suyin A Lum , Gosemann Jan-Hendrik , Deprest Jan , Pascoe Christopher D. , Tse Wai Hei , Lacher Martin , Mookherjee Neeloffer , Keijzer Richard
Published: August 2022

The pathogenesis of lung hypoplasia in congenital diaphragmatic hernia (CDH), a common birth defect, is poorly understood. The diaphragmatic defect can be repaired surgically, but the abnormal lung development contributes to a high mortality in these patients. To understand the underlying pathobiology, we compared the proteomic profiles of fetal rat lungs at the alveolar stage (E21) that were either exposed to nitrofen in utero (CDH lungs, n=5) or exposed to vehicle only (non-CDH control lungs, n=5). Pathway analysis of proteomic datasets showed significant enrichment in inflammatory response proteins associated with cytokine signaling and Epstein Barr Virus in nitrofen CDH lungs. Among the 218 significantly altered proteins between CDH and non-CDH control lungs were Tenascin C, CREBBP, LYN, and STAT3. We showed that Tenascin C was decreased around the distal airway branches in nitrofen rat lungs and human CDH lungs, obtained from stillborn fetuses that did not receive pre- or postnatal treatment. In contrast, STAT3 was significantly increased in the airway epithelium of nitrofen lungs at E21. STAT3 inhibition after direct nitrofen exposure to fetal rat lung explants (E14.5) partially rescued the hypoplastic lung phenotype ex vivo by increasing peripheral lung budding. Moreover, we demonstrated that several STAT3-associated cytokines (IL-15, IL-9, andIL-2) are increased in fetal tracheal aspirates of CDH survivors compared with nonsurvivors after fetoscopic endoluminal tracheal occlusion. With our unbiased proteomics approach, we showed for the first time that downstream inflammatory processes are likely involved in the pathogenesis of abnormal lung development in CDH.
Virtual oncology research-different models and lessons learned
Authors: Ranganathan P. , Pramesh C.S.
Published: August 2022

Purpose of review

The COVID-19 pandemic posed several challenges to cancer research including halting of trials, reduced recruitment and protocol violations related to inflexible processes followed in clinical trials. Researchers adopted innovative measures to mitigate these problems and continue studies without compromising their quality. This review collates these adaptations that could well continue after the pandemic.

Recent findings

The COVID-19 pandemic forced researchers globally to adopt innovative measures to overcome the challenges of the pandemic. These included protocol amendments to adjust to the pandemic and travel restrictions, and increased use of digital technologies. ’Virtual’ clinical trials were conducted increasingly with adaptations in ethics and regulatory approvals, patient recruitment and consenting, study interventions and delivery of study medications, trial assessments, and monitoring. Many of these adaptations are safe and feasible, without compromising study quality and data integrity. Although these may not be universally applicable in all types of research, they bring many benefits including more diverse patient participation, less burden on patients for study procedures and reduced resources to conduct trials.

The COVID-19 pandemic has affected cancer research adversely; however, learnings from the pandemic and adaptations from researchers are likely to improve the efficiency of clinical research beyond the pandemic.
Impact of the COVID-19 pandemic on care and psychological impact on cancer patients
Authors: Mihic-Góngora Luka , Rodriguez-Gonzalez Adán , Velasco Verónica , Obispo Berta , Jiménez-Fonseca Paula , Calderon Caterina
Published: August 2022

Purpose of review

To summarize the current literature on the psychological impact of COVID-19 on patients with cancer, both in terms of the impact of the virus itself and of changes in the healthcare system; and to describe current recommendations for supporting patients with cancer during the pandemic.

Recent findings

Multiple studies have shown that patients with cancer experience high levels of psychological distress during COVID-19. Factors of greater vulnerability have been described as: being young, being female, low socioeconomic status, lower educational level, having low levels of hope or optimism, lower social support, and having cancer with curative intent. The severe acute respiratory syndrome-coronavirus-2pandemic has accelerated the healthcare digitization process. All departments involved in the diagnosis and treatment of cancer have made contingency plans to minimize the impact on patients.

Psychological distress is one of the most frequently occurring symptoms in patients with cancer during the pandemic. The COVID-19 pandemic has led to a restructuring of the healthcare system. The paradigm shift may pose a challenge for both healthcare professionals and patients.
Tracking Eye Movements for Diagnosis in Myasthenia Gravis: A Comprehensive Review
Authors: Nguyen Minh N. L. , van der Walt Anneke , Fielding Joanne , Clough Meaghan , White Owen B.
Published: August 2022

Background:

Around 60%–-75% of myasthenia gravis (MG) patients initially present with nonspecific ocular symptoms. Failed recognition of these symptoms may delay the diagnosis of MG up to 5 years or more, leading to a reduced likelihood of remission and increased morbidity. Current diagnostic tests are either poorly sensitive for patients presenting with ocular symptoms alone or are time consuming, invasive, require a high level of technical expertise, and generally are universally difficult to obtain. This review will explore quantitative eye and pupil tracking as a potential noninvasive, time-effective, and less technically demanding alternative to current diagnostic tests of MG.

