bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Integrated Plastic Surgery Residency Program Websites and Instagram Accounts Address Diversity, Equity, and Inclusion?
Authors: Das Rishub K. , Drolet Brian C.
Published: February 2023

Background:

An authentic, programmatic commitment to diversity, equity, and inclusion (DEI) in plastic surgery is necessary to attract and retain a diverse workforce. Plastic surgery residency program websites and social media accounts are important sources of information about program values and culture for applicants, especially with the shift to virtual recruitment. Therefore, we sought to evaluate whether integrated plastic surgery residency programs address DEI through content on their websites and Instagram accounts.

Methods:

Integrated plastic surgery residency programs were identified through the Accreditation Council for Graduate Medical Education in December 2021. We searched program websites and Instagram accounts for elements of DEI. We evaluated the impact of region, program director sex, and program director race on prevalence of DEI elements on websites using chi-squared tests.

Results:

A total of 82 integrated plastic surgery residency programs were identified. Overall, 40 (48%) program websites had at least one DEI element, and 10 (12.2%) were found to have 3 or more DEI elements. The number of DEI elements per program website did not vary by region, program director sex, and program director ethnicity. Among programs with Instagram accounts, 49 (65.3%) posted about women, 30 (40.0%) posted about racial/ethnic minority groups, and 25 (33.3%) posted about LGBTQ+ identities.

Conclusions:

Despite widely heralded DEI efforts in plastic surgery residency recruitment, relatively few programs address DEI online. Programs looking to recruit diverse applicants could benefit from increased DEI content on their websites and social media accounts.
Strengthening Association through Causal Inference
Authors: Lane Megan , Berlin Nicholas L. , Chung Kevin C. , Waljee Jennifer F.
Published: February 2023

Understanding causal association and inference is critical to study health risks, treatment effectiveness, and the impact of healthcare interventions. Although defining causality has traditionally been limited to rigorous, experimental contexts, techniques to estimate causality from observational data are highly valuable for clinical questions in which randomization may not be feasible or appropriate. In this review, we highlight several methodological options to deduce causality from observational data, including regression discontinuity, interrupted time series, and difference-in-differences approaches. Understanding the potential applications, assumptions, and limitations of quasi-experimental methods for observational data can expand our interpretation of causal relationships for surgical conditions.
Making Headway in Surgical Education at Home and Abroad: Use of an Inexpensive, 3-D Learning Model to Improve Plastic Surgery Resident Confidence in Mohs Defect Assessment and Closure Planning.
Authors: Shaffrey Ellen C. , Grotting Ava G. , Michelotti Brett F. , Siebert John W. , Larson Jeffrey D. , Bentz Michael L.
Published: February 2023

Background:

The development of simulation, particularly low-cost models, has become a focus of interest within plastic surgery education. Current simulators for Mohs reconstruction are either expensive or not reusable. 1–6 The authors hypothesize that using a Styrofoam head model during an interactive teaching session will positively impact plastic surgery trainee comfort in designing Mohs reconstructive options.

Methods:

A cohort of integrated plastic surgery residents at a single institution performed a pre-activity questionnaire to obtain baseline comfort in defect assessment and design for five Mohs defects. They subsequently underwent an interactive learning session and were instructed to design flaps on life-sized Styrofoam heads with feedback from the senior author. A post-activity questionnaire was completed to assess improvement in comfort in defect assessment and flap design. Three attending surgeons then compared trainee designs with the senior author’s design to assess accuracy. All surveys were based on a 5-point Likert scale.

Results:

When analyzing all defects, average post-activity scores increased by 0.63 (SD +/- 0.24) (p = 0.008). Junior residents (n=8) had a greater increase in average score responses (mean: 1.07, [0.5-1.75]) compared to senior residents (n=9) (mean: 0.27, [0-1]) (p<0.001). When assessed by senior level surgeons, senior residents had significantly greater accuracy in design for each defect (p<0.05), except cheek advancement flap (p=0.08).

Conclusions:

Participation in an interactive educational activity using a styrofoam head model demonstrated significant improvements in trainee assessment and design of reconstructive options for Mohs defects.
Computed Tomography–Based Radiomics Analysis for Prediction of Response to Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Duan Yanli , Yang Guangjie , Miao Wenjie , Song Bingxue , Wang Yangyang , Yan Lei , Wu Fengyu , Zhang Ran , Mao Yan , Wang Zhenguang
Published: February 2023

Purpose

Previous studies have pointed out that magnetic resonance– and fluorodeoxyglucose positron emission tomography–based radiomics had a high predictive value for the response of the neoadjuvant chemotherapy (NAC) in breast cancer by respectively characterizing tumor heterogeneity of the relaxation time and the glucose metabolism. However, it is unclear whether computed tomography (CT)–based radiomics based on density heterogeneity can predict the response of NAC. This study aimed to develop and validate a CT-based radiomics nomogram to predict the response of NAC in breast cancer.

