bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacy technicians, supporting our past, shaping our future: Implementing an ASHP-ACPE–accredited pharmacy technician training program in an academic medical center
Authors: Pereda Mariel C , Goffman David , Parker Sharee’ , Polat Nigjar , Kozakiewicz Janet M
Published: June 2021

Purpose

Pharmacy technician training and education vary depending on practice site and state law. Although technician certification provides a national standard for credentialing, not all states require it, making certification a voluntary process for technicians or the organizations employing them. As the role of the pharmacist has evolved, the need for highly trained pharmacy technicians has grown. The pharmacy technician’s expanded role in specialized areas of pharmacy practice has created new opportunities that require advanced training.

Research is lacking on return on investment for workforce development programs, making it difficult to advocate for pharmacy technician training programs. Therefore, it is important to create internal metrics that link one’s program to business performance. This begins with conducting a job market analysis for the geographic area. It is imperative to identify the current occupational outlook for pharmacy technicians, identifying areas with potential for growth as well as where there are shortages or high turnover. Successful development of an American Society of Health-System Pharmacists (ASHP) and Accreditation Council for Pharmacy Education (ACPE)–accredited pharmacy technician program requires a long-term strategy to address key market issues as well as social and economic barriers and financial data to secure funding.

Conclusion

This case study details Yale New Haven Hospital’s journey from proof of concept to implementation of an ASHP-ACPE–accredited pharmacy technician training program.
False colour photography reveals the complexity of flower signalling. A Commentary on: ‘A bee’s eye view of remarkable floral colour patterns in the Southwest Australian biodiversity hotspot revealed by false colour photography’
Authors: Garcia Jair E , Dyer Adrian G
Published: June 2021

This article comments on:

Klaus Lunau, Daniela Scaccabarozzi, Larissa Willing and Kingsley Dixon, A bee’s eye view of remarkable floral colour patterns in the Southwest Australian biodiversity hotspot revealed by false colour photography’, Annals of Botany, Volume 128, Issue 7, 2 December 2021, Pages 821–824 https://doi.org/10.1093/aob/mcab088
Self-renewal and differentiation of rat epididymal basal cells using a novel in vitro organoid model
Authors: Pinel Laurie , Cyr Daniel G
Published: June 2021

The epididymis is composed of a pseudostratified epithelium that is comprised of various cell types. Studies have shown that rat basal cells share common properties with adult stem cells and begin to differentiate in vitro in response to fibroblast growth factor and 5α-dihydrotestosterone. The characterization of rat basal cells is therefore necessary to fully understand the role of these cells. The objectives of this study were to assess the ability of single basal cells to develop organoids and to assess their ability to self-renew and differentiate in vitro. We isolated basal cells from the rat epididymis and established three-dimensional cell cultures from the basal and nonbasal cell fractions. Organoids were formed by single adult epididymal basal cells. Organoids were dissociated into single basal cells, which were able to reform new organoids, and were maintained over 10 generations. Long-term culture of organoids revealed that these cells could be differentiated into cells expressing the principal cell markers aquaporin 9 and cystic fibrosis transmembrane conductance regulator. Electron microscopy demonstrated that organoids were composed of several polarized cell types displaying microvilli and the ability to form tight junctions. Additionally, organoids could be formed by basal cells from either the proximal or distal region of the epididymis and are able to secrete clusterin, a protein implicated in the maturation of spermatozoa. These data indicate that rat basal cells can be used to derive epididymal organoids and further support that notion that these may represent a stem cell population in the epididymis.
Efficient Bernoulli factory Markov chain Monte Carlo for intractable posteriors
Authors: Vats D , Gonçalves F B , Łatuszyński K , Roberts G O
Published: June 2021

