bluuebunny/crossref_metadata_2025 huggingface dataset:
Next-Generation Sequencing Reveals a New Class of Melanocytic Neoplasms With Hybrid Genomic Features of PEM Including Protein Kinase R 1 Alpha Gene Inactivation and Spitz Tumor–Defining Protein Kinase Fusions
Authors: Zhao Jeffrey , Lampley Nathaniel , Benton Sarah , Olivares Shantel , Zhang Bin , Roth Andrew , Boutko Anastasiya , Zembowicz Artur , Gerami Pedram
Published: May 2022

Background:

Pigmented epithelioid melanocytoma (PEM) is a subtype of melanocytic tumor with frequent involvement of the sentinel lymph node but rare distant metastasis. Rendering a diagnosis and prognosis based on histology can be challenging. Recent genomic studies identified 2 molecular variants of PEM. One variant is characterized by the activation of the mitogen-activated protein kinase pathway and inactivation of the PRKAR1a gene. The other is associated with genomic fusions involving the protein kinase C (PRKC) gene family.

Objective:

We investigated the molecular and clinicopathologic features of previously unreported PEM cases to improve tumor classification and report new classes of PEM.

Methods:

Next-generation sequencing and histomorphologic assessment was performed on 13 PEM cases.

Results:

We identified 2 novel PEM classes. Three cases harbored PRKAR1a inactivation and genomic fusions (ALK, NTRK, and MAP3K8). These tumors had overlapping histologic features with pigmented Spitz neoplasms. Three cases had genomic fusions involving PRKCB. These cases had overlapping features with PRKCA fusions but, in 2 cases, had a notable spindle cell component.

Limitations:

The overall sample size and amount of clinical follow-up is limited, leaving some uncertainty regarding the expected clinical course of these novel cases.

Conclusions:

PRKAR1a-inactivated/Spitz fusion–associated PEMs and PRKCB fusion–associated PEMs represent 2 new molecular classes of PEM.
PREDICTIVE FACTORS ASSOCIATED WITH ANATOMICAL AND FUNCTIONAL OUTCOMES AFTER PANRETINAL PHOTOCOAGULATION IN PEOPLE WITH PROLIFERATIVE DIABETIC RETINOPATHY
Authors: Perais Jennifer A. , McCullough Philip G. , McLaughlin Grainne A. , Pritchard Edward W. J. , Reid Gerard A. , Mohite Ajay A. , Virgili Gianni , Lois Noemi
Published: May 2022

Purpose:

To determine effects of baseline characteristics and laser type performed on outcomes in people with proliferative diabetic retinopathy (PDR) undergoing panretinal photocoagulation (PRP).

Methods:

Medical records of all consecutive patients with PDR naïve to PRP, identified using an electronic database, evaluated at the Macula Clinic, Belfast Health and Social Care Trust, receiving their first PRP between January 1, 2016, and June 30, 2017, and followed for a minimum of 6 months after stabilization of PDR, were retrospectively reviewed. Outcomes included time to stabilization after PRP, progression of PDR, and mean change in the best-corrected visual acuity from baseline to the last follow-up. Cox regression was used to estimate hazard ratios (HRs) for the effect of baseline characteristics and type of laser on outcomes after treatment.

Results:

One hundred and fourteen patients (135 eyes) with a mean age of 56.9 (SD: 12.9) years were included, 67% males. People receiving pattern or mixed laser had a statistically significantly delayed stabilization (HR: 0.57, P = 0.020; and HR: 0.44, P ≤ 0.001, respectively) and increased risk of progression (HR: 1.87, P = 0.045; and HR: 1.96, P = 0.028, respectively) when compared with those receiving standard laser. Among other potential predictors in multivariable regression analysis, only vitreous hemorrhage and fibrosis or traction at baseline increased the risk of progression (HR: 1.58, P = 0.047; and HR: 4.29, P ≤ 0.001, respectively). Baseline characteristics and type of laser had no statistically significant effect on vision.

Conclusion:

These findings should be considered when selecting laser treatment, planning surveillance, and counselling patients with PDR undergoing PRP.
Globe Fixation Caused by Intraocular Migration of an Orbital Floor Implant
Authors: De Clerck Ivo , Veckeneer Marc , Reyntjens Bruno , De Groot Veva
Published: May 2022

A 30-year-old male presented with diplopia 1 month after implantation of an orbital floor plate for a blowout fracture. The orbital plate was removed 3 months later, however, the fixation bar was left in place as it had migrated full thickness through the inferior oblique muscle, sclera, choroid, and retina.

