bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal correlative imaging and modelling of phosphorus uptake from soil by hyphae of mycorrhizal fungi
Authors: Keyes Sam , van Veelen Arjen , McKay Fletcher Dan , Scotson Callum , Koebernick Nico , Petroselli Chiara , Williams Katherine , Ruiz Siul , Cooper Laura , Mayon Robbie , Duncan Simon , Dumont Marc , Jakobsen Iver , Oldroyd Giles , Tkacz Andrzej , Poole Philip , Mosselmans Fred , Borca Camelia , Huthwelker Thomas , Jones David L. , Roose Tiina
Published: January 2022

Phosphorus (P) is essential for plant growth. Arbuscular mycorrhizal fungi (AMF) aid its uptake by acquiring P from sources distant from roots in return for carbon. Little is known about how AMF colonise soil pore‐space, and models of AMF‐enhanced P‐uptake are poorly validated.

We used synchrotron X‐ray computed tomography to visualize mycorrhizas in soil and synchrotron X‐ray fluorescence/X‐ray absorption near edge structure (XRF/XANES) elemental mapping for P, sulphur (S) and aluminium (Al) in combination with modelling.

We found that AMF inoculation had a suppressive effect on colonisation by other soil fungi and identified differences in structure and growth rate between hyphae of AMF and nonmycorrhizal fungi. Our results showed that AMF co‐locate with areas of high P and low Al, and preferentially associate with organic‐type P species over Al‐rich inorganic P.

We discovered that AMF avoid Al‐rich areas as a source of P. Sulphur‐rich regions were found to be correlated with higher hyphal density and an increased organic‐associated P‐pool, whilst oxidized S‐species were found close to AMF hyphae. Increased S oxidation close to AMF suggested the observed changes were microbiome‐related. Our experimentally‐validated model led to an estimate of P‐uptake by AMF hyphae that is an order of magnitude lower than rates previously estimated – a result with significant implications for the modelling of plant–soil–AMF interactions.
Chronic wounds in persons living with dementia: An integrative review
Authors: Sefcik Justine S. , McLaurin Elease J. , Bass Ellen J. , DiMaria‐Ghalili Rose Ann
Published: January 2022

Background

Persons living with dementia (PLWD) are at risk for chronic wounds; however, they are rarely included in research.

Objectives

To inform practice and research directions, the aim of this integrative review was to identify and synthesise previous knowledge about the characteristics of chronic wounds in PLWD, in terms of chronic wound types, prevalence, setting and interventions.

Design

A literature search was conducted for publications in English using PubMed, Web of Science and CINAHL. The minimum information required for inclusion was how many PLWD enrolled in the study had wounds.

Methods

This integrative review followed the Whittemore and Knafl methodology. Data extraction and synthesis were guided by a directed content analysis, with a coding structure based on an initial review of the literature.

Results

Thirty‐six articles met the inclusion criteria. The majority were missing characteristics of PLWD including severity of dementia and race/ethnicity/nationality, and none mentioned skin tone. Most focused on pressure injuries in the nursing home and acute care setting. Few included information on interventions. Only one discussed challenges of wound care for a PLWD exhibiting aggression.

Conclusion

There is a gap in the literature regarding PLWD and chronic wounds other than pressure injuries that are common in older adults (e.g. diabetic foot ulcers, venous leg ulcers). Research is warranted among those PLWD who live alone and those who receive wound care from family caregivers to understand experiences. Knowledge can inform the development of future novel interventions for wound healing. Future research is needed regarding chronic wounds in those who exhibit behavioural and psychological symptoms of dementia.

Relevance to Clinical Practice

Nurses that care for chronic wounds in PLWD can contribute their knowledge to include information in guidelines on best care practices and contribute their perspective to research teams for future research.
Expression of oxytocin receptors and oxytocin assisted electroejaculation in the domestic cat (Felis catus)
Authors: Tiptanavattana Narong , Pakdeesanaeha Thitida , Thongsima Thitiporn , Techarungchaikul Sirichai , Tharasanit Theerawat
Published: January 2022

Oxytocin is a peptide hormone that mainly functions to control the contractility of smooth muscles and sex‐related steroidogenesis in male reproductive tracts. However, specific information concerning this hormone in controlling the reproductive organs of cats is limited. This study aimed to investigate the expression of oxytocin receptors (OTRs) and their signal mediator via prostacyclin synthase (PTGIS) in reproductive structures following oxytocin assisted electroejaculation. In Experiment 1, the testis, cauda epididymis and vas deferens from five cats were examined by immunohistochemistry and quantitative polymerase chain reaction in order to study the responses of OTR and PTGIS mRNA to oxytocin injection. Experiment 2 examined the effect of oxytocin administration prior to electroejaculation on ejaculate characteristics and sperm quality in terms of motility, viability and fertilizing ability. Immunohistochemistry revealed the expression of OTRs in Leydig's, peritubular myoid cells and some spermatogenic cells. The expression was found in the epithelium and smooth muscle of the epididymis and vas deferens. After oxytocin administration, the OTR mRNA was upregulated in the epididymis (p > .05) and vas deferens (p = .01). The expression level of PTGIS mRNA increased in the response to oxytocin treatment only for the vas deferens (p > .05). Oxytocin treatment before electroejaculation resulted in an approximately twofold increase in sperm concentration and total sperm output/ejaculate, while this intervention did not significantly affect ejaculate volume, sperm quality or fertilizing ability. This study concluded that the oxytocin cascade is locally present in the reproductive structures and plays a role in promoting sperm delivery during electroejaculation in cats.
Ceci n'est pas un État: The Order of Malta and the Holy See as precedents for deterritorialized statehood?
Authors: Allen Emma , Prost Mario
Published: January 2022