Methods

A total of 162 breast cancer patients (110 in the training cohort and 52 in the validation cohort) who underwent CT scans before receiving NAC and had pathological response results were retrospectively enrolled. Grades 4 to 5 cases were classified as response to NAC. According to the Miller-Payne grading system, grades 1 to 3 cases were classified as nonresponse to NAC. Radiomics features were extracted, and the optimal radiomics features were obtained to construct a radiomics signature. Multivariate logistic regression was used to develop the clinical prediction model and the radiomics nomogram that incorporated clinical characteristics and radiomics score. We assessed the performance of different models, including calibration and clinical usefulness.

Results

Eight optimal radiomics features were obtained. Human epidermal growth factor receptor 2 status and molecular subtype showed statistical differences between the response group and the nonresponse group. The radiomics nomogram had more favorable predictive efficacy than the clinical prediction model (areas under the curve, 0.82 vs 0.70 in the training cohort; 0.79 vs 0.71 in the validation cohort). The Delong test showed that there are statistical differences between the clinical prediction model and the radiomics nomogram (z= 2.811,P= 0.005 in the training cohort). The decision curve analysis showed that the radiomics nomogram had higher overall net benefit than the clinical prediction model.

Conclusion

The radiomics nomogram based on CT radiomics signature and clinical characteristics has favorable predictive efficacy for the response of NAC in breast cancer.
Three-Dimensional Gradient-Echo–Based Amide Proton Transfer-Weighted Imaging of Brain Tumors: Comparison With Two-Dimensional Spin-Echo–Based Amide Proton Transfer-Weighted Imaging
Authors: Murayama Kazuhiro , Ohno Yoshiharu , Yui Masao , Yamamoto Kaori , Ikedo Masato , Ohba Shigeo , Hanamatsu Satomu , Iwase Akiyoshi , Ikeda Hirotaka , Hirose Yuichi , Toyama Hiroshi
Published: February 2023

Objective

Although amide proton transfer–weighted (APTw) imaging is reported by 2-dimensional (2D) spin-echo–based sequencing, 3-dimensional (3D) APTw imaging can be obtained by gradient-echo–based sequencing. The purpose of this study was to compare the efficacy of APTw imaging between 2D and 3D imaging in patients with various brain tumors.

Methods

A total of 49 patients who had undergone 53 examinations [5 low-grade gliomas (LGG), 16 high-grade gliomas (HGG), 6 malignant lymphomas, 4 metastases, and 22 meningiomas] underwent APTw imaging using 2D and 3D sequences. The magnetization transfer ratio asymmetry (MTRasym) was assessed by means of region of interest measurements. Pearson correlation was performed to determine the relationship between MTRasym for the 2 methods, and Student's t test to compare MTRasym for LGG and HGG. The diagnostic accuracy to differentiate HGG from LGG of the 2 methods was compared by means of the McNemar test.

Results

Three-dimensional APTw imaging showed a significant correlation with 2D APTw imaging (r = 0.79, P < 0.0001). The limits of agreement between the 2 methods were −0.021 ± 1.42%. The MTRasym of HGG (2D: 1.97 ± 0.96, 3D: 2.11 ± 0.95) was significantly higher than those of LGG (2D: 0.46 ± 0.89%, P < 0.01; 3D: 0.15 ± 1.09%, P < 0.001). The diagnostic performance of the 2 methods to differentiate HGG from LGG was not significantly different (P = 1).

Conclusions

The potential capability of 3D APTw imaging is equal to or greater than that of 2D APTw imaging and is considered at least as valuable in patients with brain tumors.
Efficacy and Safety of Dl-3-n-Butylphthalide Combined With Human Urinary Kallidinogenase in the Treatment of Acute Ischemic Stroke
Authors: Zhang Yaqian , Zhou Feng , Li Huiqing , Lei Junjie , Mo Zhihuai , Li Guangrong , Wang Junfeng
Published: February 2023

Objectives

Intravenous thrombolysis and mechanical endovascular thrombectomy are recommended for patients whose stroke onsets are within the first 6 hours; however, patients beyond this time window have very limited options. Dl-3-n-butylphthalide (NBP) and human urinary kallidinogenase (HUK) have shown potential clinical benefits in the treatment of acute ischemic stroke (AIS) patients. This research aims to investigate the efficacy and safety of NBP combined with HUK in the treatment of ischemic stroke patients.

Patients and Methods

We reviewed the 215 AIS patients registered in the database of the Fifth Affiliated Hospital of Sun Yat-sen University from April 2019 to October 2020. Among them, 65 patients received NBP sodium chloride injection treatment, 55 patients received HUK treatment, and 95 patients received NBP sodium chloride injection combined with HUK treatment. The recovery of neural function was evaluated by the National Institutes of Health Stroke Scale (NIHSS), and the recovery of daily function was evaluated by the modified Rankin Scale (mRS). The NIHSS and mRS scores after the 7-day treatment, 6-month independency rate (6-month mRS score ≤1), and related factors were compared among the 3 groups. The safety was monitored by recording adverse events.

