bluuebunny/crossref_metadata_2025 huggingface dataset:
Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis
Authors: Ulloa Bianca A , Habbsa Samima S , Potts Kathryn S. , Lewis Alana , McKinstry Mia , Payne Sara G. , Flores Julio , Nizhnik Anastasia , Norberto Maria Feliz , Mosimann Christian , Bowman Teresa V
Published: May 2021

Hematopoietic stem cells (HSCs) are rare cells that arise in the embryo and sustain adult hematopoiesis. Although the functional potential of nascent HSCs is detectable by transplantation, their native contribution during development is unknown, in part due to the overlapping genesis and marker gene expression with other embryonic blood progenitors. Using single cell transcriptomics, we defined gene signatures that distinguish nascent HSCs from embryonic blood progenitors. Applying a new lineage tracing approach, we selectively tracked HSC outputin situand discovered significantly delayed lymphomyeloid contribution. Using a novel inducible HSC injury model, we demonstrated a negligible impact on larval lymphomyelopoiesis following HSC depletion. HSCs are not merely dormant at this developmental stage as they showed robust regeneration after injury. Combined, our findings illuminate that nascent HSCs self-renew but display differentiation latency, while HSC-independent embryonic progenitors sustain developmental hematopoiesis. Understanding the differences among embryonic HSC and progenitor populations will guide improvedde novogeneration and expansion of functional HSCs.
A Coupled Flow-Thermoregulation Lumped Model to Investigate Cardiac Function
Authors: Deyranlou Amin , Revell Alistair , Keshmiri Amir
Published: May 2021

Abstract

Lumped (zero-dimensional) technique is a robust and widely used approach to mathematically model and explore bulk behaviour of different physical phenomena in a lower expense. In modelling of cardio/cerebrovascular fluid dynamics, this technique facilitates the assessment of relevant metrics such as flow, pressure, and temperature at different locations over a large network/domain. Furthermore, they can be employed as boundary conditions in multiscale modelling of physiological flows. In this methodology paper, a lumped model for the cardiovascular flow simulation along with a two-node thermoregulation model are employed. The lumped models are built upon previous studies and are amended appropriately to focus on cardiac function. The output of the coupled model can either be used for assessing the cardiac function in different physiological conditions or it can provide the input data for other investigations. Noteworthy to mention that, the present model has been specifically developed for investigation on the effects of atrial fibrillation on cardiac performance.
An Omics Analysis Search and Information System (OASIS) for Enabling Biological Discovery in the Old Order Amish
Authors: Perry James A , Gaynor Brady J , Mitchell Braxton D , O’Connell Jeffrey R
Published: May 2021

The “Omics Analysis Search and Information System” (OASIS), developed at the University of Maryland School of Medicine, enables discovery by allowing researchers to mine results from genome wide association studies (GWAS). When interesting signals are found, the research can immediately ask follow-up questions and get answers in real-time. OASIS provides this unique capability with a web-based, scientist-friendly search system and a variety of real-time analysis tools (linkage disequilibrium calculations, conditional analysis, and direct variant comparison) plus on-demand visualizations (boxplots, histograms, LocusZoom & Haploview plots, and pedigree charts). Because OASIS uses a web-based user interface, an understanding of programming or the UNIX operating system is not required. The OASIS application has been used to enable discovery from whole-exome, whole-genome, metabolome, transcriptome and methylome association results for Old Order Amish studies at the University of Maryland School of Medicine.
Metagenomics and Metatranscriptomics Suggest Pathways of 3-Chloroaniline Degradation in Wastewater Reactors
Authors: Seshan Hari , Santillan Ezequiel , Constancias Florentin , Chandra Segaran Uma Shankari , Williams Rohan B. H. , Wuertz Stefan
Published: May 2021

Biological wastewater treatment systems are often affected by major shifts in influent quality, including the input of various toxic chemicals. Yet the mechanisms underlying adaptation of activated sludge process performance when challenged with a sustained toxin input are rarely studied in a controlled and replicated experimental setting. Three replicate bench-scale bioreactors were subjected to a chemical disturbance in the form of 3-chloroaniline (3-CA) over 132 days, after an acclimation period of 58 days, while three control reactors received no 3-CA input. Nitrification was initially affected by 3-CA but the microbial communities in all three treatment reactors adapted to biologically degrade 3-CA within three weeks of the experiment, resulting in partial nitrification recovery. Combining process and microbial community data from amplicon sequencing with potential functions gleaned from assembled metagenomics and metatranscriptomics data, two putative degradation pathways for 3-CA were identified. The first pathway proceeds via a phenol monooxygenase followed by ortho-cleavage of the aromatic ring, and the second one involves a benzoate dioxygenase and subsequent meta-cleavage of the aromatic ring. The generaGemmatimonas,OLB8, andTaibaiellacorrelated significantly with 3-CA degradation. Metagenome-assembled genome data also showed the genusOLB8to be differentially enriched in treatment reactors, making it a strong candidate as 3-CA degrader. Using replicated reactors, this study has demonstrated the impact of a sustained stress on the activated sludge community and processes carried out by its members, followed by process recovery. By a combination of techniques, we showed that microbial communities can develop degradative capacity following a sustained xenobiotic input, and that targeted culture-independent approaches can suggest plausible mechanisms for 3-CA degradation and identify the taxa potentially contributing to it.
A DUF1068 protein acts as a pectin biosynthesis scaffold and maintains Golgi morphology and cell adhesion in Arabidopsis
Authors: Lathe Rahul S. , McFarlane Heather E. , Khan Ghazanfar Abbas , Ebert Berit , Ramírez-Rodríguez Eduardo Antonio , Noord Niels , Bhalerao Rishikesh , Persson Staffan
Published: May 2021