Sinking island States have become allegories of the Anthropocene and a symbol of the radical violence of climate change. Various theories have been advanced supporting the continued existence of sunken islands as deterritorialized States. A common view among advocates of the deterritorialized statehood thesis is that, while at odds with the dominant concept of States as territorial entities, it is supported by precedent. In this article, we engage critically with this strand of argument and argue that the appeal to precedent raises important paradoxes for the continuation thesis. We seek to make clear that a landless State in the full sense of the term is a proposition for which there is, in actual fact, no precedent in international law and that some of the precedents that are cited in support of deterritorialised statehood—such as the Order of Malta and the Holy See—are precedents of non‐State sovereign entities. Pursuing deterritorialized existence on the basis of those precedents would therefore involve a downgrade from State to non‐State status, an outcome we show to be normatively undesirable.
Quantitative comparison of dose–effect and time–course of fluticasone furoate and fluticasone propionate in adult and adolescent patients with persistent asthma: A systematic review and meta‐analysis
Authors: Zhong Ying , Li Lujin , Chen Rui , Zheng Qingshan
Published: January 2022

This study aimed to quantitatively compare the efficacy of fluticasone furoate (FF) and fluticasone propionate (FP) in adolescents and adults with asthma. We searched the PubMed and EMBASE databases for placebo‐controlled trials that met the inclusion criteria. Pharmacodynamic models were established to describe the time–course of the primary outcome (trough forced expiratory volume in the first second [FEV1]). Secondary outcomes (asthma symptoms, quality of life and exacerbations) were also compared via a meta‐analysis. A total of 14 articles were included in the analysis, involving 6640 subjects. The efficacy plateau of the two drugs could be reached in 2 weeks. The changes from the baseline in trough FEV1 (95% CI) at week 2 of FF at 200 and 100 μg/day were 0.168 L (0.064–0.199) and 0.127 L (0.048–0.163), respectively. The changes from the baseline in trough FEV1 (95% CI) at week 2 of FP at 1000, 500, 250 and 100 μg/day were 0.133 L (0.049–0.171), 0.127 L (0.043–0.163), 0.117 L (0.039–0.150) and 0.093 L (0.032–0.129), respectively. The efficacy of FP had reached a plateau at the maximum evaluated dose (1000 μg/day), while a plateau effect was not seen at the maximum evaluated dose of FF (200 μg/day). In terms of secondary outcomes, the relative effects of the two drugs relative to the placebo were similar and did not show obvious dose–effect relationships. In this study, the time–course and dose–effect characteristics of FP, FF and placebo were quantitatively evaluated, providing necessary quantitative information for asthma‐related guidelines.
Is routine blood typing and screening necessary before primary total hip or knee arthroplasty in the 21st century?
Authors: Nuñez Jorge H. , Mora Lidia , Carbonell Carla , Barro Víctor , Casaccia Marcelo , Pérez Marta , Minguell Joan
Published: January 2022

Background

Blood loss warranting transfusion is a relatively rare complication of major‐joint arthroplasty procedures like total knee arthroplasty (TKA) and total hip arthroplasty (THA). Despite this rarity, pre‐transfusion testing (blood typing, screening, and cross‐matching) has become routine. We sought to determine if such routine testing is necessary for patients who undergo a primary TKA or THA by (1) measuring the current rate of intraoperative transfusions in primary TKA and THA patients, (2) identifying risk factors for transfusions, and (3) calculating the costs of such blood typing and screening.

Study Methods

We retrospectively examined the records of 992 patients who underwent primary TKA, THA, or unicompartmental knee arthroplasty (UKA) to identify patients requiring intra‐operative or in‐hospital postoperative transfusions. Demographic and baseline clinical and laboratory data also were collected and analyzed to identify predictors of transfusion. Cost analysis was performed.

Results

The rate of intraoperative transfusion was 1.7% (17/992 patients), with rates of 2.1%, 1.6%, and 0% for TKA, THA, and UKA respectively. The in‐hospital transfusion rate was 10.3%, with corresponding postoperative transfusion rates of 9.1%, 12.9%, and 2%. The only baseline variable significantly linked to transfusions on multivariable analysis was preoperative hemoglobin level, with preoperative Hgb <12 g/dl predictive of transfusions in both TKA (p = .02) and THA (p = .024) patients.