After 5 years of head tilt, the patient was referred to our department with a metallic intraocular foreign body visible in fundo and an important elevation deficit. CT imaging confirmed our clinical suspicion of a retained fixation bar. The extraocular part of the fixation bar was removed via a transconjunctival inferior orbitotomy, leaving the intraocular part in place due to the high risk of ocular complications upon removal. Postoperative ocular motility improved greatly and the patient no longer experiences diplopia in daily life. Orbital plate migration is a rare complication that should be considered in de novo diplopia after orbital reconstruction.
Lessons learned from hepatocellular carcinoma may cause a paradigm shift in intraductal papillary mucinous neoplasms: a narrative review and discussion of conceptual similarities in tumor progression and recurrence
Authors: Margonis Georgios Antonios , Andreatos Nikolaos , Wang Jane , Weiss Matthew J. , Wolfgang Christopher L.
Published: May 2022

Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality (“field defect”) in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic “field defect”may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression; thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.
An evaluation of safety and survival for patients with locally advanced pancreatic cancer treated with irreversible electroporation combined with chemotherapy: a retrospectively observational study
Authors: He Chaobin , Wang Jun , Mao Yize , Lao Xiangming , Li Shengping
Published: May 2022

Objective:

Irreversible electroporation (IRE) is emerging as a new therapy for locally advanced pancreatic cancer (LAPC). We aimed to conduct survival and safety analyses in LAPC patients after treatment with IRE combined with chemotherapy.

Methods:

A total of 64 patients with LAPC who had received IRE and chemotherapy were retrospectively collected from August 2015 to March 2019 at Sun Yat-sen University Cancer Center. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier method and compared by the log-rank test. A multivariate Cox regression model was used to determine the prognostic factors of survival. The perioperative complications of IRE were also evaluated. The study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center (approval No. C2021-003).

Results:

The median survival of all included patients were 24.63 (95% confidence interval: 21.78–27.49) for overall survival and 13.00 (95% confidence interval: 8.81–17.19) months for progression-free survival, with 96.8%, 51.9%, 18.3%; and 52.3%, 21.5%, 7.9% as the 1-, 2- and 3-year OS and PFS rates, respectively. Tumor size [OS, hazard ratio (HR)=1.768, P = 0.048; PFS, HR = 0.304, P = 0.010], neoadjuvant chemotherapy (OS, HR = 0.338, P = 0.030; PFS, HR = 0.358, P = 0.034), carbohydrate antigen 19-9 variation after IRE (OS, HR = 19.320, P = 0.003; PFS, HR = 14.591, P = 0.021) and tumor response after neoadjuvant chemotherapy (OS, HR = 8.779, P = 0.033; PFS, HR = 5.562, P = 0.008) were predictive factors of survival in patients with LAPC after IRE. Complications were observed in 20.3% of patients. Grade B pancreatic fistula was the most common complication. The complication rates of the late treatment group (6.1%) were significantly lower than those of the first 15 patients after IRE treatment (66.7%). The median length of hospital stay of late treatment group was 8.6 days, which was also shorter than that of the early treatment group (10.0 days).

Conclusions:

IRE combined with chemotherapy could improve survival of LAPC patients with acceptable complication rates. Therefore, it may be a suitable method for LAPC but should be validated in prospective randomized trials.
Asynchronous Peer Review Feedback in an Undergraduate Nursing Course
Authors: Brown Lynn Greenleaf , Cicchino Amy
Published: May 2022

Background:

Because patient care depends on nurses' ability to effectively communicate, nursing students need opportunities to develop written and oral communication skills through low-stakes activities. However, content-intensive classes and clinical schedules are obstacles to explicit writing support. Online asynchronous peer review can be an effective solution.

Purpose:

Students participated in an online asynchronous peer review intervention. Students reported their perceptions of the peer review and subsequent revisions.

Methods:

The authors developed a peer review activity, designed to guide students to give online asynchronous feedback. Students evaluated its effectiveness and value through pre- and posttest surveys.

Results:

Ninety-four percent (n = 68) of participants reported peer review as beneficial to the writing process, with 74% reporting they revised their writing in meaningful ways. Students felt peer feedback was useful, positive, valid, and reliable.

Conclusion:

Findings suggest that even when delivered asynchronously online, peer review can support nursing students' writing process and scaffold content learning.
A scoping review of psychosocial oncology interventions promoting posttraumatic growth
Authors: Wong Kennedy L. , McClure Kelly S. , Psillos Danielle E.
Published: May 2022

Problem Identification:

Many cancer patients experience posttraumatic growth (PTG), and psycho-oncologists are exploring ways to facilitate PTG through psychosocial intervention. This study utilized a scoping review protocol to provide a comprehensive evaluation of psychosocial interventions aiming to promote PTG in oncology.

Literature Search:

Three databases were used to identify empirical studies implementing psychosocial interventions to promote PTG in cancer patients, according to Calhoun and Tedeschi's Posttraumatic Growth Inventory.

Data Evaluation:

Two independent reviewers screened articles for inclusion and extracted data for qualitative synthesis. 8275 abstracts and 116 full-text articles were assessed, with 33 studies included in this review.