Accept-reject-based Markov chain Monte Carlo algorithms have traditionally utilized acceptance probabilities that can be explicitly written as a function of the ratio of the target density at the two contested points. This feature is rendered almost useless in Bayesian posteriors with unknown functional forms. We introduce a new family of Markov chain Monte Carlo acceptance probabilities that has the distinguishing feature of not being a function of the ratio of the target density at the two points. We present two stable Bernoulli factories that generate events within this class of acceptance probabilities. The efficiency of our methods relies on obtaining reasonable local upper or lower bounds on the target density, and we present two classes of problems where such bounds are viable: Bayesian inference for diffusions, and Markov chain Monte Carlo on constrained spaces. The resulting portkey Barker’s algorithms are exact and computationally more efficient that the current state of the art.
Artificial intelligence in the management and treatment of burns: a systematic review
Authors: E Moura Francisco Serra , Amin Kavit , Ekwobi Chidi
Published: June 2021

Background

Artificial intelligence (AI) is an innovative field with potential for improving burn care. This article provides an updated review on machine learning in burn care and discusses future challenges and the role of healthcare professionals in the successful implementation of AI technologies.

Methods

A systematic search was carried out on MEDLINE, Embase and PubMed databases for English-language articles studying machine learning in burns. Articles were reviewed quantitatively and qualitatively for clinical applications, key features, algorithms, outcomes and validation methods.

Results

A total of 46 observational studies were included for review. Assessment of burn depth (n = 26), support vector machines (n = 19) and 10-fold cross-validation (n = 11) were the most common application, algorithm and validation tool used, respectively.

Conclusion

AI should be incorporated into clinical practice as an adjunct to the experienced burns provider once direct comparative analysis to current gold standards outlining its benefits and risks have been studied. Future considerations must include the development of a burn-specific common framework. Authors should use common validation tools to allow for effective comparisons. Level I/II evidence is required to produce robust proof about clinical and economic impacts.
Low-Intensity Pulsed Ultrasound Enhances Neurotrophic Factors and Alleviates Neuroinflammation in a Rat Model of Parkinson’s Disease
Authors: Sung Chen-Yu , Chiang Pai-Kai , Tsai Che-Wen , Yang Feng-Yi
Published: June 2021

Low-intensity pulsed ultrasound (LIPUS) has also been reported to improve behavioral functions in Parkinson’s disease (PD) animal models; however, the effect of LIPUS stimulation on the neurotrophic factors and neuroinflammation has not yet been addressed. PD rat model was built by injection of 6-hydroxydopamine (6-OHDA) in 2 sites in the right striatum. The levels of neurotrophic factors and lipocalin-2 (LCN2)-induced neuroinflammation were quantified using a western blot. Rotational test and cylinder test were conducted biweekly for 8 weeks. When the 6-OHDA + LIPUS and 6-OHDA groups were compared, the locomotor function of the 6-OHDA + LIPUS rats was significantly improved. After LIPUS stimulation, the tyrosine hydroxylase staining density was significantly increased in the striatum and substantia nigra pars compacta (SNpc) of lesioned rats. Unilateral LIPUS stimulation did not increase brain-derived neurotrophic factor in the striatum and SNpc of lesioned rats. In contrast, unilateral LIPUS stimulation increased glial cell line-derived neurotrophic factor (GDNF) protein 1.98-fold unilaterally in the SNpc. Additionally, LCN2-induced neuroinflammation can be attenuated following LIPUS stimulation. Our data indicated that LIPUS stimulation may be a potential therapeutic tool against PD via enhancement of GDNF level and inhibition of inflammatory responses in the SNpc of the brain.
Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart
Authors: Davidson Sean M , Padró Teresa , Bollini Sveva , Vilahur Gemma , Duncker Dirk J , Evans Paul C , Guzik Tomasz , Hoefer Imo E , Waltenberger Johannes , Wojta Johann , Weber Christian
Published: June 2021

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.
Identification of sur2 mutation affecting the lifespan of fission yeast
Authors: Kurauchi Tatsuhiro , Matsui Kotaro , Shimasaki Takafumi , Ohtsuka Hokuto , Tsubouchi Satoshi , Ihara Kunio , Tani Motohiro , Aiba Hirofumi
Published: June 2021

