bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographic Financial Analysis of Craniosynostosis Surgery in the United States
Authors: Kalmar Christopher L. , Zapatero Zachary D. , Kosyk Mychajlo S. , Bartlett Scott P. , Taylor Jesse A.
Published: March 2022

Background:

The purpose of this study was to investigate the financial implications of demographic and socioeconomic factors upon the cost of surgical procedures for craniosynostosis.

Methods:

A retrospective cohort study was conducted of admissions for craniosynostosis surgery in the United States from 2015 through 2020 using the Pediatric Health Information System. Patient demographics, case volume, and surgical approach were analyzed in context of hospital charges.

Results:

During the study interval, 3869 patients were admitted for surgery for craniosynostosis. In multivariate regression accounting for demographic and socioeconomic factors, hospital admission charges were significantly higher in patients with longer hospital length of stay (P < 0.001), longer ICU length of stay (P < 0.001), living in an underserved area (P = 0.046), preoperative risk factors (P = 0.016), and those undergoing open procedures (P < 0.001); hospital admission charges were significantly lower in patients with White race (P = 0.020) and those treated at high-volume centers (P < 0.001). In multivariate regression, ICU length of stay was significantly higher in patients with preoperative risk factors (P < 0.001), undergoing open procedures (P < 0.001), government insurance (P = 0.018), and not treated at high-volume centers (P = 0.005). There were significant differences in admission charges (P < 0.001), charge-to-cost ratios (P < 0.001), and likelihood of being treated at high-volume craniofacial centers (P < 0.001) across geographic regions of the country.

Conclusions:

In the United States, there is significant sociodemographic variability in charges for craniosynostosis care, with increased hospital charges independently associated with non-White race, preoperative risk factors, and living in an underserved area.
Prevalence and Risk Factors for Chronic Maxillary Sinusitis After Surgery for Mid-Facial Fracture: A Cross-Sectional Study
Authors: Jiang Linli , Wu Mengsong , Li Hui , Liang Jiayu , Chen Jinlong , Liu Lei
Published: March 2022

Posttraumatic chronic maxillary sinusitis deleteriously affects the life quality of patients with recurrent episodes and related discomfort. However, few studies have been performed to investigate the prevalence of chronic maxillary sinusitis after surgery of mid-facial fracture and related risk factors. The early prevention and cure of posttraumatic chronic maxillary sinusitis have received little attention. This study aimed to investigate the prevalence of chronic maxillary sinusitis after surgery for mid-facial fracture and to identify related risk factors. The authors retrospectively collected the medical history, radiographic examination, and clinical examination of patients with mid-facial fracture (experimental group) and patients with mandibular cyst (control group) in our department between January 2015 and December 2020. A total of 298 patients (416 maxillary sinuses) in the experimental group and 172 patients (344 maxillary sinuses) in the control group were included for analyses. The prevalence of chronic maxillary sinusitis in the experimental group and control group were, respectively, 9.14% and 2.04% (P < 0.05). History of sinusitis/rhinitis (odds ratio = 63.70, P = 0.000) was an independent risk factor for posttraumatic chronic maxillary sinusitis. In conclusion, these findings showed that the prevalence of chronic maxillary sinusitis after surgery for midfacial fracture was significantly higher than that in the control group and long-term follow-up may be beneficial for these patients. Moreover, patients with a history of sinusitis/rhinitis should be informed of the increased risk.
Technical Strategies for Custom–Made Surgical Guide in Removal of Impacted Supernumerary Mandibular Premolars
Authors: Zheng Xianghuai , Lin Xi , Zhang Zhaoqiang
Published: March 2022

The aim of this study is to evaluate the technique of surgical guide in the extraction of impacted supernumerary mandibular premolars. This case series included 5 patients. Impacted supernumerary mandibular premolars were removed through a lateral window approach using the surgical guides. The mental nerve and adjacent teeth were properly protected by our custom made surgical guides. All cases successfully underwent the operation. An average of 5.01 ± 1.10 min was required to locate the supernumerary mandibular premolar. There were no complications involving injury to the mental nerve injury or adjacent teeth in any case. The application of custom–made surgical guides in the extraction of impacted supernumerary mandibular premolars showed an acceptable clinical outcome in this case series.
Physiotherapy Management of Migraine Pain: Facial Proprioceptive Neuromuscular Facilitation Technique Versus Connective Tissue Massage
Authors: Kurt Asliham , Turhan Begümhan
Published: March 2022

Objective:

Physical therapy modalities are often used by patients with migraine pain. The effectiveness of the methods in the treatment of migraine has not been clarified yet. This prospective study was planned to investigate whether facial proprioceptive neuromuscular facilitation is superior to connective tissue massage in the treatment of migraine pain.