Conclusions:

Common treatment components of psychoeducation, peer support, and mindfulness skills identified by this review may be considered for future interventions targeting post-traumatic growth. The results of this review also identified areas where PTG research may be strengthened, including standardized reporting of PTG outcomes and cancer-related variables.
Eye Sphincter Reanimation in Facial Paralysis
Authors: Carlson Terri L. , Hamidian Jahromi Alireza , Chelnis James G. , Konofaos Petros
Published: May 2022

Facial nerve paralysis (FNP) sequela includes dysregulation of the ocular surface protective mechanism, nasolacrimal system pump failure and punctal eversion causing chronic epiphora, foreign body sensation, corneal injury, and, in the most severe cases, visual loss, particularly in the presence of comorbid corneal hypesthesia. Concerns over the ocular surface protection in FNP patients have led to the development of numerous static and dynamic procedures. While initial assessment of the FNP patients is complex and requires a comprehensive understanding of the blink reflex physiology, clinical evaluation and the use of additional work should be directed toward potential eye sphincter reanimation using a multidisciplinary approach. As with any treatment algorithm, numerous factors must be considered to provide an individualized treatment plan. In the case of FNP, it is important to consider denervation time, patient age, cause of paralysis, and neurologic severity of the paralysis. The aim of this article is to provide a thorough review of the physiology of the blink reflex, evaluation of the eye sphincter mechanism in FNP, and a comprehensive treatment algorithm incorporating static and dynamic procedures, along with a historical perspective.
The Tai Chi Flap
Authors: Cai Tingting , Chen Shuhong , Li Qunxing , Fang Zezhen , Cao Haotian , Xie Zhijun , Liu Niu , Li Yanyan , Ye Xiuhua , Li Jinsong , Fan Song
Published: May 2022

Objective

Tai Chi is an ancient philosophy used to explain the universe. The Tai Chi symbol is represented by Yin/Yang fishes. The authors describe a novel radial forearm flap (RFF) design for the reconstruction of circular defects based on the Tai Chi symbol.

Methods

Eleven consecutive patients with craniofacial skin or mucus defects underwent reconstruction with a Tai Chi RFF. Patient perioperative and follow-up information was collected.

Results

The diameter of the Tai Chi RFF was 5 to 6 cm. All flaps healed uneventfully without ischemic problems, and all donor site defects were closed primarily without skin grafts. Remarkably, 2 patients received a tattoo to mark the Tai Chi symbol and greatly appreciate the shape of the flap.

Conclusions

The Tai Chi flap is an economically friendly flap design that can be used to prevent skin grafts while providing psychological comfort to patients.
Genetics, Clinical Presentation, Radiological Features, and Midterm Outcome of Closing Wedge Osteotomy in Children With Brachydactyly Type C
Authors: Al-Qattan Mohammad M.
Published: May 2022

Background

Brachydactyly (BD) type C is a rare form of familial BD caused by GDF5 mutations. Some of the affected children have severe clinodactyly requiring surgery. The literature is limited to case reports.

Patients and Methods

The current retrospective study included 15 Saudi Arabian families with 42 affected children seen by the author for 25 years. A total of 23 digits (in 23 hands) underwent surgical correction of clinodactyly using a closing wedge osteotomy. The current study reports on the genetics, clinical presentation, radiological features, and midterm outcome of surgery.

Results

Genetic analysis was done in 6 families and confirmed the presence of 2 novel missense mutations (p.Met173Val in 3 families and p.Thr203Asn in 3 families) in the GDF5 gene. All cases in the study group demonstrated the classical clinical and radiographic features of BD type C. However, only 1 hand showed all the features of angel-shaped bony defect. The clinodactyly defect was mostly observed in the index or middle fingers. Surgery for the clinodactyly defect was only done if there was finger overlap. Closing wedge osteotomy was done in a total of 23 digits with a satisfactory outcome.

Conclusions

This study represents the largest reported series of children undergoing surgery for correction of BD type C clinodactyly with a uniform technique performed by a single surgeon. The closing wedge osteotomy used resulted in good midterm outcomes, although long-term follow-up is lacking.
GeneVector: Identification of transcriptional programs using dense vector representations defined by mutual information
Authors: Ceglia Nicholas , Sethna Zachary , Freeman Samuel S. , Uhlitz Florian , Bojilova Viktoria , Rusk Nicole , Burman Bharat , Chow Andrew , Salehi Sohrab , Kabeer Farhia , Aparicio Samuel , Greenbaum Benjamin , Shah Sohrab P. , McPherson Andrew
Published: May 2022

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. We describe GeneVector, a scalable framework for dimensionality reduction implemented as a vector space model using mutual information between gene expression. Unlike other methods, including principal component analysis and variational autoencoders, GeneVector uses latent space arithmetic in a lower dimensional gene embedding to identify transcriptional programs and classify cell types. In this work, we show in four single cell RNA-seq datasets that GeneVector was able to capture phenotypespecific pathways, perform batch effect correction, interactively annotate cell types, and identify pathway variation with treatment over time.
The impact of relationship to cancer patient and extent of caregiving on adherence to cancer screening in a diverse inner-city community
Authors: Matsumura Cynthia , Reaves Brieyona C. , Rapkin Bruce D.
Published: May 2022