Adjacent plant cells are connected by specialized cell wall regions, called middle lamellae, which influence critical agricultural characteristics, including fruit ripening and organ abscission. Middle lamellae are enriched in pectin polysaccharides, specifically homogalacturonan (HG). Here, we identify a plant-specific Arabidopsis DUF1068 protein, called NKS1, that is required for middle lamellae integrity and cell adhesion. NKS1 localises to the Golgi apparatus and loss of the protein results in changes to Golgi structure and function. Thenks1mutants also display HG deficient phenotypes, including reduced seedling growth, changes to cell wall composition, and tissue integrity defects. These phenotypes are identical to those of the HG deficient mutantsqua1andqua2. Notably, NKS1 physically interacts with both QUA1 and QUA2, and genetic interaction analyses reveal that they work in the same pathway. Based on these results we propose that NKS1 works as a scaffold for HG synthesis and that such scaffolding is important to support Golgi function and the organization of the pectin synthesis machinery.
Soils and sediments host novel archaea with divergent monooxygenases implicated in ammonia oxidation
Authors: Diamond Spencer , Lavy Adi , Crits-Christoph Alexander , Carnevali Paula B. Matheus , Sharrar Allison , Williams Kenneth H. , Banfield Jillian F.
Published: May 2021

Copper membrane monooxygenases (CuMMOs) play critical roles in the global carbon and nitrogen cycles. Organisms harboring these enzymes perform the first, and rate limiting, step in aerobic oxidation of ammonia, methane, or other simple hydrocarbons. Within archaea, only organisms in the order Nitrososphaerales (Thaumarchaeota) encode CuMMOs, which function exclusively as ammonia monooxygenases. From grassland and hillslope soils and aquifer sediments, we identified 20 genomes from distinct archaeal species encoding divergent CuMMO sequences. These archaea are phylogenetically clustered in a previously unnamed Thermoplasmatota order, herein named the Ca. Angelarcheales. The CuMMO proteins in Ca. Angelarcheales are more similar in structure to those in ammonia-oxidizing archaea than those of bacteria, and they contain all functional residues required for activity. Similarly to the Nitrososphaerales, Ca. Angelarcheales genomes are significantly enriched in blue copper proteins (BCPs) relative to sibling lineages, including plastocyanin-like electron carriers and divergent nitrite reductase-like (nirK) 2-domain cupredoxin proteins co-located with electron transport machinery. Angelarcheales do not have identifiable genes for methanol oxidation or carbon fixation, encode significant capacity for peptide/amino acid uptake and degradation, and share numerous electron transport mechanisms with the Nitrososphaerales. In the studied soils and sediments Ca. Angelarcheales were at least as abundant as ammonia-oxidizing Nitrososphaerales. Thus, we predict that Angelarcheales live a mixotrophic lifestyle based on oxidation of ammonia liberated from peptide and amino acid degradation. This work expands the known diversity of Thermoplasmatota and of CuMMO enzymes in archaea and suggests that these organisms are important and previously unaccounted for contributors to nitrogen cycling.
Occurrence, functionality, and abundance of theTERTpromoter mutations
Authors: Rachakonda Sivaramakrishna , Hoheisel Jörg D. , Kumar Rajiv
Published: May 2021

Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase inTERTtranscription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of theTERTpromoter mutations. The promoter mutations link transcription ofTERTwith oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism ofTERTactivation. We further deliberate on the foundational question of the abundance of theTERTpromoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within theTERTpromoter may be less than a common occurrence in other noncoding functional elements. The evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.
Mapping RNA with Nuclease S1
Authors: Green Michael R. , Sambrook Joseph
Published: May 2021

This protocol provides details for nuclease S1 mapping of mRNA using a uniformly labeled, single-stranded DNA probe. DNA–RNA hybrids are generated, which are subsequently digested with nuclease S1. The digestion products are separated using gel electrophoresis and analyzed by radiography.
The entrepreneurial diary – a reflective learning activity to enhance the judgmental abilities of student entrepreneurs
Authors: Hägg Gustav
Published: May 2021

Purpose

The purpose of the paper is to theorize how to develop student entrepreneurs' ability to reflect by means of a learning activity called the entrepreneurial diary, which seeks to develop self-regulated learners capable of intelligent entrepreneurial action. The importance of self-regulation in entrepreneurship is linked to the individual's ability to make judgments under conditions of uncertainty, which requires reflective thinking.