Discussion

Our study suggests that pre‐transfusion testing for all patients undergoing primary UKA, TKA or THA is unnecessary. We recommend reserving routine pre‐transfusion testing for patients with preoperative hemoglobin levels below 12 g/dl.
Profit‐raising entry under oligopolistic trade with endogenous input prices
Authors: Naylor Robin , Soegaard Christian
Published: January 2022

Firms which face the threat of import competition from foreign rivals are conventionally seen as favouring import protection. We show that this is not necessarily the case when domestic firms’ input prices are determined endogenously. In a framework where the input price is determined through contracting with an upstream agent, which could be an input supplier or a labour union, the relationship between a domestic downstream firm's profits and the number of foreign competitors depends on trade costs and the curvature of the demand function. If trade costs are sufficiently high, an increase in the number of foreign entrants can raise the profits of a downstream firm in a home market characterised by Cournot competition. For any concave and linear demand function and for any demand function which is not ‘too convex’, this occurs due to the upstream agent moderating its input price allowing downstream firms to increase profits. For sufficiently convex demand functions, on the other hand, profit‐raising entry still occurs, albeit through a substantively different mechanism, and depending upon the extent to which an increase in the input price is passed on to the final consumer.
Efficacy of cryotherapy in the treatment of cutaneous horn associated with papillomatosis in a dog
Authors: Noleto de Paiva Felipe , Silva Gomes de Souza Manuela , Correia Fernandes Junior Laercio , Souza Costa Thiago , Sampaio Martins Land Manier Bruna , Caicó Collares Araujo Dayane , Bazaga Botelho Cristiane , Israel Fernandes Julio
Published: January 2022

Cutaneous horn is a skin disease with low incidence and few citations in the literature. This report describes a dog with multiple cutaneous lesions of papillomatosis and one giant cutaneous horn on the face. Two sessions of cryotherapy achieved complete remission of the lesions.
Abdominocentesis techniques in horses
Authors: Radcliffe Rolfe M. , Hill Jacqueline A. , Liu Sharon Y. , Cook Vanessa L. , Hurcombe Samuel D. A. , Divers Thomas J.
Published: January 2022

Background

Abdominocentesis is commonly used to evaluate the abdominal cavity of the horse. This technique provides valuable diagnostic information as well as the means to monitor patients with abdominal diseases being managed medically and to determine their need for surgical management. Complications are uncommon and include trauma to the gastrointestinal tract or spleen, septic peritonitis, or abdominal wall infection.

Procedures

This review describes the indications, utility, patient preparation, and instructions for performing abdominocentesis as well as possible complications reported in horses. Step‐by‐step instructions are provided for the two most commonly used abdominocentesis techniques in horses, which include the use of a needle (18 Ga, 3.8 cm [1.5 in]) and a teat cannula (9.5 cm [3.75 in]).

Peritoneal fluid collection and fluid analysis can be used to confirm diagnosis of intraabdominal pathology including inflammatory, infectious, neoplastic, obstructive, and bowel strangulation, leading to additional diagnostic and therapeutic plans.

Key points

Abdominocentesis is useful as a diagnostic procedure in horses suffering from colic, diarrhea, weight loss, or other conditions involving the abdominal cavity and is an integral component of diagnostic testing for colic at referral institutions or in the field.

Abdominal fluid collection using an 18‐Ga, 3.8‐cm (1.5‐in) needle is recommended for adult horses because the needle is long enough to penetrate the peritoneal cavity.

The teat cannula technique is recommended for use in adult horses, foals, and miniature horses to reduce the risk of enterocentesis, even though this procedure is more traumatic than using an 18‐Ga, 3.8‐cm needle.

Ultrasonography of the abdomen is a valuable tool in the assessment of any horse with signs of colic, but it is not essential for performing an abdominocentesis successfully.
Topically administered purified clinoptilolite‐tuff for the treatment of cutaneous wounds: A prospective, randomised phase I clinical trial
Authors: Deinsberger Julia , Marquart Elias , Nizet Stephane , Meisslitzer Claudia , Tschegg Cornelius , Uspenska Kateryna , Gouya Ghazaleh , Niederdöckl Jan , Freissmuth Michael , Wolzt Michael , Weber Benedikt
Published: January 2022

In an ageing society, chronic ulcers pose an increasingly relevant healthcare issue associated with significant morbidity and an increasing financial burden. Hence, there is an unmet medical need for novel, cost‐effective therapies that improve healing of chronic cutaneous wounds. This prospective, randomised, open‐label, phase I trial investigated the safety and tolerability of topically administered purified clinoptilolite‐tuff (PCT), mainly consisting of the naturally occurring zeolite‐mineral clinoptilolite, in artificial wounds in healthy male volunteers compared to the standard of care (SoC). We found that topically administered PCT was safe for therapeutic application in acute wounds in healthy male volunteers. No significant differences in wound healing or wound conditions were observed compared to SoC‐treated wounds. However, we found a significantly higher proportion of CD68‐positive cells and a significantly lower proportion of α‐smooth muscle actin‐positive cells in PCT‐treated wounds. Scanning electron microscopy revealed PCT particles in the restored dermis in some cases. However, these did not impede wound healing or clinical symptoms. Hence, purified PCT could represent an attractive, cost‐effective wound treatment promoting the process of healing.
Experimental and Numerical Investigation of Parameters Affecting High-Frequency Irreversible Electroporation for Prostate Cancer Ablation
Authors: Aycock Kenneth N. , Vadlamani Ram Anand , Jacobs Edward J. , Imran Khan Mohammad , Verbridge Scott S. , Allen Irving C. , Manuchehrabadi Navid , Davalos Rafael V.
Published: January 2022