The authors have withdrawn their manuscript because of the nature of the errors inadvertently found in data analysis and their potential impact on the results. Younger age ranges in the analyses for screening were not consistent throughout the manuscript. The authors plan to correct accordingly. Therefore, they do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Survival analysis of coronary care unit patients from MIMIC IV database
Authors: Lanzieri Pedro G. , Palmer Dayanna Q. , Gismondi Ronaldo A. , T. Baltar Valéria , Seixas Flavio L.
Published: May 2022

The profile of hospitalizations in coronary care units (CCU) includes patients with different age groups, multiple comorbidities and causes of hospitalization that may or may not be primarily cardiac. This study aimed to estimate survival time and evaluate the association and impact of different factors on this time in a cohort of patients admitted to CCU. A cohort of 7120 adult patients admitted to CCU was analyzed from a subset of data from the MIMIC-IV database (Medical Information Mart for Intensive Care, version 4). A descriptive analysis was performed using Kaplan-Meier survival analysis, with a Log-rank test to establish comparisons between groups. Survival regression was modeled using Cox’s proportional risk models for the multiple analysis. The p-value was defined as ¡ 0.05 as statistically significant. In patients who died during hospitalization, there was a higher average age, longer hospital stay, and a higher rate of heart and respiratory rate, all with p ¡ 0.001. Median overall survival was 28 days (95% CI 26-30 days). The survival probability curve presented a higher inclination in the first weeks, reaching a stable value close to 20% at 10 weeks after hospitalization. When Cox’s regression adjusted for age, gender and comorbidities was performed, hyperpotassemia was shown to be an independent risk factor for in-hospital mortality (RR = 1.22, 95% CI: 1.14-1.30) in this group of patients. These results reinforced that the electronic health record may contain, already in the first hours of hospitalization, relevant information to understand the progression of diseases and identify future directions for research. This study is expected to clarify important topics related to the MIMIC-IV database and enable further research using this patient database. Knowledge of the characteristics of the CCU population can allow better management of physical and human hospital resources.
Frontline healthcare workers’ mental health and wellbeing during the first year of the COVID-19 pandemic: Analysis of interviews and social media data
Authors: San Juan Norha Vera , Martin Sam , Badley Anna , Maio Laura , Gronholm Petra C. , Buck Caroline , Flores Elaine C. , Vanderslott Samantha , Syversen Aron , Symmons Sophie Mulcahy , Uddin Inayah , Karia Amelia , Iqbal Syka , Vindrola-Padros Cecilia
Published: May 2022

Background

The COVID-19 pandemic has shed light on the fractures of healthcare systems around the world, particularly in relation to the healthcare workforce. Frontline staff have been exposed to unprecedented strain and delivering care during the pandemic has impacted their safety, mental health and wellbeing. Rapid Research methods and big qualitative data offered a unique opportunity to gain insight into perceptions and experiences during this time.

Objective

The aim of this paper was to explore the experiences of Health Care Workers (HCWs) delivering care in the UK during the COVID-19 pandemic to understand their wellbeing needs, experiences and strategies used to maintain wellbeing at individual and organizational levels.

Methods

We analysed 94 telephone interviews with HCWs and 2000 tweets about HCWs mental health during the first year of the COVID-19 pandemic applying Collaborative and Digital Analysis of Big Qualitative Data in Time Sensitive Contexts (LISTEN).

Results

Results fell under six themes: redeployment, clinical work, and sense of duty; wellbeing support and HCW’s coping strategies; negative mental health effects; organisational support; social network and support; and public and government support. Redeployment generated anxiety mainly due to limited prior training and risk assessments, and the barriers of adapting to a new working environment while wearing PPE. HCWs struggled to access wellbeing support due to time constraints. In terms of ill mental health, mentions of feelings of trauma, PTSD and anxiety were prominent. HCWs’ mental health was particularly affected by the copious amount of bad news on media and at home and the fear of infecting their loved ones.

Conclusions

These findings demonstrate a need for open conversations, where staff wellbeing needs and the strategies they adopted can be shared and encouraged, rather than implementing solely top-down psychological interventions. At the macro level, findings also highlighted the impact on HCW’s wellbeing of public and government support, as well as the need for ensuring protection through PPE, testing, and/or vaccines for frontline workers.
Boosting polygenic risk scores
Authors: Klinkhammer Hannah , Staerk Christian , Maj Carlo , Krawitz Peter M. , Mayr Andreas
Published: May 2022

Polygenic risk scores (PRS) evaluate the individual genetic liability to a certain trait and are expected to play an increasingly important role in the field of clinical risk stratification. Most often, PRS are estimated based on summary statistics of univariate effects derived from genome-wide association studies. To improve the predictive performance of PRS, it is desirable to fit multivariable models directly on the genetic data. Due to the large and high-dimensional data, a direct application of existing methods is often not feasible and new efficient algorithms are required to overcome the computational burden regarding efficiency and memory demands.