Design/methodology/approach

The paper builds on a synthesized conceptualization of three main literature strands, reflective thinking, cognitive-load theory and experiential entrepreneurship education. In addition to the synthesized conceptualization, it builds on some empirical insights derived from a venture creation master programme in which the learning activity has been developed and refined for the last seven years.

Findings

The main finding from the paper is the theoretical justification for why reflective thinking deserves an important place in the educational process and how the entrepreneurial diary as a learning activity can create a bridge between theory and practice in venture creation programmes that take an experience-based pedagogical approach. Furthermore, the study also provides some empirical insights of how students create self-awareness of their learning through the method and the metareflection reports. Self-awareness is foundational for developing conditional knowledge on why and when to make entrepreneurial decisions to balance the often action-oriented processes seen in venture creation programmes.

Originality/value

The paper provides both a practical learning activity to be used in the entrepreneurial classroom and a theoretical contribution on how entrepreneurial experience is transformed into entrepreneurial knowledge to enhance students' judgmental abilities to make entrepreneurial decisions in future entrepreneurial endeavours.
Housing prices and the probability of marriage among the young: evidence from land reform in China
Authors: Hu Mingzhi , Wu Lina , Xiang Guocheng , Zhong Shihu
Published: May 2021

Purpose

Using data from the China Health and Nutrition Survey, this work examines the relationship between housing price and the probability of marriage among the young.

Design/methodology/approach

By exploiting land reform as an exogenous change in housing price and employing a differences-in-differences framework, this study investigates the effects of housing price on the marriage probability of young people.

Findings

This work confirms that land reform decreased young people's likelihood of marriage. This finding is robust to a series of model specifications. The effects of land reform increased over time because of rising housing unaffordability from progressively inflating housing prices. Moreover, land reform had larger effects on renters and young adults aged below 30 than homeowners and young adults aged above 30.

Social implications

Overall, this study highlights the negative consequences of an overheated housing market on marriage in developing countries.

Originality/value

Housing prices have increased dramatically in urban China after 2002 upon the implementation of the assignment system of the use right of all kinds of profit-oriented lands by means of public bidding, auction and quotation. High housing prices indicate serious housing unaffordability, especially for young people who typically have low income and wealth. Homeownership that comes with various benefits can theoretically increase the likelihood of marriage, particularly in China where a house is often regarded as a prerequisite for marriage.
Re-mediating designs for equity: making commitments concrete
Authors: Jurow A. Susan , Freeman Quinton
Published: May 2021

Purpose

The purpose of the paper is to detail how a social design experiment focused on equity was systematically reorganized to address changing historical and social contexts of injustice.

Design/methodology/approach

This paper presents a design narrative.

Findings

The design narrative presents the principled foundations that guided our re-design of the social design experiment.

Originality/value

The value of this design narrative is in demonstrating how designs for equity need to be revised in light of dynamic social, cultural and historical circumstances.
Does narcissistic leadership enhance employee resilience? A moderated mediation model of goal-directed energy and psychological availability
Authors: Li Jin , Tong Yiwen
Published: May 2021

Purpose

Drawing on the conservation of resources (COR) theory, this study highlights the mediating role of goal-directed energy as a critical psychological resource. The purpose of this study is to examine the mediating effect of goal-directed energy on the relationship between narcissistic leadership and employee resilience. The study also explores the moderating effect of psychological availability on the relationship between narcissistic leadership and goal-directed energy.

Design/methodology/approach

Data were collected from 857 employees and their supervisors at 137 enterprises in China. Confirmatory factor analysis, hierarchical multiple regression analysis and path analysis were adopted to analyze the data.

Findings

The results indicate that narcissistic leadership has a positive effect on goal-directed energy, which, in turn, enhances employee resilience. Furthermore, the effect of narcissistic leadership on goal-directed energy becomes more prominent in the context of lower psychological availability.

Practical implications

First, narcissistic leadership is supposed to play an effective role in helping employees gain resources. Second, organizations should attach importance to implementing resilience-building programs on employees to cope with uncertainty. Third, organizations should offer multiple training opportunities to stimulate employees’ goal-directed energy.

Originality/value

First, the findings suggest that employee resilience is influenced by narcissistic leadership, which provides more possibilities for the study on the antecedents of resilience. Second, the study offers novel insights regarding the effect of narcissistic leadership on employee resilience through goal-directed energy. Finally, it also examines psychological availability as the boundary condition between narcissistic leadership and goal-directed energy.
Artificial intelligence model for building investment portfolio optimization mix using historical stock prices data
Authors: Adebiyi Sulaimon Olanrewaju , Ogunbiyi Oludayo Olatosimi , Amole Bilqis Bolanle
Published: May 2021

Purpose

The purpose of this paper is to implement a genetic algorithmic geared toward building an optimized investment portfolio exploring data set from stocks of firms listed on the Nigerian exchange market. To provide a research-driven guide toward portfolio business assessment and implementation for optimal risk-return.