While the primary goal of focal therapy for prostate cancer (PCa) is conserving patient quality of life by reducing oncological burden, available modalities use thermal energy or whole-gland radiation which can damage critical neurovascular structures within the prostate and increase risk of genitourinary dysfunction. High-frequency irreversible electroporation (H-FIRE) is a promising alternative ablation modality that utilizes bursts of pulsed electric fields (PEFs) to destroy aberrant cells via targeted membrane damage. Due to its nonthermal mechanism, H-FIRE offers several advantages over state-of-the-art treatments, but waveforms have not been optimized for treatment of PCa. In this study, we characterize lethal electric field thresholds (EFTs) for H-FIRE waveforms with three different pulse widths as well as three interpulse delays in vitro and compare them to conventional irreversible electroporation (IRE). Experiments were performed in non-neoplastic and malignant prostate cells to determine the effect of waveforms on both targeted (malignant) and adjacent (non-neoplastic) tissue. A numerical modeling approach was developed to estimate the clinical effects of each waveform including extent of nonthermal ablation, undesired thermal damage, and nerve excitation. Our findings indicate that H-FIRE waveforms with pulse durations of 5 and 10 μs provide large ablations comparable to IRE with tolerable levels of thermal damage and minimized muscle contractions. Lower duration (2 μs) H-FIRE waveforms exhibit the least amount of muscle contractions but require increased voltages which may be accompanied by unwanted thermal damage.
Research on Prediction Models for the Compression-Resilience Performance of Corrugated Metal Gaskets With Residual Stress
Authors: Zhan Yuanye , Lan Meng , Zhu Xiaolei , Lu Xiaofeng
Published: January 2022

The manufacturing process is an important factor related to the compression-resilience performance of corrugated metal gaskets, especially stainless steel gaskets. A finite element method was employed to research the mechanical properties of corrugated metal gasket based on the stamping and spring back process analysis. On this basis, the influence of structural parameters of corrugated metal gasket related to the mechanical properties was analyzed. Prediction models of mechanical properties were proposed and validated in this paper. The result shows that the maximum contact stress and resilience rate in the finite element model are in accordance with the experimental results with the relative error of 1.21% and 8.76%, respectively. Critical structural parameters affecting the properties of the corrugated metal gasket are pitch (P), lip height (H), and material thickness (T). The compression and resilience curves obtained from the prediction models are consistent with the finite element method (FEM) simulation. The models can accurately reflect the compression-resilience performance of corrugated metal gaskets with different structural parameters.
User-Centered Virtual Environment for Poststroke Motor Rehabilitation
Authors: Aguilar Acevedo Francisco , Pacheco Bautista Daniel , Acevedo Gómez Marleydy , Toledo Toledo Guadalupe , Nieva García Omar S.
Published: January 2022

The use of virtual reality in the rehabilitation of lost or diminished functions after a stroke has been shown to be an innovative means in motor recovery. However, there are still several design challenges to increment the efficiency of these systems. This paper presents the development and evaluation of a nonimmersive three-dimensional virtual environment for poststroke rehabilitation of elbow flexion–extension movements, which considers the therapist as a direct user and the patient as a secondary user. The development of virtual environment was supported by the criteria of a team of specialists in physical and occupational therapy, following the philosophy of user-centered design through three iterations, and incorporating tasks based on the activities of daily living of the Barthel scale. Tests were carried out with healthy users and a patient with a diagnosis of stroke, using the system usability scale (SUS) test and a flow status questionnaire, respectively. Average satisfaction of user group without diagnosis was 79.6 out of 100 points. On the other hand, according to mean values observed with the patient, dimensions of control sense (6.33) and positive emotional experience (6.66) reflect an “optimal” experience, which indicates an enjoyment of virtual tasks despite the effort made to fulfill them.
Building a Lightweight Digital Twin of a Crane Boom for Structural Safety Monitoring Based on a Multifidelity Surrogate Model
Authors: Lai Xiaonan , He Xiwang , Wang Shuo , Wang Xiaobang , Sun Wei , Song Xueguan
Published: January 2022