Evidence Acquisition:

Comprehensive literature review.

Results:

Thirty-two publications using oculography for the diagnosis of MG and 6 studies using pupillometry were evaluated. In MG patients, extra ocular muscle fatigue was evident in reports of intersaccadic, intrasaccadic and postsaccadic abnormalities, changes in optokinetic nystagmus, slow eye movements, disconjugate saccades, and pupillary constrictor muscle weakness.

Conclusions:

Our review identified several potentially useful variables that derive from oculography and pupillometry studies that could assist with a timely diagnosis of MG. Limitations of this review include heterogeneity in design, sample size, and quality of the studies evaluated. There is a need for larger, well-designed studies evaluating eye-tracking measures in the diagnosis of MG, especially for patients presenting with purely ocular symptoms.
Idiopathic Intracranial Hypertension and Socioeconomic Status in the Greater Toronto Area, Canada
Authors: Eshtiaghi Arshia , Margolin Edward A. , Micieli Jonathan A.
Published: August 2022

Background:

Previous studies have identified an association between obesity and socioeconomic variables such as poverty, minority status, and a low level of education. Because obesity is a major risk factor for the development of idiopathic intracranial hypertension (IIH), this study aims to identify and assess relationships between socioeconomic and geographic variables in patients with IIH in Canada.

Methods:

A retrospective chart review was performed to identify female patients with IIH presenting to 2 neuro-ophthalmology clinics in Toronto between 2014 and 2022. Consecutive female patients younger than 50 years who did not have IIH were identified as controls. Patient age, body mass index (BMI), and postal code were obtained from electronic medical records. Patient postal codes were then converted to geographic dissemination areas based on the 2016 Canadian census, and data on socioeconomic outcomes were collected from Statistics Canada.

Results:

Three hundred twenty-two female patients with IIH (mean age: 32.3 ± 10) and 400 female controls (mean age: 33.9 ± 9) were included. The mean BMI was 35.0 ± 8 for patients with IIH and 26.7 ± 7 for control patients (P < 0.00001). There was a significant difference between dissemination areas resided by patients with IIH and control patients for median income ($34640 vs $36685 CAD, P = 0.02) and rate of postsecondary degree attainment (57.7% vs 60.5%, P = 0.01). There were no significant differences in the percentage of visible minorities, percentage of immigrants, knowledge of official languages, percentage of married individuals, average household size, or unemployment rate. There was a weak but significant inverse relationship between the rate of postsecondary degree attainment in dissemination areas resided by patients with IIH and their BMI (P = 0.01, R2 = 0.02).

Conclusion:

Patients with IIH reside in geographic areas with lower average levels of income and education than control patients. Patients with lower levels of education may be at higher risk of elevated BMI and therefore disease incidence and progression.
Vision Loss as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy: A Case Series
Authors: Kruszewski Adam M. , Tauqeer Zujaja , Meer Elana A. , Bautista Sana Ali , Cherayil Neena R. , Cimino Marcus E. , Khella Sami L. , Lancaster Eric , Bird Shawn J. , Scherer Steven S. , Revere Karen E. , Hamedani Ali G. , Liu Grant T. , Tamhankar Madhura A.
Published: August 2022

Background:

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, and clinically heterogeneous demyelinating disease affecting the nerve roots and peripheral nerves. We report a series of 4 patients who presented with early and progressive vision loss in the context of new-onset CIDP: 3 due to papilledema and 1 due to optic neuropathy without papilledema.

Methods:

This was a retrospective case series of 4 patients with vision loss as a presenting feature of CIDP evaluated at the Hospital of the University of Pennsylvania from January 2016 to August 2021. Demographic, clinical, diagnostic, and treatment data were collected via retrospective medical record review.

Results:

Case 1 was a 51-year-old man with 2 months of progressive bilateral papilledema associated with reduced visual acuity (count fingers at 1 foot in each eye) and severely constricted visual fields. Case 2 was a 36-year-old man with 4 months of worsening headaches, reduced visual acuity (count fingers at 1 foot in each eye), severely constricted visual fields, and papilledema. Case 3 was a 39-year-old man with papilledema causing progressive vision loss (20/80 in both eyes), headaches, and relapsing limb sensorimotor deficits. Case 4 was a 19-year-old man with 3 months of progressive bilateral visual decline (20/400 in the right eye, 20/600 in the left eye), central scotoma, and optic disc pallor consistent with optic neuropathy without papilledema. All 4 patients met clinical and electrodiagnostic criteria of CIDP. Cases 3 and 4 each tested positive for serum neurofascin-155 IgG4 antibodies. All patients were managed with immunomodulatory therapy. Cases 1 and 2 also each required surgical intervention with bilateral optic nerve sheath fenestration and cerebrospinal fluid (CSF) shunting procedures.