We develop an adapted component-wise L2-boosting algorithm to fit genotype data from large cohort studies to continuous outcomes using linear base-learners for the genetic variants. Similar to the snpnet approach implementing lasso regression, the proposed snpboost approach iteratively works on smaller batches of variants. By restricting the set of possible base-learners in each boosting step to variants most correlated with the residuals from previous iterations, the computational efficiency can be substantially increased without losing prediction accuracy. Furthermore, for large-scale data based on various traits from the UK Biobank we show that our method yields competitive prediction accuracy and computational efficiency compared to the snpnet approach. Due to the modular structure of boosting, our framework can be further extended to construct PRS for different outcome data and effect types.
Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development
Authors: Wilmouth James J , Olabe Julie , Garcia-Garcia Diana , Lucas Cécily , Guiton Rachel , Roucher-Boulez Florence , Dufour Damien , Damon-Soubeyrand Christelle , Sahut-Barnola Isabelle , Pointud Jean-Christophe , Renaud Yoan , Levasseur Adrien , Tauveron Igor , Lefrançois-Martinez Anne-Marie , Martinez Antoine , Val Pierre
Published: May 2022

In contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTKhigh active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.
Inter-organ Wingless/Ror/Akt signaling regulates nutrient-dependent hyperarborization of somatosensory neurons
Authors: Kanaoka Yasutetsu , Onodera Koun , Watanabe Kaori , Usui Tadao , Uemura Tadashi , Hattori Yukako
Published: May 2022

Nutrition in early life has profound effects on an organism, altering processes such as organogenesis. However, little is known about how specific nutrients affect neuronal development. Dendrites of class IV neurons in Drosophila larvae become more complex when the larvae are reared on a low-yeast diet compared to a high-yeast diet. Our systematic search for key nutrients revealed that the neurons increase their dendrite densities in response to a combined deficiency in vitamins, metal ions, and cholesterol. These nutrients affect dendrite branching through the Wingless/Ror/Akt pathway between the neuron and closely located muscles, and this short range-pathway is regulated by a systemic Upd2-Stat92E pathway between the fat body and muscles. Additionally, the low-yeast diet blunts neuronal light responsiveness and light avoidance behavior, which may help larvae optimize their survival strategies under low-nutritional conditions. Together, our studies illustrate how the availability of specific nutrients affects neuronal development through inter-organ signaling.
A new species of deep-water Lethrinops (Cichlidae) from Lake Malawi
Authors: Turner George F.
Published: May 2022

A new species of cichlid fish, Lethrinops atrilabris is described from specimens collected by trawling at a depth of around 90m off Monkey Bay, southern Lake Malawi. It is assigned to the genus Lethrinops on the basis of its vertical flank barring, lack of enlarged cephalic lateral line canal pores and the form of the lower jaw dental arcade. It can be distinguished from congeneric species by its male breeding dress of contrasting flank barring and dark ventral surface, most strikingly on the lips, throat and chest, its relatively small known maximum size (<75mm SL), large eyes (38-41% head length), laterally compressed body (depth 2.5-2.7 times max head width) and lower gillraker count (13-14).
Quantum pBac: An effective, high-capacitypiggyBac-based gene integration vector system for unlocking gene therapy potential
Authors: Hua Wei-Kai , Hsu Jeff C. , Chen Yi-Chun , Chang Peter S. , Wen Kuo-Lan Karen , Wang Po-Nan , Yu Yi-Shan , Chen Ying-Chun , Cheng I-Cheng , Wu Sareina Chiung-Yuan
Published: May 2022

Recent advances in gene therapy have brought novel treatment options for cancer. However, the full potential of this approach has yet to be unlocked due to the safety concerns and limited payload capacity of commonly utilized viral vectors. Virus-free DNA transposons, includingpiggyBac, have potential to obviate these shortcomings. In this study, we improved a previously developed modifiedpiggyBacsystem with superior transposition efficiency. We demonstrated that the internal domain sequences (IDS) within the 3’ terminal repeat domain of hyperactivepiggyBac(hyPB) donor vector contain dominant enhancer elements. Plasmid-free donor vector devoid of IDS was used in conjunction with a helper plasmid expressingQuantum PBase™ v2 to generate an optimalpiggyBacsystem,Quantum pBac™ (qPB), for use in T cells. Cells transfected withqPBexpressing CD20/CD19 CAR outperformed those transfected with the same donor vector and plasmid expressinghyPBtransposase in terms of CAR-T cell production. Importantly,qPByielded mainly CD8+CAR-TSCMcells, and theqPB-induced CAR-T cells effectively eliminated CD20/CD19-expressing tumor cells bothin vitroandin vivo. Our findings confirmqPBas a promising virus-free vector system with a payload capacity to incorporate multiple genes. This system is highly efficient and potentially safe for mediating transgene integration.
The dual character of the inhibitory functions of CD6
Authors: Santos Rita F. , De Sousa Linhares Annika , Cardoso Marcos S. , Nóvoa Ana , Luche Hervé , Gärtner Fátima , Malissen Bernard , Steinberger Peter , Davis Simon. J. , Mallo Moisés , Oliveira Liliana , Carmo Alexandre M.
Published: May 2022