Undetected fatigue and overload damages at the key locations of the crane boom are among the biggest threats in construction, leading to structural failure. Thus, the structural health of the crane boom should be monitored in real time to ensure that it works under the designed load capacity. In this study, we developed a lightweight digital twin by the multifidelity surrogate (MFS) model to improve the real-time monitoring and prediction accuracy of the structural safety of a crane boom. Digital twin technology, which can establish real-time mapping between the physical space and the digital space, has a promising potential for online monitoring and analysis of structures, equipment, and even human bodies. By combining the MFS model and sensor data, the lightweight digital twin can dynamically mirror the crane boom postures and predict its structural performance in real time. In this study, the structural analysis of the crane boom is limited to the linear elastic stage of materials. Numerical experiments showed that the accuracy of the lightweight digital twin was enhanced compared with that established by the single-fidelity surrogate model, and the computational cost of the lightweight digital twin was decreased with respect to the digital twin built by the numerical method. Meanwhile, the uncertainty from the physical space was analyzed to enhance the reliability of the lightweight digital twin. Thus, the lightweight digital twin developed in our work can ensure accurate safety prediction and design optimization for crane booms.
Flow-induced crystallization of polylactides
Authors: Zhang Ziyue , Hatzikiriakos Savvas G.
Published: January 2022

In this work, the flow-induced crystallization of two polylactides (PLAs) with different microstructures (different l-lactic acid contents) is studied using simple shear, uniaxial extension and capillary flow experiments. In a simple shear and capillary flow, an increase in shear rate and a decrease in temperature were found to enhance the crystallization kinetics particularly for Weissenberg numbers (based on the reptation relaxation time, Wi) greater than 1 (strong flow causing chain stretching). On the other hand, in a uniaxial extensional flow, once a critical Hencky strain is achieved, crystallization starts independently of strain rate and temperature. The amount of mechanical work per unit volume imposed/dissipated onto the polymers during flow to initialize crystallization was also calculated in the simple shear, capillary, and extensional flow. The critical mechanical work for the onset of flow-induced crystallization was found to be independent of temperature and degree of molecular chain stretch (Wi) as Wi becomes greater than 1. The critical mechanical work for the onset of flow-induced crystallization in an extensional flow was found to be much smaller than that in a shear flow. The PLA sample with higher content of PLLA showed slightly higher zero-shear viscosity and a smaller thermodynamic barrier for the onset of crystallization. Finally, the degree of crystallinity increases linearly from 0% at the start of the flow-induced crystallization region and reaches a plateau at Wi equals to around 1.
Poor Reliability of Measurement Instruments to Assess Acute Responses to Load in Soccer Players Irrespective of Biological Maturity Status
Authors: Ruf Ludwig , Drust Barry , Ehmann Paul , Forster Sabrina , Hecksteden Anne , Meyer Tim
Published: January 2022

Purpose: To assess the short-term reliability of measurement instruments to quantify the acute psychophysiological response to load in adolescent soccer players in relation to biological maturity. Methods: Data were collected from 108 U12 to U17 soccer players on 2 consecutive weeks (pre, n = 32; at, n = 34; and post, n = 42 estimated peak height velocity). Measurements consisted of the Short Recovery and Stress Scale, a countermovement jump, assessment of leg stiffness, and a submaximal run to assess exercise heart rate and heart rate recovery. Test–retest reliability was assessed with the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Results: Items of the Short Recovery and Stress Scale showed poor reliability across maturity groups (CV = 7.0%–53.5%; ICC = .28 to .79). Only few countermovement jump variables (jump height, concentric impulse, and concentric velocity) possessed good reliability. For most variables of the countermovement jump, reliability was better for the post peak height velocity group followed by at-peak height velocity and prepeak height velocity. Very high levels of reliability across maturity groups were observed for exercise heart rate (CV < 1.8%; ICC > .94), while heart rate recovery was more variable (CV < 16.5%; ICC > .48). Conclusion: Results suggest that the majority of investigated variables have poor reliability, questioning their ability to detect small, yet meaningful changes in acute responses to load in adolescent soccer players.
Peptide framework for screening the effects of amino acids on assembly
Authors: Hamsici Seren , White Andrew D. , Acar Handan
Published: January 2022

Discovery of peptide domains with unique intermolecular interactions is essential for engineering peptide-based materials. Rather than attempting a brute-force approach, we instead identify a previously unexplored strategy for discovery and study of intermolecular interactions: “co-assembly of oppositely charged peptide” (CoOP), a framework that “encourages” peptide assembly by mixing two oppositely charged hexapeptides. We used an integrated computational and experimental approach, probed the free energy of association and probability of amino acid contacts during co-assembly with atomic-resolution simulations, and correlated them to the physical properties of the aggregates. We introduce CoOP with three examples: dialanine, ditryptophan, and diisoleucine. Our results indicated that the opposite charges initiate the assembly, and the subsequent stability is enhanced by the presence of an undisturbed hydrophobic core. CoOP represents a unique, simple, and elegant framework that can be used to identify the structure-property relationships of self-assembling peptide-based materials.
Biallelic
BUB1
mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
Authors: Carvalhal Sara , Bader Ingrid , Rooimans Martin A. , Oostra Anneke B. , Balk Jesper A. , Feichtinger René G. , Beichler Christine , Speicher Michael R. , van Hagen Johanna M. , Waisfisz Quinten , van Haelst Mieke , Bruijn Martijn , Tavares Alexandra , Mayr Johannes A. , Wolthuis Rob M. F. , Oliveira Raquel A. , de Lange Job
Published: January 2022

Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic
BUB1
germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion,
BUB1
mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.
Widespread occurrence of hybrid internal-terminal exons in human transcriptomes
Authors: Fiszbein Ana , McGurk Michael , Calvo-Roitberg Ezequiel , Kim GyeungYun , Burge Christopher B. , Pai Athma A.
Published: January 2022

Messenger RNA isoform differences are predominantly driven by alternative first, internal, and last exons. Despite the importance of classifying exons to understand isoform structure, few tools examine isoform-specific exon usage. We recently observed that alternative transcription start sites often arise near internal exons, often creating “hybrid” first/internal exons. To systematically detect hybrid exons, we built the hybrid-internal-terminal (HIT) pipeline to classify exons depending on their isoform-specific usage. On the basis of splice junction reads in RNA sequencing data and probabilistic modeling, the HIT index identified thousands of previously misclassified hybrid first-internal and internal-last exons. Hybrid exons are enriched in long genes and genes involved in RNA splicing and have longer flanking introns and strong splice sites. Their usage varies considerably across human tissues. By developing the first method to classify exons according to isoform contexts, our findings document the occurrence of hybrid exons, a common quirk of the human transcriptome.
Preneoplastic somatic mutations including
MYD88
L265P
in lymphoplasmacytic lymphoma
Authors: Rodriguez Sara , Celay Jon , Goicoechea Ibai , Jimenez Cristina , Botta Cirino , Garcia-Barchino Maria-José , Garces Juan-Jose , Larrayoz Marta , Santos Susana , Alignani Diego , Vilas-Zornoza Amaia , Perez Cristina , Garate Sonia , Sarvide Sarai , Lopez Aitziber , Reinhardt Hans-Christian , Carrasco Yolanda R. , Sanchez-Garcia Isidro , Larrayoz Maria-Jose , Calasanz Maria-Jose , Panizo Carlos , Prosper Felipe , Lamo-Espinosa Jose-Maria , Motta Marina , Tucci Alessandra , Sacco Antonio , Gentile Massimo , Duarte Sara , Vitoria Helena , Geraldes Catarina , Paiva Artur , Puig Noemi , Garcia-Sanz Ramon , Roccaro Aldo M. , Fuerte Gema , San Miguel Jesus F. , Martinez-Climent Jose-Angel , Paiva Bruno
Published: January 2022

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated
MYD88
. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found
MYD88
L265P
in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated
MYD88
in B cell precursors and
BCL2
overexpression. Thus,
MYD88
L265P
is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation
Authors: Hakui Hideyuki , Kioka Hidetaka , Miyashita Yohei , Nishimura Shunsuke , Matsuoka Ken , Kato Hisakazu , Tsukamoto Osamu , Kuramoto Yuki , Takuwa Ayako , Takahashi Yusuke , Saito Shigeyoshi , Ohta Kunio , Asanuma Hiroshi , Fu Hai Ying , Shinomiya Haruki , Yamada Noriaki , Ohtani Tomohito , Sawa Yoshiki , Kitakaze Masafumi , Takashima Seiji , Sakata Yasushi , Asano Yoshihiro
Published: January 2022

Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (
BAG5
) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding.
Bag5
mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type
BAG5
gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling.
Bag5
-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in
BAG5
can cause DCM, that
BAG5
may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.
Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies
Authors: Greco Beatrice , Malacarne Valeria , De Girardi Federica , Scotti Giulia Maria , Manfredi Francesco , Angelino Elia , Sirini Camilla , Camisa Barbara , Falcone Laura , Moresco Marta Angiola , Paolella Katia , Di Bono Mattia , Norata Rossana , Sanvito Francesca , Arcangeli Silvia , Doglioni Claudio , Ciceri Fabio , Bonini Chiara , Graziani Andrea , Bondanza Attilio , Casucci Monica
Published: January 2022