Conclusion:

Vision loss from optic neuropathy with or without papilledema has rarely been reported in CIDP, and typically has been described in the context of longstanding disease. Our cases highlight how CIDP can present with early vision loss that may be profound and challenging to manage if diagnosis is delayed. CIDP should be considered in any patient with new progressive vision loss when associated with peripheral sensorimotor symptoms and elevated CSF protein. The small subgroup of CIDP patients with neurofascin-155 antibodies may be at particular risk of optic nerve involvement.
JMM profile: rifampicin: a broad-spectrum antibiotic
Authors: Hardie Kim R. , Fenn Samuel Jacob
Published: August 2022

Rifampicin (also known as rifampin) inhibits RNA synthesis, and is used to treat tuberculosis, leprosy, staphylococcal infections and legionnaires’ disease. It can also protect at-risk populations from

Haemophilus influenzae

type b and

Neisseria meningitidis

. It is a polyketide antibiotic and is on the World Health Organization (WHO) list of essential medicines due to its critical importance to human medicine. The adverse effect of liver toxicity is controlled by testing during prolonged treatment regimes. Rifampicin’s red–orange colour can result in the colouration of sweat, tears and urine. Resistance to rifampicin arises from mutation of the target RNA polymerase or ADP ribosylation of the antibiotic or efflux. Mycobacteria may become singularly resistant to rifampicin or as part of multidrug or extensive drug resistance.
Genomic dissection of the Vibrio cholerae O-serogroup global reference strains: reassessing our view of diversity and plasticity between two chromosomes
Authors: Murase Kazunori , Arakawa Eiji , Izumiya Hidemasa , Iguchi Atsushi , Takemura Taichiro , Kikuchi Taisei , Nakagawa Ichiro , Thomson Nicholas R. , Ohnishi Makoto , Morita Masatomo
Published: August 2022

Approximately 200 O-serogroups of

Vibrio cholerae

have already been identified; however, only 2 serogroups, O1 and O139, are strongly related to pandemic cholera. The study of non-O1 and non-O139 strains has hitherto been limited. Nevertheless, there are other clinically and epidemiologically important serogroups causing outbreaks with cholera-like disease. Here, we report a comprehensive genome analysis of the whole set of

V. cholerae

O-serogroup reference strains to provide an overview of this important bacterial pathogen. It revealed structural diversity of the O-antigen biosynthesis gene clusters located at specific loci on chromosome 1 and 16 pairs of strains with almost identical O-antigen biosynthetic gene clusters but differing in serological patterns. This might be due to the presence of O-antigen biosynthesis-related genes at secondary loci on chromosome 2.
Establishment of CD8+T cell thymic central tolerance to tissue-restricted antigen requires PD-1
Authors: May Julia F. , Kelly Rees G. , Suen Alexander Y.W. , Rayat Gina R. , Anderson Colin C. , Baldwin Troy A.
Published: August 2022

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted antigen (TRA) did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. PD-1 was induced in the thymus and was required to establish cell-intrinsic tolerance to TRA in CD8+thymocytes independently of clonal deletion. PD-1 signaling in developing thymocytes was sufficient for tolerance induction, however in some cases the absence of PD-L1-mediated signaling in the periphery resulted in broken tolerance at late time points. Finally, we showed that chronic exposure to high affinity antigen supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.

Graphical Abstract
High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny
Authors: Lieberman Nicole AP , Armstrong Thaddeus D , Chung Benjamin , Pfalmer Daniel , Hennelly Christopher M , Haynes Austin , Romeis Emily , Wang Qian-Qiu , Zhang Rui-Li , Kou Cai-Xia , Ciccarese Giulia , Conte Ivano Dal , Cusini Marco , Drago Francesco , Nakayama Shu-ichi , Lee Kenichi , Ohnishi Makoto , Konda Kelika A , Vargas Silver K , Eguiluz Maria , Caceres Carlos F , Klausner Jeffrey D , Mitja Oriol , Rompalo Anne , Mulcahy Fiona , Hook Edward W , Hoffmann Irving F , Matoga Mitch M , Zheng Heping , Yang Bin , Lopez-Medina Eduardo , Ramirez Lady G , Radolf Justin D , Hawley Kelly L , Salazar Juan C , Lukehart Sheila A , Seña Arlene C , Parr Jonathan B , Giacani Lorenzo , Greninger Alexander L
Published: August 2022