Results

The NIHSS and mRS scores of 7-day and 6-month treatment in the NBP combined with HUK group were lower than the monotherapy (P < 0.05). In addition, the NBP combined with HUK treatment achieved an independency rate of 82.1%, whereas NBP and HUK treatments achieved only 53.8% and 63.6%, respectively (P < 0.001). Binary logistic regression showed that NBP combined with HUK therapy treatment could lead to a 5.28 times higher rate of patients' 6-month independency after AIS occurrence. No serious adverse events occurred in both the combined therapy and monotherapy.

Conclusions

Dl-3-n-butylphthalide combined with HUK is safe to treat AIS patients. It can significantly improve the neural function and the 6-month recovery of AIS patients.
KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice
Authors: Maamrah Baneen , Pocsai Krisztina , Bayasgalan Tsogbadrakh , Csemer Andrea , Pál Balázs
Published: February 2023

The potassium voltage-gated channel subfamily Q member 4 (KCNQ4) subunit forms channels responsible for M-current, a muscarine-sensitive potassium current regulating neuronal excitability. In contrast to other KCNQ subunits, its expression is restricted to the cochlear outer hair cells, the auditory brainstem and other brainstem nuclei in a great overlap with structures involved in startle reflex. We aimed to show whether startle reflexis affected by the loss of KCNQ4 subunit and whether these alterations are similar to the ones caused by brainstem hyperexcitability. Young adult KCNQ4 knockout mice and wild-type littermates, as well as mice expressing hM3D chemogenetic actuator in the pontine caudal nucleus and neurons innervating it were used for testing acoustic startle. The acoustic startle reflex was significantly increased in knockout mice compared with wild-type littermates. When mice expressing human M3 muscarinic (hM3D) in nuclei related to startle reflex were tested, a similar increase of the first acoustic startle amplitude and a strong habituation of the further responses was demonstrated. We found that the acoustic startle reflex is exaggerated and minimal habituation occurs in KCNQ4 knockout animals. These changes are distinct from the effects of the hyperexcitability of nuclei involved in startle. One can conclude that the exaggerated startle reflex found with the KCNQ4 subunit deletion is the consequence of both the cochlear damage and the changes in neuronal excitability of startle networks.
Vascular endothelial growth factor-A is involved in intramuscular carrageenan-induced cutaneous mechanical hyperalgesia through the vascular endothelial growth factor-A receptor 1 and transient receptor potential vanilloid 1 pathways
Authors: Ueda Takashi , Watanabe Masaya , Miwa Youko , Shibata Yasuhiro , Kumamoto Natsuko , Ugawa Shinya
Published: February 2023

Objectives

Vascular endothelial growth factor-A (VEGF-A) plays a leading role in angiogenesis and pain hypersensitivity in cancer and chronic pain. It is not only induced by ischemic conditions but is also highly correlated with proalgesic cytokines, both of which are prominent in inflammatory muscle pain. However, the molecular basis of the involvement of VEGF-A in muscle pain remains unknown.

Methods

In the present study, we performed behavioral and pharmacological analyses to determine the possible involvement of VEGF-A in the development of inflammatory muscle pain and the associated signal transduction pathway.

Results

Unilateral intramuscular injection of carrageenan, a classical model of inflammatory muscle pain, increased VEGF-A gene expression in the tissues surrounding the injection site. Intramuscular administration of recombinant VEGF-A165 on the same side induced cutaneous mechanical hyperalgesia during the acute and subacute phases. The application of a specific VEGFR1 antibody on the same side significantly reduced the mechanical hyperalgesia induced by carrageenan or VEGF-A165 injection, whereas both a VEGFR2-neutralizing antibody and a VEGFR2 antagonist showed limited effects. Local preinjection of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist, also inhibited VEGF-A165-induced hyperalgesia. Finally, intramuscular VEGF-A165-induced mechanical hyperalgesia was not found in TRPV1 knockout mice during the subacute phase.

Conclusions

These findings suggest that inflammatory stimuli increase interstitial VEGF-A165, which in turn induces cutaneous mechanical pain via the VEGFR1-mediated TRPV1 nociceptive pathway during inflammatory muscle pain. VEGFR1 could be a novel therapeutic target for inflammation-induced muscle pain.
The decision-making process of leafcutting bees when selecting patches
Authors: Fragoso Fabiana P. , Brunet Johanne
Published: February 2023

Change in land configuration is an important driver of pollinator decline. Understanding patch selection by bees in fragmented landscapes has therefore become imperative to guide the design of habitats that support pollinators and ensure their conservation. This is especially true for solitary bees that make up most bee species in the world. To elucidate the decision-making process of a solitary bee when selecting patches, we tested four models of patch attractiveness that differed in the role of patch size and isolation distance in the selection process. In these models, bees used both patch size and patch distance, only patch distance, or chose randomly among patches. When patch size was included, bees could estimate patch resources fully or partially. An experiment with a centre patch, surrounded by four peripheral patches of different sizes and distances from the centre, provided observed transition data to test against predictions derived from each of the models. The alfalfa leafcutting bee,
Megachile rotundata,
does not move randomly among patches. This bee uses both patch size and isolation distance when selecting a patch but can only evaluate patch resources partially. This knowledge can guide the design of habitats in fragmented landscapes to facilitate solitary bee conservation.
Recovery of constitutive immune function after migratory endurance flight in free-living birds
Authors: Eikenaar Cas , Ostolani Alessia , Hessler Sven , Ye Ellen Y. , Hegemann Arne
Published: February 2023