T-cell membrane scaffold proteins play important roles in T cell biology, functioning as multi-functional signaling hubs. CD6 assembles a large intracellular signalosome but, unlike typical membrane-attached scaffolds like LAT or PAG, it has a sizeable ectodomain that binds a well-characterized ligand, CD166. It is unclear whether CD6 has net inhibitory or costimulatory functions or how its ectodomain influences these activities. To explore these questions, we dissected the signaling functions of the extracellular and cytoplasmic regions of CD6. We found that CD6 was delivered to the immunological synapse and suppressed T cell responsivenessin vitrowholly dependently of its cytoplasmic domain, indicating that CD6 very potently imposes tonic inhibition, acting as a structural and signaling inhibitory hub. However, the cell-intrinsic suppression of autoimmunity by CD6in vivowas also impacted by extracellular interactions, demonstrated by the increased susceptibility of mice to experimental autoimmune encephalomyelitis after removal of the ligand binding region of the ectodomain of CD6. Our work identifies CD6 as a new class of ‘on/off switching’ scaffold-receptor that constrains immune responsiveness at two speeds. First, it sets signaling thresholds via tonic inhibition, functioning as a cytoplasmic membrane-bound scaffold and, second, by cycling between signaling-enabling and signalinginhibiting ectodomain isoforms it functions as an immune checkpoint.
Non-Invasive Cancer Detection in Canine Urine through C. elegans Chemotaxis
Authors: Namgong Chan , Kim Jong Hyuk , Lee Myon-Hee , Midkiff Daniel
Published: May 2022

Cancer is the leading cause of death of companion animals, and successful early treatment has been a challenge in the veterinary field. We have developed the Non-Invasive Cancer Screening (N.C.S.) Study to perform cancer detection through the analysis of canine urine samples. The test makes use of the strong olfactory system of the nematode C. elegans, which was previously shown to positively respond to urine samples from human cancer patients. We performed a proof-of-concept study to optimize the detection capability in urine samples obtained from dogs with naturally occurring cancers. In this study, we established a scale for identifying the cancer risk based on the magnitude of the chemotaxis index of C. elegans towards a canine urine sample. Through validation, the N.C.S. Study achieved a sensitivity of 85%, showing that it is highly sensitive to indicating the presence of cancer across multiple types of common canine cancers. The test also showed a 93% specificity to cancer samples, indicating a low rate of over-identifying cancer risk. From these results, we have demonstrated the ability to perform low-cost, non-invasive cancer detection in companion animals, a method which can increase the ability to perform cancer diagnosis and treatment.
Heterogeneity of Interaction Strengths and Its Consequences on Ecological Systems
Authors: Jackson Zachary , Xue BingKan
Published: May 2022

Ecosystems are formed by networks of species and their interactions. Traditional models of such interactions assume a constant interaction strength between a given pair of species. However, there is often significant trait variation among individual organisms even within the same species, causing heterogeneity in their interaction strengths with other species. The consequences of such heterogeneous interactions for the ecosystem have not been studied systematically. As a theoretical exploration, we analyze a simple ecosystem with trophic interactions between two predators and a shared prey, which would exhibit competitive exclusion in models with homogeneous interactions. We consider several scenarios where individuals of the prey species differentiate into subpopulations with different interaction strengths. We show that in all these cases, whether the heterogeneity is inherent, reversible, or adaptive, the ecosystem can stabilize at a new equilibrium where all three species coexist. Moreover, the prey population that has heterogeneous interactions with its predators reaches a higher density than it would without heterogeneity, and can even reach a higher density in the presence of two predators than with just one. Our results suggest that heterogeneity may be a naturally selected feature of ecological interactions that have important consequences for the stability and diversity of ecosystems.
Variant Polycomb complexes in Drosophila consistent with ancient functional diversity
Authors: Kang Hyuckjoon , Cabrera Janel R. , Zee Barry M. , Kang Heather A. , Jobe Jenny Marie , Hegarty Maeve B. , Barry Aurelie E. , Glotov Alexander , Schwartz Yuri B. , Kuroda Mitzi I.
Published: May 2022

Polycomb group (PcG) mutants were first identified in Drosophila based on their failure to maintain proper Hox gene repression during development. The proteins encoded by the corresponding fly genes mainly assemble into one of two discrete Polycomb Repressive Complexes: PRC1 or PRC2. However, biochemical analyses in mammals have revealed alternative forms of PRC2, and multiple distinct types of non-canonical or variant PRC1. Through a series of proteomic analyses, we identify analogous PRC2 and variant PRC1 complexes in Drosophila, as well as a broader repertoire of interactions implicated in early development. Our data provide strong support for the ancient diversity of PcG complexes, and a framework for future analysis in a longstanding and versatile genetic system.
People exposed to proton pump inhibitors shortly preceding COVID-19 diagnosis are not at an increased risk of subsequent hospitalizations and mortality: a nation-wide matched cohort study
Authors: Kodvanj Ivan , Homolak Jan , Trkulja Vladimir
Published: May 2022

Aim

To assess whether exposure to proton pump inhibitors (PPIs) shortly preceding COVID-19 diagnosis affected the risk of subsequent hospitalizations and mortality.