Sequencing of most Treponema pallidum (T. pallidum) genomes excludes repeat regions in tp0470 and the tp0433 gene, encoding the acidic repeat protein (arp). As a first step to understanding the evolution and function of these genes and the proteins they encode, we developed a protocol to nanopore sequence tp0470 and arp genes from 212 clinical samples collected from ten countries on six continents. Both tp0470 and arp repeat structures recapitulate the whole genome phylogeny, with subclade-specific patterns emerging. The number of tp0470 repeats is on average appears to be higher in Nichols-like clade strains than in SS14-like clade strains. Consistent with previous studies, we found that 14-repeat arp sequences predominate across both major clades, but the combination and order of repeat type varies among subclades, with many arp sequence variants limited to a single subclade. Although strains that were closely related by whole genome sequencing frequently had the same arp repeat length, this was not always the case. Structural modelling of TP0470 suggested that the eight residue repeats form an extended α-helix, predicted to be periplasmic. Modeling of the ARP revealed a C-terminal sporulation-related repeat (SPOR) domain, predicted to bind denuded peptidoglycan, with repeat regions possibly incorporated into a highly charged β- sheet. Outside of the repeats, all TP0470 and ARP amino acid sequences were identical. Together, our data, along with functional considerations, suggests that both TP0470 and ARP proteins may be involved in T. pallidum cell envelope remodeling and homeostasis, with their highly plastic repeat regions playing as-yet-undetermined roles.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic
Authors: Bonilla H , Quach TC , Tiwari A , Bonilla AE , Miglis M , Yang P , Eggert L , Sharifi H , Horomanski A , Subramanian A , Smirnoff L , Simpson N , Halawi H , Sum-Ping O , Kalinowski A , Patel Z , Shafer R , Geng L.
Published: August 2022

Background

The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well defined.

Methods

We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the ME/CFS phenotype.

Findings

The median age was 47 years, 59·0% were female; 49·3% White, 17·2% Hispanic, 14·9% Asian, and 6·7% Black. Only 12·7% required hospitalization. Seventy-two (53·5%) patients had no known comorbid conditions. Forty-five (33·9%) were significantly debilitated. The median duration of symptoms was 285·5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86·5%), post-exertional malaise (82·8%), brain fog (81·2%), unrefreshing sleep (76·7%), and lethargy (74·6%). Forty-three percent fit the criteria for ME/CFS.

Interpretations

Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

Funding

The study did not received funding.
SARS-CoV-2 Omicron subvariants Spike recognition and neutralization elicited after the third dose of mRNA vaccine
Authors: Tauzin Alexandra , Nicolas Alexandre , Ding Shilei , Benlarbi Mehdi , Medjahed Halima , Chatterjee Debashree , Dionne Katrina , Gong Shang Yu , Gendron-Lepage Gabrielle , Bo Yuxia , Perreault Josée , Goyette Guillaume , Gokool Laurie , Arlotto Pascale , Morrisseau Chantal , Tremblay Cécile , Martel-Laferrière Valérie , De Serres Gaston , Levade Inès , Kaufmann Daniel E. , Côté Marceline , Bazin Renée , Finzi Andrés
Published: August 2022

Several SARS-CoV-2 Omicron subvariants have recently emerged, becoming the dominant circulating strains in many countries. These variants contain a large number of mutations in their Spike glycoprotein, raising concerns about vaccine efficacy. In this study, we evaluate the ability of plasma from a cohort of individuals that received three doses of mRNA vaccine to recognize and neutralize these Omicron subvariant Spikes. We observed that BA.4/5 and BQ.1.1 Spikes are markedly less recognized and neutralized compared to the D614G and the other Omicron subvariant Spikes tested. Also, individuals who have been infected before or after vaccination present better humoral responses than SARS-CoV-2 naïve vaccinated individuals, thus indicating that hybrid immunity generates better humoral responses against these subvariants.
Prevalence and determinants of non-communicable diseases risk factors among reproductive-aged women of Bangladesh: Evidence from Bangladesh Demographic Health Survey 2017-2018
Authors: Chowdhury Saifur Rahman , Islam Md Nazrul , Sheekha Tasbeen Akhtar , Kader Shirmin Bintay , Hossain Ahmed
Published: August 2022

Introduction

Knowing the risk factors like hypertension, overweight/obesity, and smoking status among women of reproductive age could allow the development of an effective strategy for reducing the burden of non-noncommunicable diseases (NCD). We sought to determine the prevalence and determinants of NCD risk factors among Bangladeshi women of reproductive age.

Methods

This study utilized the Bangladesh Demographic and Health Survey (BDHS) data from 2017-2018 and analyzed 5,624 women of reproductive age. This nationally representative cross-sectional survey utilized a stratified, two-stage sample of households. Mixed-effects Poisson regression models were fitted to find the adjusted prevalence ratio for smoking, overweight and obesity, and hypertension.