Methods:

The study was conducted on 40 female patients with a neurologist-confirmed diagnosis of chronic migraine with non-aura, and who were aged between 18 and 65. They were randomly divided into 2 groups. Facial proprioceptive neuromuscular facilitation techniques were applied to the patients in the study group (Group 1), and connective tissue massage was applied to the patients in the control group (Group 2). The interventions were performed 3 times a week for approximately 20 minutes. Pain and pressure pain threshold scores were recorded on the first day of treatment before starting the session and were reassessed immediately after the end of the 18 treatment (6 weeks) sessions.

Results:

Pretreatment and posttreatment results were similar in both groups in terms of pain scores and pressure pain threshold values (P > 0.05). Both groups improved in pain-related outcomes (P < 0.05).

Conclusions:

Our results suggest that facial proprioceptive neuromuscular facilitation was no more effective than connective tissue massage for treating migraine for the sample size used in the present study. Both methods can be used in the treatment of migraine pain.
The Feasibility of Cross-Linguistic Speech Evaluation in the Care of International Cleft Palate Patients
Authors: Stoehr Jenna R. , Park Eugene , Reddy Narainsai K. , Rychlik Karen , Raj Bharat , Gosain Arun K.
Published: March 2022

Many patients with cleft palate in developing countries never receive postoperative speech assessment or therapy. The use of audiovisual recordings could improve access to post-repair speech care. The present study evaluated whether English-speaking speech-language pathologists (SLPs) could assess cleft palate patients speaking an unfamiliar language (Tamil) using recorded media. Recordings obtained from Tamil-speaking participants were rated by 1 Tamil-speaking SLP and 3 English-speaking SLPs. Ratings were analyzed for inter-rater reliability and scored for percent correct. Accuracy of the English SLPs was compared with independent t tests and Analysis of Variance. Sixteen participants (mean age 14.5 years, standard deviation [SD] 7.4 years; mean age of surgery of 2.7 years, SD 3.7 years; time since surgery: 10.8 years, SD 5.7 years) were evaluated. Across the 4 SLPs, 5 speech elements were found to have moderate agreement, and the mean kappa was 0.145 (slight agreement). Amongst the English-speaking SLPs, 10 speech elements were found to have substantial or moderate agreement, and the mean kappa was 0.333 (fair agreement). Speech measures with the highest inter-rater reliability were hypernasality and consonant production errors. The average percent correct of the English SLPs was 60.7% (SD 20.2%). English SLPs were more accurate if the participant was female, under eighteen, bilingual, or had speech therapy. The results demonstrate that English SLPs without training in a specific language (Tamil) have limited potential to assess speech elements accurately. This research could guide training interventions to augment the ability of SLPs to conduct cross-linguistic evaluations and improve international cleft care by global health teams.
Intraoperative Redosing of Surgical Antibiotic Prophylaxis in Addition to Preoperative Prophylaxis Versus Single-dose Prophylaxis for the Prevention of Surgical Site Infection
Authors: Wolfhagen Niels , Boldingh Quirine J. J. , de Lange Mats , Boermeester Marja A. , de Jonge Stijn W.
Published: March 2022

Objective:

The aim of this study was to determine the effect of preoperative surgical antibiotic prophylaxis (SAP) with additional intraoperative redosing compared to single-dose preoperative surgical antibiotic prophylaxis on the incidence of surgical site infections (SSI).

Summary Background Data:

Preoperative SAP is standard care for the prevention of SSI. During long surgical procedures, additional intraoperative redosing of SAP is advised, but there is great variability in redosing strategies and compliance rates.

Methods:

We performed a systematic search of MEDLINE (PubMed), Embase, CINAHL and CENTRAL on June 25th, 2021 according to PROSPERO registration CRD42021229035. We included studies that compared the effect of preoperative SAP with additional intraoperative redosing to single dose preoperative SAP (no redosing) on SSI incidence in patients undergoing any type of surgery. Two researchers performed data appraisal and extraction of summary data independently. Meta-analyses were stratified per study type. We used a generic inverse variance random-effects model to estimate a pooled odds ratio with corresponding 95% confidence intervals (CIs).

Results:

We included 2 randomized controlled trials (RCT) and 8 cohort studies comprising of 9470 patients. Pooled odds ratios for SSI in patients receiving intraoperative redosing compared to those without redosing were 0.47 (95% CI: 0.19–1.16. I
2 = 36%) for RCTs and 0.55 (95% CI: 0.38–0.79, I
2 = 56%) for observational cohorts. There was considerable clinical heterogeneity among antibiotics used and redosing protocols. GRADE-assessment showed overall low certainty of evidence.