Design/methodology/approach

The approach was to formulate the portfolio selection problem as a mathematical programming problem to optimize returns of portfolio; calculated by a Sharpe ratio. A genetic algorithm (GA) is then applied to solve the formulated model. The GA lead to an optimized portfolio, suggesting an effective asset allocation to achieve the optimized returns.

Findings

The approach enables an investor to take a calculated risk in selecting and investing in an investment portfolio best minimizes the risks and maximizes returns. The investor can make a sound investment decision based on expected returns suggested from the optimal portfolio.

Research limitations/implications

The data used for the GA model building and implementation GA was limited to stock market prices. Thus, portfolio investment that which to combines another capital market instrument was used.

Practical implications

Investment managers can implement this GA method to solve the usual bottleneck in selecting or determining which stock to advise potential investors to invest in, and also advise on which capital sharing ratio to reduce risk and attain optimal portfolio-mix targeted at achieving an optimal return on investment.

Originality/value

The value proposition of this paper is due to its exhaustiveness in considering the very important measures in the selection of an optimal portfolio such as risk, liquidity ratio, returns, diversification and asset allocation.
Alternative flowers affect model and mimic flower discrimination performance of bumblebees
Authors: Tsujimoto Shohei G. , Ishii Hiroshi S.
Published: May 2021

Some animal‐pollinated flowers produce no rewards but attract pollinators by imitating rewarding flowers. Termed Batesian floral mimicry, this phenomenon has generally been understood in terms of a common system of the organisms performing one of three roles as model flowers, mimic flowers or signal receivers (a Batesian mimicry trinity). However, organisms other than those of the mimicry trinity may play important roles in the relationships of the trinity members.

This study examined the effect of alternative flowers that are dissimilar to either model or mimic flowers on bumblebee discrimination between model and mimic flowers. To this end, we observed bumblebees Bombus ignitus (Smith), foraging in mixed arrays of artificial flowers mirroring either model, mimic or alternative flowers.

Bumblebees’ ability to discriminate mimic from model flowers was impacted by the presence of alternative flowers; however, the effect was dependent on the similarity between the model and mimic flowers. This might occur because the presence of alternative flowers imposed an additional cognitive load on the bees’ working memory.

Our study suggests that alternative flowers in a community may have beneficial effects on mimic flowers by reducing the discrimination performance of pollinators. A variety of environmental factors that impose complex sensory inputs on pollinators’ working memory might have contributed to the maintenance of Batesian floral mimicry.

A free Plain Language Summary can be found within the Supporting Information of this article.
Degradation of ester linkages in rice straw components by Sphingobium species recovered from the sea bottom using a non‐secretory tannase‐family α/β hydrolase
Authors: Ohta Yukari , Katsumata Madoka , Kurosawa Kanako , Takaki Yoshihiro , Nishimura Hiroshi , Watanabe Takashi , Kasuya Ken‐ichi
Published: May 2021

Microbial decomposition of allochthonous plant components imported into the aquatic environment is one of the vital steps of the carbon cycle on earth. To expand the knowledge of the biodegradation of complex plant materials in aquatic environments, we recovered a sunken wood from the bottom of Otsuchi Bay, situated in northeastern Japan in 2012. We isolated Sphingobium with high ferulic acid esterase activity. The strain, designated as OW59, grew on various aromatic compounds and sugars, occurring naturally in terrestrial plants. A genomic study of the strain suggested its role in degrading hemicelluloses. We identified a gene encoding a non‐secretory tannase‐family α/β hydrolase, which exhibited ferulic acid esterase activity. This enzyme shares the consensus catalytic triad (Ser‐His‐Asp) within the tannase family block X in the ESTHER database. The molecules, which had the same calculated elemental compositions, were produced consistently in both the enzymatic and microbial degradation of rice straw crude extracts. The non‐secretory tannase‐family α/β hydrolase activity may confer an important phenotypic feature on the strain to accelerate plant biomass degradation. Our study provides insights into the underlying biodegradation process of terrestrial plant polymers in aquatic environments.
FurC (PerR) from Anabaena sp. PCC7120: a versatile transcriptional regulator engaged in the regulatory network of heterocyst development and nitrogen fixation
Authors: Sarasa‐Buisan Cristina , Guio Jorge , Broset Esther , Peleato M. Luisa , Fillat María F. , Sevilla Emma
Published: May 2021