Strenuous physical activity can negatively affect constitutive innate immune function (CIF), the always present first line of defence against pathogens. CIF is non-specific, and thus vital when encountering novel pathogens. A lowered CIF likely increases the risk of infection and disease. Migratory birds engage in truly extreme physical activity during their endurance flights, however, little is known about how they deal with the negative impact this has on their immune function. By collecting both between- and within-individual data we show, for the first time, that free-flying migratory birds can recover several parameters of CIF during stopovers, which are stationary periods in between migratory flights. With this, we provide an important piece of the puzzle on how migrating birds cope with the physiological challenges they face on their biannual journeys. Furthermore, our study stresses the importance of migratory stopovers beyond fuel accumulation.
Characterization of bird formations using fuzzy modelling
Authors: Perinot Elisa , Fritz Johannes , Fusani Leonida , Voelkl Bernhard , Nobile Marco S.
Published: February 2023

The investigation of the emergent collective behaviour in flying birds is a challenging task, yet it has always fascinated scientists from different disciplines. In the attempt of studying and modelling line formation, we collected high-precision position data of 29 free-flying northern bald ibises (Geronticus eremita) using Global Navigation Satellite System loggers, to investigate whether the spatial relationships within a flock can be explained by birds maintaining energetically advantageous positions. Specifically, we exploited domain knowledge and available literature information to model by means of fuzzy logic where the air vortices lie behind a flying bird. This allowed us to determine when a leading bird provides the upwash to a following bird, reducing its overall effort. Our results show that the fuzzy model allows to easily distinguish which bird is flying in the wake of another individual, provides a clear indication about flying flock dynamics and also gives a hint about birds' social relationships.
The genetic basis and potential molecular mechanism of yellow-albino northern snakehead (Channa argus)
Authors: Sun Donglei , Qi Xin , Wen Haishen , Li Chao , Li Jianlong , Chen Jiwei , Tao Zexin , Zhu Mingxin , Zhang Xiaoyan , Li Yun
Published: February 2023

Body colour is an important economic trait for commercial fishes. Recently, a new colour morph displaying market-favoured yellow skin (termed as yellow-mutant, YM) of northern snakehead (Channa argus) was discovered in China. We confirmed that YM snakehead is an albino with complete loss of melanin in the skin and eyes by histological and ultrastructural observations, and inherited as a recessive Mendelian trait. By applying genomic analysis approaches, in combination with gene knockdown and rescue experiments, we suggested a non-sense mutation inslc45a2(c.383G > A) is the causation for the YM snakehead. Notably, significantly higher levels of key melanogenesis genes (tyr,tyrp1,dctandpmel) and phospho-MITF protein were detected in YM snakehead than those in wild-type individuals, and the underlying mechanism was further investigated by comparative transcriptomic analysis. Results revealed that differential expressed genes involved in pathways like MAPK, WNT and calcium signalling were significantly induced in YM snakehead, which might account for the increased amount of melanogenesis elements, and presumably be stimulated by fibroblast-derived melanogenic factors in a paracrine manner. Our study clarified the genetic basis of colour variation inC. argusand provided the preliminary clue indicating the potential involvement of fibroblasts in pigmentation in fish.
Streptococcus suis outbreak caused by an emerging zoonotic strain with acquired multi-drug resistance in Thailand
Authors: Brizuela Jaime , Kajeekul Rattagan , Roodsant Thomas J. , Riwload Athita , Boueroy Parichart , Pattanapongpaibool Auttapong , Thaipadungpanit Janjira , Jenjaroenpun Piroon , Wongsurawat Thidathip , Batty Elizabeth M. , van der Putten Boas C. L. , Schultsz Constance , Kerdsin Anusak
Published: February 2023

Streptococcus suisis an emerging zoonotic swine pathogen which can cause severe infections in humans. In March 2021, an outbreak ofS. suisinfections with 19 confirmed cases of septicemia and meningitis leading to two deaths, occurred in Nakhon Ratchasima province, Thailand. We characterized the outbreak through an epidemiological investigation combined with Illumina and Nanopore whole genome sequencing (WGS). The source of the outbreak was traced back to a raw pork dish prepared from a single pig during a Buddhist ceremony attended by 241 people. WGS analysis revealed that a singleS. suisserotype 2 strain belonging to a novel sequence type (ST) of the emergent Thai zoonotic clade CC233/379, was responsible for the infections. The outbreak clone grouped together with other Thai zoonotic strains from CC233/379 and CC104 in a globalS. suisphylogeny and capsule switching events between serotype 2 zoonotic strains and serotype 7 porcine strains were identified. The outbreak strain showed reduced susceptibility to penicillin corresponding with mutations in key residues in the penicillin binding proteins (PBPs). Furthermore, the outbreak strain was resistant to tetracycline, erythromycin, clindamycin, linezolid and chloramphenicol, having acquired an integrative and conjugative element (ICE) carrying resistance genestetOandermB,as well as a transposon from the IS1216 family carryingoptrAandermA. This investigation demonstrates that multi-drug resistant zoonotic lineages ofS. suiswhich pose a threat to human health continue to emerge.
Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA)
Authors: Lafzi Atefeh , Borrelli Costanza , Bach Karsten , Kretz Jonas A. , Handler Kristina , Regan-Komito Daniel , Ficht Xenia , Frei Andreas , Moor Andreas
Published: February 2023