Conclusion:

Intraoperative redosing of SAP may reduce incidence of SSI compared to a single dose preoperative SAP in any type of surgery, based on studies with considerable heterogeneity of antibiotic regimens and redosing protocols.
Assessment and nonpharmacological management for patients with cancer anorexia–cachexia syndrome: a best practice implementation project
Authors: Zhang Lanfang , Zhou Chunlan , Wu Yanni , Du Dong , He Ling , He Lian , Xie Guozhu , Wang Li , Chen Peijuan
Published: March 2022

Introduction and aims:

Cancer anorexia-cachexia syndrome (CACS) is a common multifactorial syndrome, which affects up to 80% patients with advanced cancer. At present, evidence to support the benefit of pharmacological intervention in the management of CACS is limited. Patients would benefit from standard procedures for early assessment and identification of cancer anorexia-cachexia, and using nonpharmacological strategies to manage patients with CACS. This best practice implementation project aimed to implement an evidence-based practice in assessing and managing patients with CACS, thereby improving the compliance of clinical practice with the best evidence and the quality of life of patients with CACS.

Methods:

This was an evidence-based audit and feedback project that used a three-phase approach at a public hospital in China. Phase 1 included the development of seven evidence-based audit criteria and carrying out a baseline audit on 30 patients using the JBI's Practical Application of Clinical Evidence System in the Department of Radiation Oncology of Nanfang Hospital. Phase 2 utilized the Getting Research into Practice component of the Practical Application of Clinical Evidence System to identify barriers to compliance with best practice principles and developed strategies and resources to improve compliance. Phase 3 involved conducting a follow-up audit using the same sample size and audit criteria to assess the results of interventions implemented to improve practice and identify issues that would be addressed in future audit.

Results:

The compliance rates of audit criteria 1, 2 and 6 were 100% at both baseline and follow-up audit. After the application of evidence, the compliance rate increased from 0 to 100% for audit criterion 3, from 0 to 76.6% for audit criterion 4, from 23 to 70% for audit criterion 5, and from 0 to 40% for audit criterion 5.

Conclusion:

The best evidence for the assessment and nonpharmacological management of cancer patients with CACS can improve clinical practice, the quality of clinical nursing, and patient satisfaction. The application of electronic informatization promotes the implementation and maintenance of best practice.
Improving the diagnosis of endometrial hyperplasia using computerized analysis and immunohistochemical biomarkers
Authors: Sanderson Peter A , Esnal-Zufiaurre Arantza , Arends Mark J , Herrington C Simon , Collins Frances , Williams Alistair RW , Saunders Philippa TK
Published: March 2022

Endometrial hyperplasia (EH) is a precursor lesion to endometrial carcinoma (EC). Risks for EC include genetic, hormonal and metabolic factors most notably those associated with obesity: rates are rising and there is concern that cases in pre-menopausal women may remain undetected. Making an accurate distinction between benign and pre-malignant disease is both a challenge for the pathologist and important to the gynaecologist who wants to deliver the most appropriate care to meet the needs of the patient. Premalignant change may be recognised by histological changes of endometrial hyperplasia (which may occur with or without atypia) and endometrial intraepithelial neoplasia (EIN).

In this study we created a tissue resource of EH samples diagnosed between 2004 and 2009 (n=125) and used this to address key questions: 1. Are the EIN/WHO2014 diagnostic criteria able to consistently identify premalignant endometrium? 2. Can computer aided image analysis inform identification of EIN? 3. Can we improve diagnosis by incorporating analysis of protein expression using immunohistochemistry.

Our findings confirmed the inclusion of EIN in diagnostic criteria resulted in a better agreement between expert pathologists compared with the previous WHO94 criteria used for the original diagnosis of our sample set. A computer model based on assessment of stromal:epithelial ratio appeared most accurate in classification of areas of tissue without EIN. From an extensive panel of putative endometrial protein tissue biomarkers a score based on assessment of HAND2, PTEN and PAX2 was able to identify four clusters one of which appeared to be more likely to be benign.

In summary, our study has highlighted new opportunities to improve diagnosis of pre-malignant disease in endometrium and provide a platform for further research on this important topic.

Highlights

Blinded re-analysis of n=125 samples previously classified as endometrial hyperplasia found improved intra-observer agreement (67%) using EIN/WHO2014 compared with standard WHO1994 criteria (52%)

Computerised analysis of endometrial hyperplasia tissue architecture showed promise as a tool to assist pathologists in diagnosis of difficult to classify cases

A diagnosis of endometrial intraepithelial neoplasia (EIN) using the WHO2014 criteria more accurately predicted risk of endometrial cancer than WHO1994 system.

EIN samples exhibited altered expression of ARID1A (negative glands) and HAND2 (reduced or absent from stroma)

Unsupervised hierarchical cluster analysis based on immunostaining for PTEN, PAX2 and HAND2 identified 4 subtypes one of which segregated with benign disease.