Immunotherapy with chimeric antigen receptor (CAR)–engineered T cells showed exceptional successes in patients with refractory B cell malignancies. However, first-in-human studies in solid tumors revealed unique hurdles contributing to poor demonstration of efficacy. Understanding the determinants of tumor recognition by CAR T cells should translate into the design of strategies that can overcome resistance. Here, we show that multiple carcinomas express extracellular N-glycans, whose abundance negatively correlates with CAR T cell killing. By knocking out mannoside acetyl-glucosaminyltransferase 5 (
MGAT5
) in pancreatic adenocarcinoma (PAC), we showed that N-glycans protect tumors from CAR T cell killing by interfering with proper immunological synapse formation and reducing transcriptional activation, cytokine production, and cytotoxicity. To overcome this barrier, we exploited the high metabolic demand of tumors to safely inhibit N-glycans synthesis with the glucose/mannose analog 2-deoxy-
d
-glucose (2DG). Treatment with 2DG disrupts the N-glycan cover on tumor cells and results in enhanced CAR T cell activity in different xenograft mouse models of PAC. Moreover, 2DG treatment interferes with the PD-1–PD-L1 axis and results in a reduced exhaustion profile of tumor-infiltrating CAR T cells in vivo. The combined 2DG and CAR T cell therapy was successful against multiple carcinomas besides PAC, including those arising from the lung, ovary, and bladder, and with different clinically relevant CAR specificities, such as CD44v6 and CEA. Overall, our results indicate that tumor N-glycosylation regulates the quality and magnitude of CAR T cell responses, paving the way for the rational design of improved therapies against solid malignancies.
Human brain mapping with multithousand-channel PtNRGrids resolves spatiotemporal dynamics
Authors: Tchoe Youngbin , Bourhis Andrew M. , Cleary Daniel R. , Stedelin Brittany , Lee Jihwan , Tonsfeldt Karen J. , Brown Erik C. , Siler Dominic A. , Paulk Angelique C. , Yang Jimmy C. , Oh Hongseok , Ro Yun Goo , Lee Keundong , Russman Samantha M. , Ganji Mehran , Galton Ian , Ben-Haim Sharona , Raslan Ahmed M. , Dayeh Shadi A.
Published: January 2022

Electrophysiological devices are critical for mapping eloquent and diseased brain regions and for therapeutic neuromodulation in clinical settings and are extensively used for research in brain-machine interfaces. However, the existing clinical and experimental devices are often limited in either spatial resolution or cortical coverage. Here, we developed scalable manufacturing processes with a dense electrical connection scheme to achieve reconfigurable thin-film, multithousand-channel neurophysiological recording grids using platinum nanorods (PtNRGrids). With PtNRGrids, we have achieved a multithousand-channel array of small (30 μm) contacts with low impedance, providing high spatial and temporal resolution over a large cortical area. We demonstrated that PtNRGrids can resolve submillimeter functional organization of the barrel cortex in anesthetized rats that captured the tissue structure. In the clinical setting, PtNRGrids resolved fine, complex temporal dynamics from the cortical surface in an awake human patient performing grasping tasks. In addition, the PtNRGrids identified the spatial spread and dynamics of epileptic discharges in a patient undergoing epilepsy surgery at 1-mm spatial resolution, including activity induced by direct electrical stimulation. Collectively, these findings demonstrated the power of the PtNRGrids to transform clinical mapping and research with brain-machine interfaces.
Systems-Level Analysis of the Global Regulatory Mechanism of CodY in Lactococcus lactis Metabolism and Nisin Immunity Modulation
Authors: Wu Hao , Tian Kairen , Feng Jia , Qi Hao , Qiao Jianjun
Published: January 2022

Lactococcus lactis
, a species of lactic acid bacteria (LAB) widely used in food fermentation, has been the model strain in genetic engineering, and its application has extended from food to microbial cell factories. CodY is a global regulator in low-G+C Gram-positive bacteria.
Organic Hydroperoxide Induces Prodigiosin Biosynthesis in
Serratia
sp. ATCC 39006 in an OhrR-Dependent Manner
Authors: Sun Di , Liu Weijie , Zhou Xuge , Ru Yunrui , Liu Jiawen , Zhu Jingrong , Liu Cong
Published: January 2022

Bacteria naturally encounter various environmental and cellular stresses. Organic hydroperoxides generated from the oxidation of polyunsaturated fatty acids are widely distributed and usually cause lethal oxidative stress by damaging cellular components.
Environmental Dependence of Competitive Fitness in Rifampin-Resistant
rpoB
Mutants of Bacillus subtilis
Authors: Leehan Joss D. , Nicholson Wayne L.
Published: January 2022

Microbial resistance to antibiotics is a growing threat to public health across the world. Historically, resistance to antibiotics has been associated with reduced fitness.
Microglia Activate Early Antiviral Responses upon Herpes Simplex Virus 1 Entry into the Brain to Counteract Development of Encephalitis-Like Disease in Mice
Authors: Katzilieris-Petras Georgios , Lai Xin , Rashidi Ahmad S. , Verjans Georges M. G. M. , Reinert Line S. , Paludan Søren R.
Published: January 2022

One of the most devastating and acute neurological conditions is encephalitis, i.e., inflammation of brain tissue. Herpes simplex virus 1 (HSV1) is a highly prevalent pathogen in humans, and the most frequent cause of viral sporadic encephalitis called herpes simplex encephalitis (HSE).
Loss of the E6AP Ubiquitin Ligase Induces p53-Dependent Phosphorylation of Human Papillomavirus 18 E6 in Cells Derived from Cervical Cancer
Authors: Vats Arushi , Skrabar Neva , Del Sal Giannino , Banks Lawrence
Published: January 2022