Methods

This population-based study embraced first COVID-19 episodes in adults diagnosed up to August 15 2021 in Croatia. Patients were classified based on exposure to PPIs and burden of PPI-requiring morbidities as “non-users” (no issued prescriptions, no recorded treatment-requiring conditions between January 1 2019 and COVID-19 diagnosis), “possible users” (no issued prescriptions, but morbidities present; self-medication possible) and “users” (at least one prescription within 3 months prior to the COVID-19 diagnosis; morbidities present). Subsets were mutually exactly matched for pre-COVID-19 characteristics. The contrast between “users” and “possible users” informed about the effect of PPIs that is separate of the effect of PPI-requiring conditions.

Results

Among 433609 patients, “users” and “possible users” were matched 41195 (of 55098) to 17334 (of 18170) in the primary and 33272 to 16434 in the sensitivity analysis. There was no relevant difference between them regarding mortality [primary: RR=0.93 (95%CI 0.85-1.02; RD= - 0.34% (−0.73, 0.03); sensitivity: RR=0.88 (0.78-0.98); RD=-0.45% (−0.80, -0.11)] or hospitalizations [primary: RR=1.04 (0.97-1.13); RD=0.29% (−0.16, 0.73); sensitivity: RR=1.05 (0.97-1.15); RD=0.32% (−0.12, 0.75)]. The risks of both were slightly higher in “possible users” or “users” than in “non-users” (absolutely by ∼0.4%-1.6%) indicating the effect of PPI-requiring morbidities.

Conclusion

Pre-morbid exposure to PPIs does not affect the risk of death or hospitalization in adult COVID-19 patients, but PPI-requiring morbidities seemingly slightly increase the risk of both.

What is already known about this subject?

It appears biologically plausible that pre-morbid exposure to proton pump inhibitors (PPIs) might contribute to unfavorable course of COVID-19 disease

Two population-based studies in the early pandemics stage indicated no effect of PPIs, while one suggested a higher risk of death/severe COVID-19 disease in PPI pre-exposed subjects

What this study adds?

Exposure to PPIs directly preceding SarsCov-2 infection has no effect on the risk of subsequent hospitalizations and mortality

Conditions requiring PPI treatment seem to mildly increase the risk of both
The highly conserved stem-loop II motif is important for the lifecycle of astroviruses but dispensable for SARS-CoV-2
Authors: Janowski Andrew B , Jiang Hongbing , Fujii Chika , Owen Macee C , Bricker Traci L , Darling Tamarand L , Harastani Houda H. , Seehra Kuljeet , Tahan Stephen , Jung Ana , Febles Binita , Blatter Joshua A , Handley Scott A , Parikh Bijal A , Lulla Valeria , Boon Adrianus CM , Wang David
Published: May 2022

The stem-loop II motif (s2m) is an RNA element present in viruses from divergent viral families, including astroviruses and coronaviruses, but its functional significance is unknown. We created deletions or substitutions of the s2m in astrovirus VA1 (VA1), classic human astrovirus 1 (HAstV1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For VA1, recombinant virus could not be rescued upon partial deletion of the s2m or substitutions of G-C base pairs. Compensatory substitutions that restored the G-C base-pair enabled recovery of VA1. For HAstV1, a partial deletion of the s2m resulted in decreased viral titers compared to wild-type virus, and reduced activity in a replicon system. In contrast, deletion or mutation of the SARS-CoV-2 s2m had no effect on the ability to rescue the virus, growth in vitro, or growth in Syrian hamsters. Our study demonstrates the importance of the s2m is virus-dependent.
A DNA segregation module for synthetic cells
Authors: Tran Mai P. , Chatterjee Rakesh , Dreher Yannik , Fichtler Julius , Jahnke Kevin , Hilbert Lennart , Zaburdaev Vasily , Göpfrich Kerstin
Published: May 2022

The bottom-up construction of an artificial cell requires the realization of synthetic cell division. Significant progress has been made towards reliable compartment division, yet mechanisms to segregate the DNA-encoded informational content are still in their infancy. Herein, droplets of DNA Y-motifs are formed by liquid-liquid phase separation (LLPS). Entropy-driven DNA droplet segregation is obtained by cleaving the linking component between two populations of DNA Y-motifs. In addition to enzymatic cleavage, photolabile sites are introduced for spatio-temporally controlled DNA segregation in bulk as well as in cell-sized water-in-oil droplets and giant unilamellar lipid vesicles (GUVs). Notably, the segregation process is slower in confinement than in bulk. The ionic strength of the solution and the nucleobase sequences are employed to regulate the segregation dynamics. The experimental results are corroborated in a lattice-based theoretical model which mimics the interactions between the DNA Y-motif populations. Altogether, engineered DNA droplets, reconstituted in GUVs, could represent a strategy towards an entropy-driven DNA segregation module within bottom-up assembled synthetic cells.