These results provide a framework for improved classification of pre-malignant lesions in endometrium that may inform personalized care pathways
Adequacy of Nasal Self-Swabbing for SARS-CoV-2 Testing in Children
Authors: Waggoner Jesse J. , Vos Miriam B. , Tyburski Erika A. , Nguyen Phuong-Vi , Ingersoll Jessica M. , Miller Candace , Sullivan Julie , Griffiths Mark , Stone Cheryl , Benoit Macarthur , Benedit Laura , Seitter Brooke , Jerris Robert , Levy Joshua M. , Kraft Colleen S. , Farmer Sarah , Foster Amanda , Wood Anna , Westbrook Adrianna L. , Morris Claudia R. , Sathian Usha N. , Heetderks William , Li Li , Roth Kristian , Barcus Mary , Stenzel Timothy , Martin Greg S. , Lam Wilbur A.
Published: March 2022

Background

The goal of this study was to characterize the ability of school-aged children to self-collect adequate anterior nares (AN) swabs for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing.

Methods

From July to August 2021, 287 children, age 4-14 years-old, were prospectively enrolled in the Atlanta area. Symptomatic (n=197) and asymptomatic (n=90) children watched a short instructional video before providing a self-collected AN specimen. Health care workers (HCWs) then collected a second specimen, and useability was assessed by the child and HCW. Swabs were tested side-by-side for SARS-CoV-2. RNase P RNA detection was investigated as a measure of specimen adequacy.

Results

Among symptomatic children, 87/196 (44.4%) tested positive for SARS-CoV-2 by both self- and HCW-swab. Two children each were positive by self- or HCW-swab; one child had an invalid HCW-swab. Compared to HCW-swabs, self-collected swabs had 97.8% and 98.1% positive and negative percent agreements, respectively, and SARS-CoV-2 Ct values did not differ significantly between groups. Participants ≤8 years-old were less likely than those >8 to be rated as correctly completing self-collection, but SARS-CoV-2 detection did not differ. Based on RNase P RNA detection, 270/287 children (94.1%) provided adequate self-swabs versus 277/287 (96.5%) HCW-swabs (p=0.24) with no difference when stratified by age.

Conclusions

Children, aged 4-14 years-old, can provide adequate AN specimens for SARS-CoV-2 detection when presented with age-appropriate instructional material, consisting of a video and a handout, at a single timepoint. These data support the use of self-collected AN swabs among school-age children for SARS-CoV-2 testing.
The Sequence Effect Worsens over Time in Parkinson’s disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation
Authors: Kehnemouyi Yasmine , Petrucci Matthew , Wilkins Kevin , Bronte-Stewart Helen
Published: March 2022

Background

The sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open and closed-loop deep brain stimulation in people with PD.

Objective

To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) and closed-loop deep brain stimulation (DBS).

Methods

Twenty-one people with PD with bilateral STN DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS.

Results

The sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and even further improvement on closed-loop DBS.

Conclusions

Sequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open and closed-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and that closed-loop DBS may offer added improvement.
Genetic context effects can override canonicalcisregulatory elements inEscherichia coli
Authors: Scholz Scott A. , Lindeboom Chase D. , Freddolino Peter L.
Published: March 2022

Recent experiments have shown that in addition to control bycisregulatory elements, the local chromosomal context of a gene also has a profound impact on its transcription. Although this chromosome-position dependent expression variation has been empirically mapped at high-resolution, the underlying causes of the variation have not been elucidated. Here, we demonstrate that 1 kb of flanking, non-coding synthetic sequences with a low frequency of guanosine and cytosine (GC) can dramatically reduce reporter expression compared to neutral and high GC-content flanks inE. coli. Despite the strong reduction in the maximal expression level from the fully-induced reporter, low GC synthetic flanks do not affect the time required to reach the maximal expression level after induction. Expression of the reporter construct is also affected by proximity to highly expressed ribosomal RNA operons depending on the relative orientation of transcription despite being insulated by strong transcriptional terminators, in a manner consistent with supercoiling competition. Overall, we demonstrate key determinants of transcriptional propensity that appear to act as tunable modulators of transcription, independent of regulatory sequences such as the promoter. These findings provide insight into the regulation of naturally occurring genes and specific rules for optimizing control of synthetic biology constructs.
Sustained high prevalence of COVID-19 deaths from a systematic post-mortem study in Lusaka, Zambia: one year later
Authors: Gill Christopher J , Mwananyanda Lawrence , MacLeod William , Kwenda Geoffrey , Pieciak Rachel , Etter Lauren E , Bridges Daniel , Chikot Chilufya , Chirwa Sarah , Chimoga Charles , Forman Leah , Katowa Benjamin , Lapidot Rotem , Lungu James , Matoba Japhet , Mwinga Gift , Mubemba Benjamin , Mupila Zachariah , Muleya Walter , Mwenda Mulenga , Ngoma Benard , Nakazwe Ruth , Nzara Diana , Pawlak Natalie , Pemba Lilian , Saasa Ngonda , Simulundu Edgar , Yankonde Baron , Thea Donald M
Published: March 2022