Results

The average age of 5,624 participants was 31 years (SD=9.07). The prevalence of smoking, overweight/obesity, and hypertension was 9.55%, 31.57%, and 20.27%, respectively. More than one-third of the participants (34.55%) had one NCD risk factor, and 12.51% of participants had two NCD risk factors. Women between 40–49 years had more NCD risk factors than 18–29 years aged women (APR: 2.44; 95% CI: 2.22-2.68). Women with no education (APR: 1.15; 95% CI: 1.00-1.33), married (APR: 2.32; 95% CI: 1.78–3.04), and widowed/divorced (APR: 2.14; 95% CI: 1.59–2.89) were more prevalent in NCD risk factors. Individuals in the Barishal (APR: 1.44; 95% CI: 1.28–1.63) division were living with higher risk factors for NCD. Women who belonged to the richest (APR: 1.82; 95% CI: 1.60–2.07) wealth quintile were more likely to have the risk factors of NCD.

Conclusions

This study revealed that older women, currently married and widowed/divorced women, women from the wealthiest socio-economic group, and women with a lower level of education were more likely to have NCD risk factors. Furthermore, there was a significant relationship between the geographical division and NCD risk factors. To reduce the future prevalence of NCD, it is necessary to implement effective prevention and control programs that target women with a higher risk of having the disease.
Cooperative actin filament nucleation by the Arp2/3 complex and formins maintains the homeostatic cortical array in Arabidopsis epidermal cells
Authors: Xu Liyuan , Cao Lingyan , Li Jiejie , Staiger Christopher J.
Published: August 2022

Precise control over how and where actin filaments are created leads to the construction of unique cytoskeletal arrays within a common cytoplasm. Actin filament nucleators are key players in this activity and include the conserved Actin-Related Protein 2/3 (Arp2/3) complex, that creates dendritic networks of branched filaments, as well as a large family of formins that typically generate long, unbranched filaments and bundles. In some eukaryotic cells, these nucleators compete for a common pool of actin monomers and loss of one favors the activity of the other. To test whether this is a common mechanism, we combined the ability to image single filament dynamics in the homeostatic cortical actin array of living Arabidopsis (Arabidopsis thaliana) epidermal cells with genetic and/or small molecule inhibitor approaches to stably or acutely disrupt nucleator activity. We found that Arp2/3 mutants or acute CK-666 treatment markedly reduced the frequency of side-branched nucleation events as well as overall actin filament abundance. We also confirmed that plant formins contribute to side-branched filament nucleation in vivo. Surprisingly, simultaneous inhibition of both classes of nucleator increased overall actin filament abundance and enhanced the frequency ofde novonucleation events by an unknown mechanism. Collectively, our findings suggest that multiple actin nucleation mechanisms cooperate to generate and maintain the homeostatic cortical array of plant epidermal cells.
Systematic Analysis of Autophagy Identifies Atg9 Vesicles as the Origin of the Phagophore
Authors: Broadbent David , Barnaba Carlo , Schmidt Jens C.
Published: August 2022

Autophagy is a catabolic pathway required for the clearance and recycling of cytoplasmic materials. Upregulation and dysfunction of autophagy contributes to the pathology of cancer and neurogenerative diseases, respectively. To define the molecular mechanisms that control autophagic flux it is critical to quantitatively characterize the dynamic behavior of autophagy factors in living cells. Using a panel of 9 cell lines expressing HaloTagged autophagy factors from their endogenous loci, we systematically analyze the abundance, single-molecule dynamics, and autophagosome association kinetics of a wide variety of autophagy proteins involved in the initiation and maturation of the autophagosome. Our results reveal that phagophores are initiated by the accumulation of autophagy factors on mobile ATG9 vesicles and tethering of these ATG9 vesicles to donor membranes by ATG2 is a key step in phagophore maturation. In addition, we demonstrate that the overall lifetime of an autophagosome is approximately 160 seconds and the majority of phagophore initiation events fail to produce mature autophagosomes. In total our work establishes a new experimental framework to quantitatively analyze autophagy and demonstrates that ATG9 vesicles are the seeds for autophagosome formation in human cells.
Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence in collective cell migration
Authors: Marwaha Rituraj , Rawal Simran , Khuntia Purnati , Banerjee Sanak , Manoj Diya , Jaiswal Manish , Das Tamal
Published: August 2022

Collective cell migration during embryonic development, wound healing, and cancer metastasis entails the emergence of leader cells at the migration front. These cells with conspicuous lamellipodial structures provide directional guidance to the collective. Despite their physiological relevance, the mechanisms underlying the emergence of leader cells remain elusive. Here we report that in diverse model systems for wound healing, including cultured epithelial monolayer,Drosophilaembryo, and mouse embryonic skin, leader cells display a peripheral accumulation of lysosomes. This accumulation appears essential for leader cell emergence, involves lysosomal movement along microtubules, and depends on the actomyosin contractility-generated cellular forces. Peripheral lysosomes associate with inactive Rac1 molecules to remove them from the leading periphery, which increases local Rac1-activity, triggering actin polymerization and promoting lamellipodium formation. Taken together, we demonstrate that beyond their catabolic role, lysosomes act as the intracellular platform that links mechanical and biochemical signals to control the emergence of leader cells.
Phages against non-capsulatedKlebsiella pneumoniae: broader host range, slower resistance
Authors: Lourenço Marta , Osbelt Lisa , Passet Virginie , Gravey François , Strowig Till , Rodrigues Carla , Brisse Sylvain
Published: August 2022