FurC (PerR) from Anabaena sp. PCC7120 was previously described as a key transcriptional regulator involved in setting off the oxidative stress response. In the last years, the cross‐talk between oxidative stress, iron homeostasis and nitrogen metabolism is becoming more and more evident. In this work, the transcriptome of a furC‐overexpressing strain was compared with that of a wild‐type strain under both standard and nitrogen‐deficiency conditions. The results showed that the overexpression of furC deregulates genes involved in several categories standing out photosynthesis, iron transport and nitrogen metabolism. The novel FurC‐direct targets included some regulatory elements that control heterocyst development (hetZ and asr1734), genes directly involved in the heterocyst envelope formation (devBCA and hepC) and genes which participate in the nitrogen fixation process (nifHDK and nifH2, rbrA rubrerythrin and xisHI excisionase). Likewise, furC overexpression notably impacts the mRNA levels of patA encoding a key protein in the heterocyst pattern formation. The relevance of FurC in these processes is bringing out by the fact that the overexpression of furC impairs heterocyst development and cell growth under nitrogen step‐down conditions. In summary, this work reveals a new player in the complex regulatory network of heterocyst formation and nitrogen fixation.
Comprehensive single‐PCR 16S and 18S rRNA community analysis validated with mock communities, and estimation of sequencing bias against 18S
Authors: Yeh Yi‐Chun , McNichol Jesse , Needham David M. , Fichot Erin B. , Berdjeb Lyria , Fuhrman Jed A.
Published: May 2021

Universal primers for SSU rRNA genes allow profiling of natural communities by simultaneously amplifying templates from Bacteria, Archaea, and Eukaryota in a single PCR reaction. Despite the potential to show relative abundance for all rRNA genes, universal primers are rarely used, due to various concerns including amplicon length variation and its effect on bioinformatic pipelines. We thus developed 16S and 18S rRNA mock communities and a bioinformatic pipeline to validate this approach. Using these mocks, we show that universal primers (515Y/926R) outperformed eukaryote‐specific V4 primers in observed versus expected abundance correlations (slope = 0.88 vs. 0.67–0.79), and mock community members with single mismatches to the primer were strongly underestimated (threefold to eightfold). Using field samples, both primers yielded similar 18S beta‐diversity patterns (Mantel test, p < 0.001) but differences in relative proportions of many rarer taxa. To test for length biases, we mixed mock communities (16S + 18S) before PCR and found a twofold underestimation of 18S sequences due to sequencing bias. Correcting for the twofold underestimation, we estimate that, in Southern California field samples (1.2–80 μm), there were averages of 35% 18S, 28% chloroplast 16S, and 37% prokaryote 16S rRNA genes. These data demonstrate the potential for universal primers to generate comprehensive microbiome profiles.
Comparative genomics reveals a core gene toolbox for lifestyle transitions in Hypocreales fungi
Authors: Wu Baojun , Cox Murray P.
Published: May 2021

Fungi have evolved diverse lifestyles and adopted pivotal new roles in both natural ecosystems and human environments. However, the molecular mechanisms underlying their adaptation to new lifestyles are obscure. Here, we hypothesize that genes shared across all species with the same lifestyle, but absent in genera with alternative lifestyles, are crucial to that lifestyle. By analysing dozens of species within four genera in a fungal order, with each genus following a different lifestyle, we find that genus‐specific genes are typically few in number. Notably, not all genus‐specific genes appear to derive from de novo birth, with most instead reflecting recurrent loss across the fungi. Importantly, however, a subset of these genus‐specific genes are shared by fungi with the same lifestyle in quite different evolutionary orders, thus supporting the view that some genus‐specific genes are necessary for specific lifestyles. These lifestyle‐specific genes are enriched for key functional classes and often exhibit specialized expression patterns. Genus‐specific selection also contributes to lifestyle transitions, and is especially associated with intensity of pathogenesis. Our study, therefore, suggests that fungal adaptation to new lifestyles often requires just a small number of core genes, with gene turnover and positive selection playing complementary roles.
Probiotics in the dairy industry—Advances and opportunities
Authors: Gao Jie , Li Xiyu , Zhang Guohua , Sadiq Faizan Ahmed , Simal‐Gandara Jesus , Xiao Jianbo , Sang Yaxin
Published: May 2021

The past two decades have witnessed a global surge in the application of probiotics as functional ingredients in food, animal feed, and pharmaceutical products. Among food industries, the dairy industry is the largest sector where probiotics are employed in a number of dairy products including sour/fermented milk, yogurt, cheese, butter/cream, ice cream, and infant formula. These probiotics are either used as starter culture alone or in combination with traditional starters, or incorporated into dairy products following fermentation, where their presence imparts many functional characteristics to the product (for instance, improved aroma, taste, and textural characteristics), in addition to conferring many health‐promoting properties. However, there are still many challenges related to the stability and functionality of probiotics in dairy products. This review highlights the advances, opportunities, and challenges of application of probiotics in dairy industries. Benefits imparted by probiotics to dairy products including their role in physicochemical characteristics and nutritional properties (clinical and functional perspective) are also discussed. We transcend the traditional concept of the application of probiotics in dairy products and discuss paraprobiotics and postbiotics as a newly emerged concept in the field of probiotics in a particular relation to the dairy industry. Some potential applications of paraprobiotics and postbiotics in dairy products as functional ingredients for the development of functional dairy products with health‐promoting properties are briefly elucidated.
ALK‐positive lung cancer in a patient with recurrent brain metastases and meningeal dissemination who achieved long‐term survival of more than seven years with sequential treatment of five ALK‐inhibitors: A case report
Authors: Yamamoto Keisuke , Toyokawa Gouji , Kozuma Yuka , Shoji Fumihiro , Yamazaki Koji , Takeo Sadanori
Published: May 2021