Background.
Sparse data documenting the impact of COVID-19 in Africa has fostered the belief that COVID-19 skipped Africa. We previously published results from a systematic postmortem surveillance at a busy inner-city morgue in Lusaka, Zambia. Between June-October 2021, we detected COVID-19 in 15-19% of all deaths and concentrated in community settings where testing for COVID-19 was absent. Yet these conclusions rested on a small cohort of 70 COVID-19+ individuals. Subsequently, we conducted a longer and far larger follow-on survey using the same methodology.
Methods
We obtained a nasopharyngeal swab from each enrolled decedent and tested these using reverse transcriptase quantitative PCR (RT-qPCR). A subset of samples with a PCR cycle threshold <30 underwent genotyping to identify viral variants. We weighted our results to adjust for enrolment ratios and stratified them by setting (facility vs. community), time of year, age, and location.
Results
From 1,118 enrolled decedents, COVID-19 was detected among 32.0% (358/1,116). We observed three waves of transmission that peaked in July 2020, January 2021, and ~June 2021 (end of surveillance). These were dominated by viral variants AE.1, Beta, and Delta, respectively. During peak transmission, COVID-19 was detected in ~90% of all deaths. COVID-19 deaths clustered in Lusakas poorest city wards. Roughly four COVID-19 deaths occurred in the community for every facility death. Antemortem testing occurred for 52.6% (302/574) of facility deaths but only 1.8% (10/544) of community deaths; overall, only ~10% of COVID-19+ deaths were identified in life.
Conclusions
COVID-19 had a devastating impact in Lusaka. COVID-19+ deaths occurred in all age groups and was the leading cause of death during peak transmission periods. Testing was rarely done for the vast majority of COVID-19 deaths that occurred in the community, yielding a substantial undercount. If typical, these findings contradict assertions that Africa was spared from the COVID-19 pandemic.
A systematic review and meta-analysis of Long COVID symptoms
Authors: Natarajan Arun , Shetty Ashish , Delanerolle Gayathri , Zeng Yutian , Zhang Yingzhe , Raymont Vanessa , Rathod Shanaya , Halabi Sam , Elliot Kathryn , Phiri Peter , Shi Jian Qing
Published: March 2022

Background

Ongoing symptoms or the development of new symptoms following a SARS-CoV-2 diagnosis has caused a complex clinical problem known as “:Long COVID”: (LC). This has introduced further pressure on global healthcare systems as there appears to be a need for ongoing clinical management of these patients. LC personifies heterogeneous symptoms at varying frequencies. The most complex symptoms appear to be driven by the neurology and neuropsychiatry spheres.

Methods

A systematic protocol was developed, peer reviewed and published in PROSPERO. The systematic review included publications from the 1st of December 2019-30th June 2021 published in English. Multiple electronic databases were used. The dataset has been analysed using a random-effects model and a subgroup analysis based on geographical location. Prevalence and 95% confidence intervals (CIs) were established based on the data identified.

Results

Of the 302 studies, 49 met the inclusion criteria, although 36 studies were included in the meta-analysis. The 36 studies had a collective sample size of 11598 LC patients. 18 of the 36 studies were designed as cohorts and the remainder were cross-sectional. Symptoms of mental health, gastrointestinal, cardiopulmonary, neurological, and pain were reported.

Conclusions

The quality that differentiates this meta-analysis is that they are cohort and cross-sectional studies with follow-up. It is evident that there is limited knowledge available of LC and current clinical management strategies may be suboptimal as a result. Clinical practice improvements will require more comprehensive clinical research, enabling effective evidence-based approaches to better support patients.

Funding

None
Analyses of Mutational Patterns Induced by Formaldehyde and Acetaldehyde Reveal Similarity to a Common Mutational Signature
Authors: Thapa Mahanish J. , Fabros Reena M. , Alasmar Salma , Chan Kin
Published: March 2022

Formaldehyde (CH2O) and acetaldehyde (C2H4O) are reactive small molecules produced endogenously in cells as well as being environmental contaminants. Both of these small aldehydes are classified as human carcinogens, since they are known to damage DNA and exposure is linked to cancer incidence. However, the mutagenic properties of formaldehyde and acetaldehyde remain incompletely understood, at least in part because they are relatively weak mutagens. Here, we use a highly sensitive yeast genetic reporter system featuring controlled generation of long single-stranded DNA regions to show that both small aldehydes induced mutational patterns characterized by predominantly C/G → A/T, C/G → T/A, and T/A → C/G substitutions, each in similar proportions. We observed an excess of C/G → A/T transversions when compared to mock-treated controls. Many of these C/G → A/T transversions occurred at TC/GA motifs. Interestingly, the formaldehyde mutational pattern resembles single base substitution (SBS) signature 40 from the Catalog of Somatic Mutations in Cancer (COSMIC). SBS40 is a mutational signature of unknown etiology. We also noted that acetaldehyde treatment caused an excess of deletion events longer than four bases while formaldehyde did not. This latter result could be another distinguishing feature between the mutational patterns of these simple aldehydes. These findings shed new light on the characteristics of two important, commonly occurring mutagens.
Type two secretion systems secretins are necessary for exopolymeric slime secretion in cyanobacteria and myxobacteria
Authors: Zuckerman David M. , Man To So Jeffery , Hoiczyk Egbert
Published: March 2022