Spatial transcriptomics techniques are able to chart the distribution and localization of cell types and RNA molecules across a tissue. Here, we generated matched sequencing-based (Visium) and hybridization-based (Molecular Cartography) spatial transcriptomics data of human IBD samples. We then developed ISCHIA (Identifying Spatial Co-occurrence in Healthy and InflAmed tissues), a computational framework to analyze the spatial co-occurrence of cell types and transcript species in the tissue environment. ISCHIA revealed tightly associated cellular networks, ligand-receptor interactions enriched in the inflamed human colon, and their associated gene signatures, highlighting the hypothesis-generating power of co-occurrence analysis on spatial transcriptomics data.
AMLs harboring DNMT3A-destabilizing variants show increased intratumor DNA methylation heterogeneity at bivalent chromatin domains
Authors: Lee Dohoon , Koo Bonil , Kim Seok-Hyun , Byun Jamin , Hong Junshik , Shin Dong-Yeop , Sun Choong-Hyun , Song Ji-Joon , Kim Jaesung , Jaiswal Siddhartha , Yoon Sung-Soo , Kim Sun , Koh Youngil
Published: February 2023

The mechanistic link between the complex mutational landscape ofde novomethyltransferaseDNMT3Aand the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. A recent discovery on the catalogue of DNMT3A-destabilizing mutations throughout theDNMT3Agene as well as the oligomerization-dependent catalytic property of DNMT3A prompted us to investigate the common effect of DNMT3A-destabilizing mutations (DNMT3AINS) on the genomewide methylation patterns of AML cells. In this study, we describe the characteristics ofDNMT3AINSAML methylomes through the comprehensive computational analyses on three independent AML cohorts. As a result, we show that methylomes ofDNMT3AINSAMLs are considerably different from those ofDNMT3AR882AMLs in that they exhibit both locally disordered DNA methylation states and increased across-cell DNA methylation heterogeneity in bivalent chromatin domains. This increased epigenetic heterogeneity was functionally associated with heterogeneous expression of membrane-associated factors shaping stem cell niche, implying the diversification of the modes of leukemic stem cell-niche interactions. We also present that the level of methylation disorder at bivalent domains predicts the response of AML cells to hypomethylating agents through cell line- and patient-level analyses, which supports that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.
Pairtools: from sequencing data to chromosome contacts
Authors:   Open2C, Abdennur Nezar , Fudenberg Geoffrey , Flyamer Ilya M. , Galitsyna Aleksandra A. , Goloborodko Anton , Imakaev Maxim , Venev Sergey V.
Published: February 2023

The field of 3D genome organization produces large amounts of sequencing data from Hi-C and a rapidly-expanding set of other chromosome conformation protocols (3C+). Massive and heterogeneous 3C+ data require high-performance and flexible processing of sequenced reads into contact pairs. To meet these challenges, we presentpairtools– a flexible suite of tools for contact extraction from sequencing data.Pairtoolsprovides modular command-line interface (CLI) tools that can be flexibly chained into data processing pipelines.Pairtoolsprovides both crucial core tools as well as auxiliary tools for building feature-rich 3C+ pipelines, including contact pair manipulation, filtration, and quality control. Benchmarkingpairtoolsagainst popular 3C+ data pipelines shows advantages ofpairtoolsfor high-performance and flexible 3C+ analysis. Finally,pairtoolsprovides protocol-specific tools for multi-way contacts, haplotype-resolved contacts, and single-cell Hi-C. The combination of CLI tools and tight integration with Python data analysis libraries makespairtoolsa versatile foundation for a broad range of 3C+ pipelines.
Selection of a Promiscuous Minimalist cAMP Phosphodiesterase from a Library ofDe NovoDesigned Proteins
Authors: Schnettler J. David , Wang Michael S. , Gantz Maximilian , Karas Christina , Hollfelder Florian , Hecht Michael H.
Published: February 2023