Background

Klebsiella pneumoniae(Kp) is an ecologically generalist bacterium but also an opportunistic pathogen responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the last decades, few advances have been made in the use of virulent phages as alternative or complement to antibiotics to treat Kp infections. The efficiency of phages relies on their ability to recognize and attach to the bacterial surface structure, and in the case of Kp, capsule (K) is the main surface structure. However, Kp capsule is highly polymorphic and the majority of classically isolated phages are specific for unique K-types, limiting therapy prospects. In this study, we demonstrate the feasibility of an innovative strategy consisting in isolating phages that target capsule-deficient mutant Kp strains, and compare such phages with anti-capsulated cells phages phylogenetically and throughin vitroandin vivoexperiments.

Methods

We isolated 27 phages using 7 capsule-deficient Kp strains as hosts (anti-Kdphages), and 41 phages against 7 wild-type (wt) Kp strains (anti-K phages). We evaluated and compared phenotypically and genotypically their host range, resistance emergence and selected mutations andin-vivoactivity.

Results

In vitro, anti-Kdphages showed a broader host-range, with most phages being able to infect non-capsulated mutants of multiple sublineages and O-antigen locus types. Besides, the emergence of bacterial subpopulations non-susceptible to anti-Kdphages was slower when compared to anti-K phages and with a different range of genomic differences. One anti-Kdphage (mtp5) was shown to infect non-capsulated Kp strains belonging to 10 of the 12 known O-antigen types. Moreover, this phage was able to replicate in the gut of mice colonised with the wt (capsulated) parent strain.

Conclusions

This work demonstrates the potential value of an anti-Klebsiellaphage isolation strategy that addresses the issue of narrow host-range of anti-K phages. Anti Kd-phages may be active in infection sites where capsule expression is intermittent or repressed, or in combination with anti-K phages, which often induce loss of capsule escape mutants.
Novel genetic modules encoding high-level antibiotic-free protein expression in probiotic lactobacilli
Authors: Dey Sourik , Blanch-Asensio Marc , Kuttae Sanjana Balaji , Sankaran Shrikrishnan
Published: August 2022

Lactobacilli are ubiquitous in nature, often beneficially associated with animals as commensals and probiotics, and are extensively used in food fermentation. Due to this close-knit association, there is considerable interest to engineer them for healthcare applications in both humans and animals, for which high-performance and versatile genetic parts are greatly desired. For the first time, we describe two genetic modules inLactiplantibacillus plantarumthat achieve high-level gene expression using plasmids that can be retained without antibiotics, bacteriocins or genomic manipulations. These include (i) a promoter, PtlpA, from a phylogenetically distant bacterium,Salmonella typhimurium, that drives up to 5-fold higher level of gene expression compared to previously reported promoters and (ii) multiple toxin-antitoxin systems as a self-contained and easy-to-implement plasmid retention strategy that facilitates the engineering of tunable transient Genetically Modified Organisms. These modules and the fundamental factors underlying their functionality that are described in this work will greatly contribute to expanding the genetic programmability of lactobacilli for healthcare applications.
Starships are active eukaryotic transposable elements mobilized by a new family of tyrosine recombinases
Authors: Urquhart Andrew S , Vogan Aaron A , Gardiner Donald M , Idnurm Alexander
Published: August 2022

Transposable elements in eukaryotic organisms have historically been considered ‘selfish’, at best conferring indirect benefits to their host organisms. The Starships are a recently discovered feature in fungal genomes that are predicted to confer beneficial traits to their hosts and also have hallmarks of being transposable elements. Here, we provide experimental evidence that Starships are indeed autonomous transposons, using the model Paecilomyces variotii, and identify the HhpA ‘Captain’ tyrosine recombinase as essential for their mobilization into genomic sites with a specific target site consensus sequence. Furthermore, we identify multiple recent horizontal gene transfer of Starships, implying that they frequency jump between species. Fungal genomes have mechanisms to defend against mobile elements, which are frequently detrimental to the host. We discover that Starships are also vulnerable to repeat-induced point mutation defence, thereby having implications on the evolutionary stability of such elements.
A conserved motif suggests a common origin for a group of proteins involved in the cell division of Gram-positive bacteria
Authors: Martinez-Goikoetxea Mikel , Lupas Andrei N.
Published: August 2022