While protein translocation in Gram-negative bacteria is well understood, our knowledge about the translocation of other high-molecular-weight substances is limited. Nozzle-like structures that secrete exopolymeric substances during gliding motility have previously been observed in the outer membranes of cyanobacteria and myxobacteria. Here, we show that these nozzles are composed of the secretins PilQ/GspD, the outer membrane component of the type II and III secretion systems, the type IV pilus apparatus, and filamentous phage extrusion machinery. Our results show for the first time that secretins may be used for secretion of non-proteinaceous polymers in some bacteria, considerably expanding the repertoire of substrates of these multifunctional outer membrane gates. Moreover, we show that gspD is an essential gene in Myxococcus xanthus, which, when depleted, renders this bacterium defective in slime secretion and gliding motility.

Significance

Many bacteria exhibit gliding motility, movement across surfaces. This motility has been correlated with the deposit of slime trails in their wake. To date, the mechanism of slime secretion has not been understood, and no cell envelope-structures have been identified that are involved in slime secretion during gliding motility. Here, we show that cyanobacteria and myxobacteria use the secretins PilQ/GspD, the outer membrane channels of the T2SS, for slime secretion, which demonstrates a novel cargo transport capacity of these multifunctional outer membrane gates.
Insights into β-manno-oligosaccharide uptake and metabolism inBifidobacterium adolescentisDSMZ 20083 from whole-genome microarray analysis
Authors: Rose Mary Priyanka , Monica P , Kapoor Mukesh
Published: March 2022

Aims

To determine the ability of adult-associatedB. adolescentisDSMZ 20083 to utilize dietary β-manno-oligosaccharides and understand the underlying molecular mechanism.

Methods and Results

In-vitrofermentation and TLC were used to determine the ability ofB. adolescentisDSMZ 20083 to utilize β-manno-oligosaccharides from guar gum, locust bean gum, konjac and copra meal. Further, Whole-genome transcriptome analysis, q-RT-PCR and molecular docking were employed to reconstruct copra meal β-manno-oligosaccharides (CM-β-MOS) utilization pathway inB. adolescentisDSMZ 20083.

B. adolescentisDSMZ 20083 grew appreciably (A600nmup to 0.8) on all tested β-manno-oligosaccharides but maximally on CM-β-MOS. Transcriptome analysis revealed differential up-regulation of three distinct gene clusters encoding, ABC transporter cassette (ESBP’s and permeases), MFS transporter, GH1 β-glucosidase and, GH32 β-fructofuranosidases. ABC and MFS possibly transported majorly DP≥2 and DP≥3 CM-β-MOS, respectively. Sugar absorption and utilization pathways; ABC transport system, pyruvate metabolism, glycolysis/gluconeogenesis, pentose, and glucouronate inter-conversions were also up-regulated.

Conclusions

B. adolescentisDSMZ 20083 possibly utilizes ABC & MFS transporters to internalise and GH1 β-glucosidase, and GH32 β-fructofuranosidase to deconstruct CM-β-MOS.

Significance and Impact of the Study

First study reporting possible molecular determinants used byB. adolescentisDSMZ 20083 to utilize β-manno-oligosaccharides and thus, can prove resourceful in precision microbiome modulation.
Origin and persistence of polymorphism in loci targeted by disassortative preference: a general model
Authors: Coron Camille , Costa Manon , Leman Hélène , Llaurens Violaine , Smadi Charline
Published: March 2022