The incidence of central nervous system (CNS) metastases in patients with anaplastic lymphoma kinase (ALK) fusion gene‐positive (ALK+) non‐small cell lung cancer (NSCLC) is high, ranging from approximately 20%–70%. Although ALK inhibitors (ALKis) are generally effective for CNS metastases in patients with ALK+ NSCLC, relapse with CNS metastases is frequently observed. A 37‐year‐old woman with a high level of carcinoembryonic antigen was diagnosed with right lung adenocarcinoma (pathological stage IIIA) and underwent right lower lobectomy. Despite the administration of postoperative chemotherapy, her carcinoembryonic antigen (CEA) level remained elevated. Although crizotinib was administered due to the positivity for ALK fusion, brain metastases appeared at 19.0 months after the start of treatment. Treatment with alectinib following crizotinib resulted in the complete disappearance of brain metastases. However, brain metastases relapsed, and meningeal dissemination appeared at 38.3 months after the start of treatment with alectinib. Although ceritinib, brigatinib, and alectinib rechallenge were attempted, the CNS lesions worsened. Lorlatinib was then administered, resulting in the normalization of the CEA level (4.5 ng/ml) 4.1 months after the start of lorlatinib. The brain metastases and meningeal dissemination almost disappeared. The overall time from the start of crizotinib to lorlatinib is 89.5 months at present, and the patient continues to be treated with lorlatinib without relapse. Lorlatinib was effective in this case with brain metastases and meningeal dissemination after resistance to first‐ and second‐generation ALKis. Appropriate sequential treatment with first‐, second‐ and third‐generation ALKis can lead to a long‐term survival in ALK+ patients with brain metastases and meningeal dissemination.
Bioenergetic and inflammatory systemic phenotypes in Alzheimer’s disease APOE ε4‐carriers
Authors: Wilkins Heather M. , Wang Xiaowan , Menta Blaise W. , Koppel Scott J. , Bothwell Rebecca , Becker Annette M. , Anderson Heidi , Schwartz Erin , Pei Dong , Yellapu Nanda K. , Chalise Prabhakar , Gouvion Cynthia M. , Haeri Mohammad , Burns Jeffrey M. , Swerdlow Russell H.
Published: May 2021

We examined the impact of an APOE ε4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE ε4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post‐mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE ε4 lymphocytes. Lymphocyte ACC changes were also observed in post‐mortem brain tissue. Lymphocyte RNAseq showed lower APOE ε4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE ε4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE ε4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain‐localized AD histopathology can account for these findings, which define an APOE ε4‐determined molecular and systemic phenotype that informs AD etiology.
PR interval prolongation is significantly associated with aortic root abscess: An age‐ and gender‐matched study
Authors: Kohli Utkarsh , Obuobi Shirlene , Addetia Karima , Ota Takeyoshi , Nayak Hemal M.
Published: May 2021

Background

Electrocardiographic abnormalities, such as PR interval prolongation, have been anecdotally reported in patients with aortic root abscess (ARA). An electrocardiographic marker may be useful in identifying those patients with aortic valve endocarditis who may progress to ARA. The objective of this study is to evaluate the change in the PR interval in patients with surgically confirmed ARA and compare it to age‐ and gender‐matched controls with echocardiographically or surgically confirmed aortic valve endocarditis but without aortic root abscess and those hospitalized with diagnoses other than endocarditis.

Methods

Patients were eligible for enrollment if they were 18 years or older and were hospitalized for either ARA, aortic valve endocarditis, or for unrelated reasons and had at least one 12‐lead electrocardiogram (ECG) prior to or on the day of hospitalization and at least one ECG after hospitalization but prior to any cardiac surgical procedure. Delta PR interval, defined as the difference between the pre‐ and post‐admission PR interval, was the primary outcome of interest. The patients in the ARA group were age‐ and gender‐matched to patients with aortic valve endocarditis and to those without endocarditis. Comparisons of demographic variables and study outcomes were performed.

Results

Eighteen patients with surgically confirmed ARA were enrolled. These patients were age‐ and gender‐matched to 19 patients with aortic valve endocarditis and 18 patients with no past history or evidence of endocarditis during hospitalization. No difference was noted in the baseline PR interval between the groups. However, the PR interval following admission in the aortic root abscess group (201 ± 66 ms) was significantly longer than the PR interval in both the aortic valve endocarditis (162 ± 27 ms) (24%, p = .009) and no endocarditis (143 ± 24 ms) (40%, p < .001) groups. The primary outcome measure, delta PR interval, was significantly longer in the ARA group (35 ± 51 ms) than no endocarditis (−5 ± 17 ms) (p = .001) and aortic valve endocarditis groups (0.2 ± 18) (p = .003).