This study demonstrates that the knockdown of E6AP from cervical cancer-derived cells leads to an increase in phosphorylation of the E6 oncoprotein. We show that this phosphorylation of E6 requires p53 transcriptional activity and the enzyme DNA PK. This study therefore defines a feedback loop whereby activation of p53 can induce phosphorylation of E6 and which in turn can inhibit p53 transcriptional activity independently of E6’s ability to target p53 for degradation.
The Species-Specific 282 Residue in the PB2 Subunit of the Polymerase Regulates RNA Synthesis and Replication of Influenza A Viruses Infecting Bat and Nonbat Hosts
Authors: Banerjee Saptarshi , De Aratrika , Kedia Nandita , Bhakta Koustav , Wang Linfa , Bhattacharjee Bornali , Mondal Arindam
Published: January 2022

Influenza A viruses are known for their ability to perform cross-species transmission, facilitated by amino acid alterations either in the surface antigen hemagglutinin (HA) or in the polymerase subunit PB2. Recent isolation of influenza A-like viruses from bats raised concern about their epizootic and zoonotic potential.
Performance of Three Tests for SARS-CoV-2 on a University Campus Estimated Jointly with Bayesian Latent Class Modeling
Authors: Perkins T. Alex , Stephens Melissa , Alvarez Barrios Wendy , Cavany Sean , Rulli Liz , Pfrender Michael E.
Published: January 2022

Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been vitally important during the COVID-19 pandemic. There are a variety of methods for testing for this virus, and it is important to understand their accuracy in choosing which one might be best suited for a given application.
Investigation of the Bacterial Contamination and Antibiotic Susceptibility Profile of Bacteria Isolated from Bottled Drinking Water
Authors: Hamad Anas Abdullah , Sharaf Mohamed , Hamza Manhal Ahmed , Selim Samy , Hetta Helal F. , El-Kazzaz Waleed
Published: January 2022

Researchers analyzed how lifestyle factors affect the overall health of people with bacterial infections from the water. The article describes significance of the research because many people do not have access to clean, safe drinking water where this water is essential to life, and many die of waterborne bacterial infections.
Intracellular Transposition and Capture of Mobile Genetic Elements following Intercellular Conjugation of Multidrug Resistance Conjugative Plasmids from Clinical
Enterobacteriaceae
Isolates
Authors: Tansirichaiya Supathep , Goodman Richard N. , Guo Xinyu , Bulgasim Issra , Samuelsen Ørjan , Al-Haroni Mohammed , Roberts Adam P.
Published: January 2022

By analyzing transposition activity within our MGE-free recipient, we can gain insights into the interaction and evolution of multidrug resistance-conferring MGEs following conjugation, including the movement of multiple ISs, the formation of composite transposons, and cointegration and/or recombination between different replicons in the same cell. This combination of recipient and entrapment vector will allow fine-scale experimental studies of factors affecting intracellular transposition and MGE formation in and from ARG-encoding MGEs from multiple species of clinically relevant
Enterobacteriaceae
.
Overweight and obesity as risk factors for COVID-19-associated hospitalisations and death: systematic review and meta-analysis
Authors: Sawadogo Wendemi , Tsegaye Medhin , Gizaw Andinet , Adera Tilahun
Published: January 2022

Objective

To quantify the current weight of evidence of the association between overweight and obesity as risk factors for COVID-19-related hospitalisations (including hospital admission, intensive care unit admission, invasive mechanical ventilation) and death, and to assess the magnitude of the association and the potential dose–response relationships.

Design

PubMed, Embase, Cochrane, Web of Sciences, WHO COVID-19 database and Google Scholar were used to identify articles published up to 20 July 2021. Peer-reviewed studies reporting adjusted estimates of the association between overweight or obesity and COVID-19 outcomes were included. Three authors reviewed the articles and agreed. The quality of eligible studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Random-effects meta-analysis was used to estimate the combined effects.

Results

A total of 208 studies with 3 550 997 participants from over 32 countries were included in this meta-analysis. Being overweight was associated with an increased risk of COVID-19-related hospitalisations (OR 1.19, 95% CI 1.12 to 1.28, n=21 studies), but not death (OR 1.02, 95% CI 0.92 to 1.13, n=21). However, patients with obesity were at increased risk of both COVID-19-related hospitalisations (OR 1.72, 95% CI 1.62 to 1.84, n=58) and death (OR 1.25, 95% CI 1.19 to 1.32, n=77). Similarly, patients with extreme obesity were at increased risk of COVID-19-related hospitalisations (OR 2.53, 95% CI 1.67 to 3.84, n=12) and death (OR 2.06, 95% CI 1.76 to 3.00, n=19). There was a linear dose–response relationship between these obesity categories and COVID-19 outcomes, but the strength of the association has decreased over time.

Conclusion

Being overweight increases the risk of COVID-19-related hospitalisations but not death, while obesity and extreme obesity increase the risk of both COVID-19-related hospitalisations and death. These findings suggest that prompt access to COVID-19 care, prioritisation for COVID-19 vaccination and other preventive measures are warranted for this vulnerable group.