The emergence and persistence of polymorphism within populations generally requires specific selective regimes. Here, we develop an unifying theoretical framework to explore how disassortative mating can generate and maintain polymorphism at the targeted loci. To this aim, we model the dynamics of alleles at a single locus A in a population of haploid individuals, where reproductive success depends on the combination of alleles carried by the parents at locus A. Our theoretical study of the model confirms that the conditions for the persistence of a given level of allelic polymorphism depend on the relative reproductive advantages among pairs of individuals. Interestingly, equilibria with unbalanced allelic frequencies were shown to emerge from successive introduction of mutants.We then investigate the role of the function linking allelic divergence to reproductive advantage on the evolutionary fate of alleles within population. Our results highlight the significance of the shape of this function on both the number of alleles maintained and their level of genetic divergence. Large number of alleles are maintained with substantial turn-over among alleles when disassortative advantage slowly increases when allelic differentiation becomes large. In contrast, few highly differentiated alleles are predicted to be maintained when genetic differentiation has a strong effect on disassortative advantage. These opposite effects predicted by our model shed light on the levels of allelic differentiation and polymorphism empirically observed in loci targeted by disassortative mate choice.
On optimal temozolomide scheduling for slowly growing gliomas
Authors: Segura-Collar Berta , Jiménez-Sánchez Juan , Gargini Ricardo , Dragoj Miodrag , Sepúlveda Juan M. , Pešić Milica , Sánchez-Gómez Pilar , Pérez-García Víctor M.
Published: March 2022

Background

Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma, and is commonly used in low-grade gliomas. In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes.

Methods

Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR wt or EGFR vIII in primary progenitors from p16/p19 ko mice and grown in vitro and in vivo in orthotopic allografts, and human glioblastoma U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study.

Results

Slow growth ‘virtual’ murine gliomas benefited from increasing TMZ dose separation in silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly-growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically-driven changes in tumor phenotype, which could explain the reduction in glioma growth speed. In-silico trials provided support for methods of implementation in human patients.

Conclusions

In-silico simulations, and in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in gliomas.

IMPORTANCE OF THE STUDY

In-vivo evidence is provided of improvements in survival, resistance, and toxicity from TMZ schemes with long rest periods between doses in slowly-growing GBM mouse models. The results match hypotheses generated in silico using a mathematical model incorporating the main biological features and fed with real patient data. An epigenetically-driven change in tumor phenotype was also revealed experimentally, which could explain the reduction in glioma growth speed under the ‘long cycle’ scheme. To determine the extent to which our results hold for human patients, large sets of simulations were performed on virtual patients. These in-silico trials suggest different ways to bring the benefits observed in experimental models into clinical practice.
A chemical molecule promotes Trop2+ biliary duct organoids differentiation into insulin-secreting cells
Authors: Liu Miao , Yu Wen , Wang Yannan , Yan Bingru , Shang Jie , Zhang Congyi , Wu Huan , Tai Sheng , Jin Liang , Teng Chun-Bo
Published: March 2022

Cell replacement therapy is a hopeful strategy for diabetes treatment, whereas lack of pancreas donors leads this strategy to a dilemma. Here, we demonstrate that Trop2 is a useful marker to enrich the progenitors with a long-term organoid formation capability from extrahepatic bile ducts in both mouse and human. Based on BMP7 initiation, the Trop2-positive mouse extrahepatic bile duct organoids (mBDOs) could be induced to produce 8.49 ± 0.45% of insulin-secreting cells. We further screened out a chemical small molecule TLY142, which significantly increased the proportion of insulin-secreting cells to 19.9 ± 0.62% and 25.50 ± 4.82% in induced mouse and human extrahepatic bile duct organoids (hBDOs) in vitro, and transplantation of these differentiated organoids into STZ-induced diabetic nude mice remarkably improved their blood glucose and enhanced glucose sensitivity. This study provides a novel strategy that using small molecules promotes biliary duct organoids differentiation into β cells to cure diabetes.

Graphic abstract
Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans
Authors: McNally Karen Perry , Danlasky Brennan , Barroso Consuelo , Gong Ting , Li Wenzhe , Martinez-Perez Enrique , McNally Francis J.
Published: March 2022

Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by analyzing mutants that lack cohesion between chromosomes. Both a spo-11, rec-8, coh-3, coh-4 quadruple mutant and a spo-11, rec-8 double mutant entered M phase with single chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on single chromatids of the double mutant was sufficient to recruit haspin- dependent Aurora B kinase, which regulated the localization of the spindle-assembly factors CLASP-2 and kinesin-13 to mediate bipolar spindle assembly in the apparent absence of chromosomal bipolarity. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion.
An integrated cell atlas of the human lung in health and disease
Authors: Sikkema L , Strobl D , Zappia L , Madissoon E , Markov NS , Zaragosi L , Ansari M , Arguel M , Apperloo L , Bécavin C , Berg M , Chichelnitskiy E , Chung M , Collin A , Gay ACA , Hooshiar Kashani B , Jain M , Kapellos T , Kole TM , Mayr C , von Papen M , Peter L , Ramírez-Suástegui C , Schniering J , Taylor C , Walzthoeni T , Xu C , Bui LT , de Donno C , Dony L , Guo M , Gutierrez AJ , Heumos L , Huang N , Ibarra I , Jackson N , Kadur Lakshminarasimha Murthy P , Lotfollahi M , Tabib T , Talavera-Lopez C , Travaglini K , Wilbrey-Clark A , Worlock KB , Yoshida M ,   Lung Biological Network Consortium, Desai T , Eickelberg O , Falk C , Kaminski N , Krasnow M , Lafyatis R , Nikolíc M , Powell J , Rajagopal J , Rozenblatt-Rosen O , Seibold MA , Sheppard D , Shepherd D , Teichmann SA , Tsankov A , Whitsett J , Xu Y , Banovich NE , Barbry P , Duong TE , Meyer KB , Kropski JA , Pe’er D , Schiller HB , Tata PR , Schultze JL , Misharin AV , Nawijn MC , Luecken MD , Theis F
Published: March 2022