DivIVA, GpsB, FilP, and Scy are all involved in bacterial cell division. They have been reported to interact with each other, and although they have been the subject of considerable research interest, not much is known about the molecular basis for their biological activity. Although they show great variability in taxonomic occurrence, phenotypic profile, and molecular properties, we find that they nevertheless share a conserved N-terminal sequence motif, which points to a common evolutionary origin. The motif always occurs N-terminally to a coiled-coil helix that mediates dimerization. We define the motif and coiled coil jointly as a new domain, which we name DivIVA-like. In a large-scale survey of this domain in the protein sequence database, we identify a new family of proteins potentially involved in cell division, whose members, unlike all other DivIVA-like proteins, have between 2 and 8 copies of the domain in tandem. AlphaFold models indicate that the domains in these proteins assemble within a single chain, therefore not mediating dimerization.
Phospholipid tail asymmetry allows cellular adaptation to anoxic environments
Authors: Panconi Luca , Lorenz Chris D , May Robin C , Owen Dylan M , Makarova Maria
Published: August 2022

Membrane biophysical properties are critical to cell fitness and depend on unsaturated phospholipid acyl tails. These can only be produced in aerobic environments since eukaryotic desaturases require molecular oxygen. This raises the question of how cells maintain bilayer properties in anoxic environments. Here, we demonstrate the existence of an alternative pathway to regulate membrane fluidity that exploits phospholipid acyl-tail length asymmetry, replacing unsaturated species in the membrane lipidome. We show that the fission yeast, S. japonicus, which can grow in aerobic and anaerobic conditions, is capable of utilizing this strategy whereas its sister species, the well-known model organism S. pombe, cannot. The incorporation of asymmetric-tailed phospholipids might be a general adaptation to hypoxic environmental niches.

One-Sentence Summary

In anoxic environments, saturated asymmetric acyl-tailed phospholipids can replace unsaturated ones to maintain membrane physical properties.
Kinesin-1, -2 and -3 motors use family-specific mechanochemical strategies to effectively compete with dynein during bidirectional transport
Authors: Gicking Allison M. , Ma Tzu-Chen , Feng Qingzhou , Jiang Rui , Badieyan Somayesadat , Cianfrocco Michael A. , Hancock William O.
Published: August 2022

Bidirectional cargo transport in neurons requires competing activity of motors from the kinesin-1, -2 and -3 superfamilies against cytoplasmic dynein-1. Previous studies demonstrated that when kinesin-1 attached to dynein-dynactin-BicD2 (DDB) complex, the tethered motors move slowly with a slight plus-end bias, suggesting kinesin-1 overpowers DDB but DDB generates a substantial hindering load. Compared to kinesin-1, motors from the kinesin-2 and -3 families display a higher sensitivity to load in single-molecule assays and are thus predicted to be overpowered by dynein complexes in cargo transport. To test this prediction, we used a DNA scaffold to pair DDB with members of the kinesin-1, -2 and -3 families to recreate bidirectional transport in vitro, and tracked the motor pairs using two-channel TIRF microscopy. Unexpectedly, we find that when both kinesin and dynein are engaged and stepping on the microtubule, kinesin-1, -2, and -3 motors are able to effectively withstand hindering loads generated by DDB. Stochastic stepping simulations reveal that kinesin-2 and -3 motors compensate for their faster detachment rates under load with faster reattachment kinetics. The similar performance between the three kinesin transport families highlights how motor kinetics play critical roles in balancing forces between kinesin and dynein, and emphasizes the importance of motor regulation by cargo adaptors, regulatory proteins, and the microtubule track for tuning the speed and directionality of cargo transport in cells.
Structural basis for lipid and copper regulation of the ABC transporter MsbA
Authors: Lyu Jixing , Liu Chang , Zhang Tianqi , Schrecke Samantha , Elam Nicklaus P. , Hochberg Georg , Russell David , Zhao Minglei , Laganowsky Arthur
Published: August 2022

A critical step in Lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although MsbA has been extensively studied, the selectivity of MsbA-lipid interactions remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15 Å resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KLA). We report a 3.6 Å-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5’-diphosphate and vanadate, revealing an unprecedented KLA binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KLA binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis.
The sum and the parts: dynamics of multiple and individual metastases during adaptive therapy
Authors: Gallaher Jill , Strobl Maximilian , West Jeffrey , Zhang Jingsong , Gatenby Robert , Robertson-Tessi Mark , Anderson Alexander R. A.
Published: August 2022