Conclusions

The findings of our study support the notion that the PR interval is more likely to be prolonged in patients with ARA. Since ARA is associated with a high morbidity and mortality, PR interval prolongation in a patient with aortic valve endocarditis should prompt a thorough evaluation for aortic root involvement.
Association between lifetime and recent stressful life events and the early course and psychopathology in patients with newly diagnosed bipolar disorder, first‐degree unaffected relatives and healthy controls: Cross‐sectional results from a prospective study
Authors: av Kák Kollsker Stina , Coello Klara , Stanislaus Sharleny , Melbye Sigurd , Lie Kjærstad Hanne , Stefanie Ormstrup Sletved Kimie , Vedel Kessing Lars , Vinberg Maj
Published: May 2021

Objective

There is an accumulation of stressful life events prior to the first mood episode, but the impact of previous severe life events on psychopathology in patients with bipolar disorder (BD) is not well studied. We aimed to examine the number of recent and lifetime life events in patients with newly diagnosed BD, their unaffected relatives (UR), and healthy controls (HC) as well as the impact of severe lifetime life events on the early course of BD.

Methods

We compared the number of recent and lifetime life events in 398 patients with newly diagnosed BD, 109 UR, and 214 HC. We subsequently dichotomized the patients with BD by >2 lifetime life events to investigate the associations of severe lifetime life events with clinical characteristics and affective symptoms.

Results

Patients with newly diagnosed BD reported significantly more life events in the last 12 months and lifetime before compared with UR and HC. Patients who reported >2 lifetime life events (n = 160) compared with patients with 0–2 life events (n = 238) had a significantly longer diagnostic delay (9.5 years ± 8.2 vs. 6.2 years ± 6.9), presented with more anxiety and depressive symptoms and had at least one previous suicide attempt (30.6% vs. 15.6%) and one previous admission (51.3% vs. 36.6%).

Conclusion

The experience of severe lifetime life events seems to impact the early course in BD in terms of longer diagnostic delay, more severe psychopathology including more admissions and a more than doubled risk for previous suicide attempts.
Evaluating the feasibility and acceptability of a mobile‐based health technology for smoking cessation: Mobile Anxiety Sensitivity Program
Authors: Garey Lorra , Hébert Emily T. , Mayorga Nubia A. , Chavez JeanFelix , Shepherd Justin M. , Businelle Michael S. , Zvolensky Michael J.
Published: May 2021

Objectives

Cigarette smoking is the leading preventable cause of death and disability. Although most US smokers want to quit, more than 95% of cessation attempts end in relapse within 6 months. To improve cessation outcomes, research has turned to targetable mechanisms, such as anxiety sensitivity (AS), which maintain smoking behaviour, impede cessation success, and can be effectively targeted in the context of psychosocial interventions. Although integrated treatment programmes that address AS reduction in the context of smoking cessation have demonstrated promising results, presently, no mobile, technology‐based integrated treatment exists to expressly address smoking and AS. The current study evaluated the initial feasibility and acceptability of a mobile smoking cessation intervention, Mobile Anxiety Sensitivity Program for smoking (MASP).

Methods

Participants were 15 daily adult combustible cigarette smokers (females n = 6, Mage = 46.5 years, SD = 13.3) who completed a 6‐week total intervention period (baseline visit, 2 weeks pre‐quit, 4 weeks post‐quit, follow‐up visit).

Results

Most participants (N = 12) completed the full 6‐week intervention, and participant engagement with MASP was high. Participants reported that MASP was acceptable. Biochemical verification of smoking abstinence indicated 25% of smokers were abstinent for at least 24 hr prior to the in‐person 4 weeks post‐quit follow‐up visit.

Conclusions

Findings indicated that MASP has the potential to provide effective assistance to those wanting to quit cigarettes.

Practitioner points

Mobile‐based smoking cessation interventions may be a promising treatment option, particularly for those of lower socio‐economic status.

Targeting AS in the context of a mobile‐based smoking cessation app may be a viable way to improve smoking cessation success and treatment outcome.