Table of Contents

An entropy-driven DNA segregation module for bottom-up assembled synthetic cells is realized. It is based on DNA droplets that are engineered to segregate upon enzymatic or photocleavage inside giant unilamellar lipid vesicles (GUVs). The segregation kinetics is altered by the confinement, as confirmed by lattice-based numerical simulations. DNA segregation is further controlled by temperature, ionic strengths and nucleobase sequence.
TME induced TRAIL secretion from engineered macrophages for anti-tumor therapy
Authors: Huang Xin , Deng Botian , Zhou Hui , Shi Binhe , Liu Junhua , Shan Xiaojiao , Fang Xiaobin , Yin Xiushan , Zhang Luo
Published: May 2022

Capacity of tumor niche chemotaxis and long-term persistency making macrophage as great vehicles for anti-tumor factor delivery. Macrophages-based delivery of chemokines or cytokines have been tested for tissue homeostasis and cancer repression. TRAIL as a promising anti-tumor cytokine, made little clinical progress due to limited stability and off-target toxicity. Here we engineered macrophages with tumor micro-environment (TME)-induced trimerized CP1-TRAIL secretion under the TME specific promoter Arg1 (Tri-TRAIL-iM). The Tri-TRAIL-iM cells displayed high specific inducible activity in both cell-based co-culture assay and in tumor baring mice models. Compared to normal TRAIL over-expressed macrophages under none-inducible promoter, Tri-TRAIL-iM infiltrated to tumor sites and showed superior apoptosis induction of cancer cells and tumor growth repression as well as less systemic side effect. This inducible delivery TRAIL strategy can be effectively further applied in clinical studies and can be coupled with other engineered methods to maximize the therapeutic outcomes for solid tumors.
Sequential functional differentiation of luminal epithelial cells regulated by maternal and embryonic signaling in the mouse endometrium
Authors: Wang Hai-Quan , Li Dong , Liu Jingyu , Jiang Yue , Zhou Ji-Dong , Wang Zhi-Long , Tang Xin-Yi , Zhang Yang , Zhen Xin , Cao Zhi-Wen , Sheng Xiao-Qiang , Yang Chao-Fan , Yue Qiu-ling , Ding Li-jun , Hu Ya-li , Hu Zhi-Bin , Li Chao-Jun , Yan Gui-Jun , Sun Hai-Xiang
Published: May 2022

Embryo implantation requires temporospatial maternal-embryo dialog to regulate the interactions between an activated blastocyst and a receptive endometrium; however, the details of the related cell-specific coordination is largely unknown because of the cellular complexity and dynamic developmental processes of both the embryo and endometrium during peri-implantation. By comparing single-cell RNA (scRNA) data obtained from entire uteri of pregnant and pseudo-pregnant mice with embryos that were in the oviduct (dpc2.5 days post-coitum [dpc]) or had entered the uterus (after 3.5 dpc), we found a maternal estrogen and progesterone signaling-dependent functional differentiation process in which progesterone induced estrogen-responsive luminal epithelial cells to differentiate into two new types of epithelial cells: adhesion epithelial cells (AECs) and supporting epithelial cells (SECs) on 2.5 dpc. In addition to maternal signaling data, the uterine scRNA and corresponding embryo bulk sequencing data were obtained, and analyses revealed that embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, enhancing the attachment of embryos to the endometrium after implantation. Specifically, embryonic signaling induced additional transformation of AECs by preventing adjacent AECs, but not AECs away from the embryo in the implantation chamber, from undergoing apoptosis. Furthermore, we demonstrated that epithelial cell differentiation and related regulatory signaling were largely conserved in humans and mice. In the human endometrium, developmental defects of SOX9-positive epithelial cells similar to luminal epithelial cells were related to thin endometrium. Our work provides comprehensive and systematic information on endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is important for endometrial receptivity and embryo implantation.
A deep learning framework for structural variant discovery and genotyping
Authors: Popic Victoria , Rohlicek Chris , Cunial Fabio , Garimella Kiran , Meleshko Dmitry , Hajirasouliha Iman
Published: May 2022

Structural variants (SV) are a major driver of genetic diversity and disease in the human genome and their discovery is imperative to advances in precision medicine and our understanding of human genetics. Existing SV callers rely on hand-engineered features and heuristics to model SVs, which cannot easily scale to the vast diversity of SV types nor fully harness all the information available in sequencing datasets. Since deep neural networks can learn complex abstractions directly from the data, they offer a promising approach for general SV discovery. Here we propose an extensible deep learning framework, Cue, to call and genotype SVs. At a high level, Cue converts sequence alignments to multi-channel images that capture multiple SV-informative signals and uses a stacked hourglass convolutional neural network to predict the type, genotype, and genomic locus of the SVs captured in each image. We show that Cue outperforms the state of the art in the detection of five classes of SVs (including two types of complex SVs and subclonal SVs) on synthetic and real short-read data and that it can be easily extended to other sequencing platforms, such as long and linked read sequencing technologies, while achieving competitive performance. By design, Cue can also be automatically extended to support new SV classes: this versatility is crucial as novel SV types are discovered in ongoing population-scale sequencing initiatives.