Evolutionary therapies, such as adaptive therapy, have shown promise in delaying treatment resistance in late-stage cancers. By alternating between drug applications and drug-free vacations, competition between sensitive and resistant cells can be exploited to maximize the time to progression. However, the optimal schedule of this dosing regimen depends on the properties of the tumor, which often are not directly measurable in clinical practice. In this work, we propose that the initial cycle of adaptive therapy can be used as a tool to probe the relevant tumor properties. We present a framework for estimating individual and collective components of a metastatic system through tumor response dynamics, which uses a system of off-lattice agent-based models to represent individual metastatic lesions within independent domains, all of which are subject to the same systemic therapy. We find that the first cycle of adaptive therapy delineates several features of the computational metastatic system: larger metastases have longer cycles; a higher proportion of drug resistant cells slows the cycles; and a faster cell turnover rate speeds up drug response time and slows the regrowth time. The number of metastases does not affect cycle times, as response dynamics are dominated by the largest tumors rather than the aggregate. In addition, the heterogeneity of the system is also a guide for therapeutic approaches: generally, systems with more between-tumor (intertumor) heterogeneity had better success with continuous therapy, while systems with more within-tumor (intratumor) heterogeneity responded better to adaptive therapy. Intertumor heterogeneity was found to correlate more with dynamics from patients with high and low Gleason scores while intratumor heterogeneity was correlated with dynamics from patients with intermediate Gleason scores.
Simulation calculation and experimental study of cathodic protection potential distribution in the tank farm
Authors: Kou Jie , Ren Zhe
Published: August 2022

Purpose

The corrosion problem of the tank bottom plate is growing more and more obvious as the usage period of the tank increases. The purpose of this study is to explore the specific effects of various factors on the potential distribution of the tank bottom plate and propose reasonable cathodic protection measures for tanks through simulation and indoor tests.

Design/methodology/approach

In this paper, several aspects (such as anode conditions, soil resistivity and so on) impacting the potential distribution of the tank bottom plate are explored by means of indoor tests and MATLAB software simulations, and the related results are presented using Origin software plots.

Findings

The results show that the potential value of the tank bottom plate is positively shifted with the increase of anode well depth and distance and the decrease of output current, and the overall potential distribution uniformity is higher; the anodic well output current has the greatest influence on potential distribution; to set up regional cathodic protection in the multitank area, the anodic well should be arranged in the central position between multiple tanks. Regional cathodic protection potential distribution for multiple anodes is more uniform, but a reasonable number of anodes should be selected, usually 2–3 anodes.

Originality/value

This paper provides solid theoretical and technical support for the future establishment of cathodic protection systems in station yards, as well as the renewal and transformation of cathodic protection systems in old tanks, by investigating the influencing factors on the potential distribution of tank bottom plate and verifying them through indoor experiments.
Relationship of public farmland and timberland REITs with their private equity counterparts and selected asset classes
Authors: Baral Srijana , Mei Bin
Published: August 2022

Purpose

The purpose of this study is to examine the return sensitivity of public farmland and timberland real estate investment trusts (REITs) to private-equity farmland, timberland and real estate, long-term corporate bonds and large- and small-cap stocks. The study also examines time-dependent contributions of selected asset classes to farmland and timberland REIT volatility.

Design/methodology/approach

The authors use a multi-factor asset pricing model under a seemingly unrelated regression framework to evaluate farmland and timberland REIT returns, and a state-space model with the Kalman filter to evaluate the time-dependent contributors of farmland and timberland REIT volatility. The authors first perform orthogonalized regressions to obtain pure independent factors, and then decompose volatility into individual asset components.

Findings

Significant loadings on financial assets are found for both farmland and timberland REITs, suggesting that they are generally driven by some common state variables. Large-cap stocks are found to be the major contributor of farmland and timberland REIT volatility, despite some differing patterns over time.

Originality/value

Empirical analysis of farmland REIT is very scarce. The authors compare the risk-return characteristics of farmland and timberland REITs under a state-space framework with the Kalman filter. This study can improve the understanding of the roles of farmland and timberland REITs in a multi-asset portfolio.
Remote working in construction: assessing the affordance of digitisation
Authors: Mokhtar Azizi Zahirah , Cochrane James , Thurairajah Niraj , Mokhtar Azizi Nurul Sakina
Published: August 2022

Purpose

As remote working becomes increasingly popular, remote working could unlock new ways of working through digitisation. However, the construction sector has been slow to adopt digitisation in its processes, making digitisation difficult to assess whether this affordance may be well received and the current capabilities of digitisation to achieve this effectively. The purpose of this paper is to investigate the interest in remote working amongst construction sector personnel and to examine the factors affecting remote working through digitisation affordances.

Design/methodology/approach

Based on a case study of one of the largest contractor firms in the United Kingdom, an online questionnaire survey was used to collect responses from 125 construction professionals. Statistical package for the social sciences (SPSS) was used to do basic statistical analysis on the results.

Findings

The findings show that there is a general appetite for remote working on a flexible basis where a mix of “on-site” and “off-site” arrangement was deemed practical. This could potentially unlock significant time and cost savings as well as productivity gains. The main factors affecting remote working were the availability of interconnected systems allowing efficient communication and digital infrastructure that enable automated processes.

Research limitations/implications

The research is limited to a large contractor company and may not be appropriate for small and medium-sized companies. The findings may benefit organisations to evaluate the practical needs of ensuring effective remote working in the construction industry and unlocking efficiencies.

Originality/value

The paper adds value to understanding the affordances and constraints of digitisation for remote working from the perspective of construction professionals.