Due to the pilot nature of this study, there was no control group. Thus, comparative conclusions and generalizability based on the current study must be made with caution.
Improving the laboratory diagnosis of pyruvate kinase deficiency
Authors: Laas Claire , Lambert Christopher , Senior McKenzie Tania , Sheldon Ewart , Davidson Philip , Rees David , Clark Barnaby
Published: May 2021

Pyruvate kinase (PK) deficiency is an autosomal recessive disease caused by mutations in the PKLR gene, which reduce erythrocyte PK enzyme activity and result in decreased energy synthesis in red cells, causing haemolytic anaemia. Historically, the investigation into pyruvate kinase deficiency (PKD) has been led by a red cell enzyme assay determining PK enzyme activity per unit of haemoglobin. For our laboratory, the reference range was set by Beutler et al. in 1977 when the test was first established. The introduction of genetic testing permitted the creation of reference sample datasets, with positive controls having two pathogenic variants causing disease. This permitted re‐assessment of the enzyme assay’s sensitivity and specificity, and was used to reassess the reference range of the enzyme assay. Using sequenced samples, we have devised an enzyme assay, DNA testing workflow, which minimises false negative/positive results and improves the diagnostic efficiency. This combined enzyme‐DNA testing strategy should improve the diagnostic accuracy whilst limiting the number of expensive DNA tests. During this evaluation, 10 novel genetic variants were identified and are described.
Histopathological patterns in atypical teratoid/rhabdoid tumors are related to molecular subgroup
Authors: Zin Francesca , Cotter Jennifer A. , Haberler Christine , Dottermusch Matthias , Neumann Julia , Schüller Ulrich , Schweizer Leonille , Thomas Christian , Nemes Karolina , Johann Pascal D. , Kool Marcel , Frühwald Michael C. , Paulus Werner , Judkins Alexander , Hasselblatt Martin
Published: May 2021

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor that may not only contain rhabdoid tumor cells but also poorly differentiated small‐round‐blue cells as well as areas with mesenchymal or epithelial differentiation. Little is known on factors associated with histopathological diversity. Recent studies demonstrated three molecular subgroups of AT/RT, namely ATRT‐TYR, ATRT‐SHH, and ATRT‐MYC. We thus aimed to investigate if morphological patterns might be related to molecular subgroup status. Hematoxylin‐eosin stained sections of 114 AT/RT with known molecular subgroup status were digitalized and independently categorized by nine blinded observers into four morphological categories, that is, “rhabdoid,” “small‐round‐blue,” “epithelial,” and “mesenchymal.” The series comprised 48 ATRT‐SHH, 40 ATRT‐TYR, and 26 ATRT‐MYC tumors. Inter‐observer agreement was moderate but significant (Fleiss’ kappa = 0.47; 95% C.I. 0.41‐0.53; p < 0.001) and there was a highly significant overall association between morphological categories and molecular subgroups for each of the nine observers (p < 0.0001). Specifically, the category “epithelial” was found to be over‐represented in ATRT‐TYR (p < 0.000001) and the category “small‐round‐blue” to be over‐represented in ATRT‐SHH (p < 0.01). The majority of ATRT‐MYC was categorized as “mesenchymal” or “rhabdoid,” but this association was less compelling. The specificity of the category “epithelial” for ATRT‐TYR was highest and accounted for 97% (range: 88‐99%) whereas sensitivity was low [49% (range: 35%–63%)]. In line with these findings, cytokeratin‐positivity was highly overrepresented in ATRT‐TYR. In conclusion, morphological features of AT/RT might reflect molecular alterations and may also provide a first hint on molecular subgroup status, which will need to be confirmed by DNA methylation profiling.
Self‐harm as the first presentation of attention deficit hyperactivity disorder in adolescents
Authors: Ward John Headley , Curran Sarah
Published: May 2021

Background

Self‐harm (SH) in adolescence has previously been shown to significantly overlap with both attention deficit hyperactivity disorder (ADHD) and emotional dysregulation (ED). Our objective as such was to investigate the relationship between self‐harm and ADHD in our population and consider its clinical relevance.

Methods

This case series analysis examined 124 presentations of SH in 13‐ to 17 year‐olds to Accident and Emergency Departments in South West London (97F:27M). Strength and Difficulties Questionnaires (SDQs) were used to screen for ADHD/hyperactivity and ED, and scores were compared with reference data obtained from Meltzer et al. (1999, International Review of Psychiatry (Abingdon, England), 15, 185).

Results

Mean SDQ ADHD/hyperactivity scores were significantly higher in our SH sample compared to reference data (p < .0001). Furthermore, significantly greater ED scores were found in our sample compared with the control reference data.

Conclusion

Our findings contribute to the evidence for an important link between ADHD and clinical presentations of SH and suggest there to be value in screening girls presenting to A&E with self‐harm for ADHD. We speculate that ED plays a role in the evolution of SH in dysregulated ADHD. We recommend that clinicians assessing adolescents have self‐harmed to be aware of possible ADHD symptoms and screen as appropriate; however, future research examining the temporal association between ADHD, emotional dysregulation and self‐harm is required to establish causal direction.
Development of humanized mouse with patient‐derived xenografts for cancer immunotherapy studies: A comprehensive review
Authors: Jin Ke‐Tao , Du Wen‐Lin , Lan Huan‐Rong , Liu Yu‐Yao , Mao Chun‐Sen , Du Jin‐Lin , Mou Xiao‐Zhou
Published: May 2021

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre‐clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient‐derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre‐clinical evaluation of onco‐immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.