The ability of unevolved amino acid sequences to become biological catalysts was key to the emergence of life on Earth. However, billions of years of evolution separate complex modern enzymes from their simpler early ancestors. To study how unevolved sequences can develop new functions, we screened for enzymatic activity in a collection of > 1 million novel sequences based on ade novo4-helix bundle library of semi-random sequences. To mirror evolutionary selection for biological function, we screened the collection using ultrahigh-throughput droplet microfluidics to identify features that yield phosphoesterase activity. Characterization of active hits demonstrated that acquiring new function required a large jump in sequence space: screening enriched for truncations that removed > 40% of the protein chain and introduced a catalytically important cysteine. The truncated protein dimerized into a dynamic α-helical structure, consistent with the idea that gain of function was accompanied by an increase in structural dynamics relative to the parental 4-helix bundle. The purified protein catalyzes the hydrolysis of a range of phosphodiesters, with the greatest activity toward the biological second messenger cyclic AMP (cAMP). The novel cAMPase is a manganese-dependent metalloenzyme and catalyzes cAMP hydrolysis with a rate acceleration on the order of 109and catalytic proficiency on the order of 1014M−1, comparable to large enzymes shaped by billions of years of evolution. These findings suggest that fragmentation to modular primordial peptides can be a fertile avenue for introducing structural and functional diversity into proteins.

GRAPHICAL ABSTRACT
Phyllotaxis as a dynamical system
Authors: Jean-Paul Walch
Published: February 2023

One of the major puzzles in phyllotaxis is the much higher frequency of Fibonacci spirals compared to other spiral arrangements such as Lucas spirals. We show that spirals are a form of symmetry, in the same way that axial symmetry is a form of symmetry, which explains why they can be the consequence of many different microscopic phenomena. We apply dynamical systems theory to the main types of phyllotaxis. We show that only Fibonacci spirals should exist and that the other spiral modes (including Lucas) are the consequence of developmental errors, such as the dislocation of a pseudo-orthostichy.
JUMP: replicability analysis of high-throughput experiments with applications to spatial transcriptomic studies
Authors: Lyu Pengfei , Li Yan , Wen Xiaoquan , Cao Hongyuan
Published: February 2023

Motivation

Replicability is the cornerstone of scientific research. The current statistical method for high-dimensional replicability analysis either cannot control the false discovery rate (FDR) or is too conservative.

Results

We propose a statistical method, JUMP, for the high-dimensional replicability analysis of two studies. The input is a high dimensional paired sequence ofp-values from two studies and the test statistic is the maximum ofp-values of the pair. JUMP uses four states of thep-value pairs to indicate whether they are null or non-null. Conditional on the hidden states, JUMP computes the cumulative distribution function of the maximum ofp-values for each state to conservatively approximate the probability of rejection under the composite null of replicability. JUMP estimates unknown parameters and uses a step-up procedure to control FDR. By incorporating different states of composite null, JUMP achieves a substantial power gain over existing methods while controlling the FDR. Analyzing two pairs of spatially resolved transcriptomic datasets, JUMP makes biological discoveries that otherwise cannot be obtained by using existing methods.

Availability

An R package JUMP implementing the JUMP method is available on CRAN (https://CRAN.R-project.org/package=JUMP).
Methane production byMethanothrix thermoacetophilavia direct interspecies electron transfer withGeobacter metallireducens
Authors: Zhou Jinjie , Smith Jessica A. , Li Meng , Holmes Dawn E.
Published: February 2023

Methanothrixis widely distributed in natural and artificial anoxic environments and plays a major role in global methane emissions. It is one of only two genera that can form methane from acetate dismutation and through participation in direct interspecies electron transfer (DIET) with exoelectrogens. AlthoughMethanothrixis a significant member of many methanogenic communities, little is known about its physiology. In this study, transcriptomics helped to identify potential routes of electron transfer during DIET betweenGeobacter metallireducensandMethanothrix thermoacetophila. Additions of magnetite to cultures significantly enhanced growth by acetoclastic methanogenesis and by DIET, while granular activated carbon (GAC) amendments impaired growth. Transcriptomics suggested that the OmaF-OmbF-OmcF porin complex and the octaheme outer membranec-type cytochrome, Gmet_0930, were important for electron transport across the outer membrane ofG. metallireducensduring DIET withMx. thermoacetophila. Clear differences in the metabolism ofMx. thermoacetophilawhen grown via DIET or acetate dismutation were not apparent. However, genes coding for proteins involved in carbon fixation and a surface associated quinoprotein, SqpA, were highly expressed in all conditions. Expression of gas vesicle genes was significantly lower in DIET-than acetate-grown cells, possibly to facilitate better contact between membrane associated redox proteins during DIET. These studies reveal potential electron transfer mechanisms utilized by bothGeobacterandMethanothrixduring DIET and provide important insights into the physiology ofMethanothrixin anoxic environments.