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.
Actin-dependent recruitment of AGO2 to the zonula adherens
Authors: Bridges Mary Catherine , Nair-Menon Joyce , Risner Alyssa , Jimenez Douglas W. , Daulagala Amanda C. , Kingsley Christina , Davis Madison E. , Kourtidis Antonis
Published: March 2022

Adherens junctions are cadherin-based structures critical for cellular architecture. E-cadherin junctions in mature epithelial cell monolayers tether to an apical actomyosin ring to form the zonula adherens (ZA). We have previously shown that the adherens junction protein PLEKHA7 associates with and regulates the function of the core RNA interference (RNAi) component AGO2 specifically at the ZA. However, the mechanism mediating Ago2 recruitment to the ZA remained unexplored. Here, we reveal that this ZA-specific recruitment of AGO2 depends on both the structural and tensile integrity of the actomyosin cytoskeleton. We found that depletion of not only PLEKHA7, but also either of three PLEKHA7-interacting, LIM-domain family proteins, namely LMO7, LIMCH1, and PDLIM1, results in disruption of actomyosin organization and tension, as well as disruption of AGO2 junctional localization and of its miRNA-binding ability. We also show that AGO2 binds Myosin IIB and that PLEKHA7, LMO7, LIMCH1, and PDLIM1 all disrupt interaction of AGO2 with Myosin IIB at the ZA. These results demonstrate that recruitment of Ago2 to the ZA is sensitive to actomyosin perturbations, introducing the concept of a mechanosensitive RNAi machinery, with potential implications in tissue remodeling and in disease.

Recruitment and miRNA-binding activity of the key RNA interference (RNAi) component AGO2 to epithelial zonula adherens depends on apical actomyosin integrity and tension, revealing the existence of a mechanosensitive RNAi machinery at the zonula adherens.

Significance Statement

Previous work has shown that PLEKHA7 recruits core RNAi components, including AGO2, to regulate tumor-suppressing miRNAs specifically at the zonula adherens (ZA), through an unknown mechanism.

Here, the authors show that three LIM domain-containing proteins, LMO7, LIMCH1, and PDLIM1, are also responsible for AGO2’s recruitment and miRNA activity at the ZA and that all four PLEKHA7, LMO7, LIMCH1, PDLIM1 mediate AGO2 recruitment to the ZA not due to their protein-protein interactions, but through stabilizing actomyosin structure and tension.

These findings introduce a mechanosensitive RNAi machinery responsive to actomyosin perturbations, with potentially broad implications in regulation of cellular plasticity.
Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase
Authors: Aljahdali Anfal S. , Musayev Faik N. , Burgner John W. , Ghatge Mohini S. , Shekar Vibha , Zhang Yan , Omar Abdelsattar M. , Safo Martin K.
Published: March 2022

Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease.
Predicting the corrosion properties of cast and hot isostatic pressed CoCrMo/W alloys in seawater by machine learning
Authors: Jiang Xue , Yan Yu , Su Yanjing
Published: March 2022

Purpose

Cobalt-based alloys exhibit a unique combination of wear resistance, strength and corrosion resistance. Localized corrosion of such alloys in seawater system can be several orders of magnitude faster than general corrosion, and direct experimental evidence of the local activation process is still lacking, which makes the accurate prediction for properties difficult, especially for long-term corrosion. The purpose of this study is revealing the relationship between multiple environments and corrosion properties to predict the corrosion of cobalt-based alloys.

Design/methodology/approach

A data-driven method for the prediction of the corrosion behavior of cast and hot isostatic-pressed CoCrMo/W alloys in seawater is proposed. The gradient boosting regression models calculate mean relative errors (MREs) of 0.160 and 0.435 by evaluating a hold-out set for breakdown potential (Eb) and maximum current density (imax), respectively, considering various compositions, synthesis methods and corrosion environments.

Findings

The models can be used to estimate the “unseen” cobalt-based alloy after immersion in 3.5 Wt.% NaCl solution for one, two, four and eight months to obtain high precision with MREs of 7.8% and 9.8% for Eb and imax, respectively.

Originality/value

Machine learning method provides novel and promising insights for the prediction of localized corrosion properties.