Importance

Methanothrixis a significant methane producer in a variety of methanogenic environments including soils and sediments as well as anaerobic digesters. Its abundance in these anoxic environments has mostly been attributed to its high affinity for acetate and its ability to grow by acetoclastic methanogenesis. However,Methanothrixspecies can also generate methane by directly accepting electrons from exoelectrogenic bacteria through direct interspecies electron transfer (DIET). Methane production through DIET is likely to further increase their contribution to methane production in natural and artificial environments. Therefore, acquiring a better understanding of DIET withMethanothrixwill help shedding light on ways to 1) minimize microbial methane production in natural terrestrial environments and 2) maximize biogas formation by anaerobic digesters treating waste.
Genomes of the Autonomous Parvovirus Minute Virus of Mice Induce Replication Stress Through RPA Exhaustion
Authors: Haubold MegAnn K. , Aquino Jessica N. Pita , Rubin Sarah R. , Jones Isabella K. , Pham Edward , Majumder Kinjal
Published: February 2023

The oncolytic autonomous parvovirus Minute Virus of Mice (MVM) establishes infection in the nuclear environment by usurping host DNA Damage Response (DDRs) in the vicinity of cellular DNA break sites. MVM replication induces a global cellular DDR that is dependent on signaling by the ATM kinase and inactivates the cellular ATR-kinase pathway. However, the mechanism of how MVM generates cellular DNA breaks remains unknown. Using single molecule DNA Fiber Analysis, we have discovered that MVM infection leads to a shortening of host replication forks as infection progresses, as well as induction of replication stress prior to the initiation of virus replication. Ectopically expressed viral non-structural proteins NS1 and NS2 are sufficient to cause host-cell replication stress, as is the presence of UV-inactivated non-replicative MVM genomes. The host single-stranded DNA binding protein Replication Protein A (RPA) associates with the UV-inactivated MVM genomes, suggesting MVM genomes might serve as a sink for cellular stores of RPA. Overexpressing RPA in host cells prior to UV-MVM infection rescues DNA fiber lengths and increases MVM replication, confirming that MVM genomes deplete RPA stores to cause replication stress. Together, these results indicate that the presence of ssDNA in the nucleus generated by MVM genomes and viral proteins induces replication stress in the host cell through RPA exhaustion, rendering the host genome vulnerable to additional DNA breaks.

AUTHOR SUMMARY

Parvoviruses are used in the clinic to design recombinant gene therapy vectors and as oncolytic agents. The autonomous parvovirus MVM utilizes the host cell’s DNA damage response machinery to replicate in host cells and cause additional DNA breaks. However, the mechanism of MVM-induced DNA damage remains unknown. We have discovered that MVM sequesters the host DNA repair protein RPA, which normally associates with single stranded DNA in the nucleus, rendering the host genome susceptible to replication stress. Our study provides insights into the mechanisms utilized by single-stranded DNA viruses to amplify host-cell DNA damage.
Predicting hearing help-seeking: What features are important for a profiling module within a hearing mHealth application?
Authors: Angonese Giulia , Buhl Mareike , Kuhlmann Inka , Kollmeier Birger , Hildebrandt Andrea
Published: February 2023

Background

Mobile health care solutions can improve quality, accessibility and equity of health services, fostering early rehabilitation. For people suffering from hearing loss, mobile applications might be designed to support the decision-making processes in auditory diagnostics and to provide treatment recommendations to the user (e.g., hearing aid need). For some individuals, such mobile app might be the first contact with a hearing diagnostic service and should motivate users with hearing loss to seek professional help.

Objective

This study aims at characterizing individuals who are more or less prone to seek professional help after the repeated use of an app-based hearing test. The goal is to develop a profiling module building upon hearing related traits and personality characteristics to secure personalized treatment recommendations in hearing mHealth solutions.

Methods

N=185 (106 females) non-aided older individuals (Mage=63.8,SDage=6.6) with subjective hearing loss participated in a comprehensive online study. We collected cross-sectional and longitudinal data on several hearing-related and psychological features that were previously found to predict hearing help-seeking. Readiness to seek help was assessed as outcome variable at study-end and after two months. Participants were classified into help-seekers and non-seekers with several supervised machine learning algorithms (Random Forest, Naïve Bayes and Support Vector Machine). The most relevant features for prediction were identified with feature importance analysis.

Results

The algorithms correctly predicted action to seek help at study-end in 66 to 70% of cases, reaching 75% classification accuracy at follow-up. Among the most important features for classifications were the degree of hearing loss and its perceived consequences in daily life, attitude towards hearing aids, and the personality traits neuroticism and conscientiousness.

Conclusions

This study contributes to the identification of individual characteristics that predict help-seeking in older individuals with self-perceived hearing loss. Suggestions for the implementation of an individual profiling algorithm and for targeted recommendations in hearing mHealth applications are derived.
Optimal Delivery Management for the Prevention of Early Neonatal SARS-CoV-2 Infection: Systematic review and Meta-analysis
Authors: Chan Christina S , Kong Juin Yee , Sultana Rehena , Mundra Vatsala , Babata Kikelomo L , Mazzarella Kelly , Adhikari Emily H , Yeo Kee Thai , Hascoët Jean-Michel , Brion Luc P
Published: February 2023

Objective

Review how specific delivery management interventions (DMI) are associated with early neonatal SARS-CoV-2 infection (ENI) and neonatal death <28 days of life (ND).

Design

Systematic review and meta-analysis of individual patient-specific data from articles published 1 January 2020 - 31 December 2021 from Cochrane review databases, Medline and Google Scholar.

Setting

International publications specifying DMI, ENI, and ND.

Patients

Pregnant women infected with SARS-CoV-2 and their infants

Main outcome measures

Article inclusion criteria: 1) mothers with SARS-CoV-2 PCR positive status within 10 days before delivery or symptomatic at delivery with a positive test within 48 hours after delivery, 2) delivery method described, 3) infant SARS-CoV-2 PCR result reported. Primary outcomes were 1) ENI confirmed by positive neonatal PCR and 2) ND.

Results

Among 11,075 screened publications, 117 publications containing data for 244 infants and 230 mothers were included. Maternal and infant characteristics were pooled using DerSimonian-Laird inverse variance method. Primary outcome analyses were completed using logit transformation and random effect. Heterogeneity of included studies was evaluated with I2statistics.

No routine care was described so comparison of DMI combinations to routine care was not possible. Sample size for each combination was too small to conduct any valid comparison of different DMI combinations.

Conclusion

Support for specific DMI in SARS-CoV-2 infected mothers is lacking. This review highlights the need for rigorous and multinational studies on the guidelines best suited to prevent transmission from mother to neonate.

KEY MESSAGES

What is already known on this topic

Several specific delivery management interventions (DMI) have been recommended for women with active SARS-CoV-2 to prevent early neonatal SARS-CoV-2 infection.

What this study adds

This systematic review shows that support for specific DMI in SARS-CoV-2 infected mothers is lacking.

How this study might affect research, practice or policy

This review highlights the need for rigorous and multinational studies on the guidelines best suited to prevent transmission from mother to neonate.
Translatome analysis reveals microglia and astrocytes to be distinct regulators of inflammation in the hyperacute and acute phases after stroke
Authors: Hernandez Victoria G. , Lechtenberg Kendra J. , Peterson Todd C. , Zhu Li , Lucas Tawaun A. , Owah Justice O. , Dorsey Alanna I. , Gentles Andrew J. , Buckwalter Marion S.
Published: February 2023

Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and long-term disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain astrocyte and microglia-derived mRNA transcripts in a hyperacute (4 hours) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 hours by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute astrocyte profile was marked by stress response genes and transcription factors, such asFosandJun, involved in pro-inflammatory pathways such as TNF-α. By 3 days, microglia shift to a proliferative state and astrocytes strengthen their inflammatory response. The astrocyte pro-inflammatory response at 3 days is partially driven by the upregulation of the transcription factorsC/EBPβ, Spi1, andRel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together our data comprehensively describe the astrocyte and microglia-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation.
Automatic identification of scientific publications describing digital reconstructions of neural morphology
Authors: Maraver Patricia , Tecuatl Carolina , Ascoli Giorgio A.
Published: February 2023

Motivation

The increasing number of peer-reviewed publications constitutes a challenge for biocuration. For example, NeuroMorpho.Org, a sharing platform for digital reconstructions of neural morphology, must evaluate more than 6000 potentially relevant articles per year to identify data of interest. Here, we describe a tool that uses natural language processing and deep learning to assess the likelihood of a publication to be relevant for the project.

Results

The tool automatically identifies articles describing digitally reconstructed neural morphologies with high accuracy. Its processing rate of 900 publications per hour is not only amply sufficient to autonomously track new research, but also allowed the successful evaluation of older publications backlogged due to limited human resources. The number of bio-entities found since launching the tool almost doubled while greatly reducing manual labor. The classification tool is open source, configurable, and simple to use, making it extensible to other biocuration projects.

Availability

https://github.com/Joindbre/TextRelevancy

Contact

ascoli@gmu.edu

Supplementary information

Supplementary information, tool installation, and API usage are available athttps://docs.joindbre.com
Genetic control of cell layer interactions in plants via tissue mechanics
Authors: Kelly-Bellow Robert , Lee Karen , Kennaway Richard , Barclay Elaine , Whibley Annabel , Bushell Claire , Spooner Jamie , Yu Man , Brett Paul , Kular Baldeep , Cheng Shujing , Chu Jinfang , Xu Ting , Lane Brendan , Fitzsimons James , Xue Yongbiao , Smith Richard , Whitewoods Christopher D. , Coen Enrico
Published: February 2023

Plant development depends on coordination of growth between different cell layers. Coordination may be mediated by molecular signalling or mechanical connectivity between cells, but evidence for genetic control via direct mechanics has been lacking. We show that a brassinosteroid-deficient dwarf mutant of the aquatic plantUtricularia gibbahas twisted internal tissue, likely caused by a mechanical constraint from a slow-growing epidermis creating tissue stresses. This conclusion is supported by showing that inhibition of brassinosteroid action in anArabidopsismutant compromised for cell adhesion, enhances epidermal crack formation, an indicator of increased tissue tension. Thus, genes driving brassinosteroid synthesis can promote growth of internal tissue by reducing mechanical epidermal constraint, showing that tissue mechanics plays a key role in coordinating growth between cell layers.

One-Sentence Summary

Internal twists in a mutant carnivorous plant reveal how genes control growth via tissue mechanics.