Yeast is a suitable model system to analyze the mechanism of lifespan. In this study, to identify novel factors involved in chronological lifespan, we isolated a mutant with a long chronological lifespan and found a missense mutation in the sur2+ gene, which encodes a homolog of Saccharomyces cerevisiae sphingolipid C4-hydroxylase in fission yeast. Characterization of the mutant revealed that loss of sur2 function resulted in an extended chronological lifespan. The effect of caloric restriction, a well-known signal for extending lifespan, is thought to be dependent on the sur2+ gene.
Rayleigh-wave H/V ratio measurement from ambient noise cross-correlations and its sensitivity to VP: a numerical study
Authors: Malkoti Ajay , Datta Arjun , Hanasoge Shravan M
Published: June 2021

The promise of passive seismology has increasingly been realized in recent years. Given the expense in installing and maintaining seismic station networks, it is important to extract as much information from the measurements as possible. In this context, the ellipticity or H/V amplitude ratio of Rayleigh waves can prove to be a valuable observable in ambient noise seismology due to its complimentary sensitivity to subsurface structure, compared to phase and group-velocity dispersion, as well as its potential for constraining VP structure in addition to VS. However, the suitability of the Rayleigh H/V ratio in noise-based studies depends on the accurate interpretation of measurements made on multicomponent ambient-noise cross-correlations. We present a synthetic study that critically examines measurements commonly interpreted as the Rayleigh-wave H/V ratio, under realistic scenarios of spatially distributed and non-uniform noise sources. Using the surface wave terms of Green’s function in a laterally homogeneous medium, we rigorously model multicomponent cross-correlations for arbitrary noise-source distributions and extract from them standard estimates of the H/V ratio. Variation of these measurements as a function of VP is studied empirically, by brute-force simulation. We find that the measurements depart significantly from the theoretical Rayleigh-wave H/V for the medium in question, when noise sources are strongly directional or anisotropic. Love waves, if present in the cross-correlations, also have the potential to significantly bias interpretation. Accurate interpretation of the H/V ratio measurement thus rests on carefully modelling these effects. However, the sensitivity to VP structure is comparable to that of the classic Rayleigh-wave H/V. We also propose a new measurement for cross-correlations that has slightly greater sensitivity to VP. Finally, uncertainty analysis on synthetic tests suggests that simplistic interpretations of Rayleigh-wave ellipticity are only effective (in resolving VP structure) when the Love-wave contamination is negligible and measurement uncertainties are less than 10 per cent.
Serum Analyte Profiles Associated With Crohn’s Disease and Disease Location
Authors: Boucher Gabrielle , Paradis Alexandre , Chabot-Roy Geneviève , Coderre Lise , Hillhouse Erin E , Bitton Alain , Des Rosiers Christine , Levings Megan K , Schumm L Philip , Lazarev Mark , Brant Steve R , Duerr Richard , McGovern Dermot , Silverberg Mark S , Cho Judy , Lesage Sylvie , Rioux John D ,   iGenoMed Consortium, Bitton Alain , Boucher Gabrielle , Charron Guy , Des Rosiers Christine , Forest Anik , Goyette Philippe , Ivinson Sabine , Joseph Lawrence , Kohen Rita , Lachaine Jean , Lesage Sylvie , Levings Megan , Rioux John D , Thompson-Legault Julie , Vachon Luc , Veilleux Sophie , White-Guay Brian ,   NIDDK IBD Genetics Consortium, Bajpai Manisha , Birch Sondra , Bitton Alain , Borowski Krzysztof , Botwin Gregory , Boucher Gabrielle , Brant Steven R , Chen Wei , Cho Judy H , Cordero Roberto , Côté-Daigneault Justin , Daly Mark J , Datta Lisa , Duerr Richard H , Filice Melissa , Fleshner Philip , Gettler Kyle , Giri Mamta , Goyette Philippe , Hao Ke , Haritunians Talin , Itan Yuval , Johnston Elyse , Konnikova Liza , Landers Carol , Lazarev Mark , Li Dalin , McGovern Dermot P B , Mengesha Emebet , Merad Miriam , Miladinova Vessela , Nayeri Shadi , Proksell Siobhan , Raquel Milgrom , Rioux John D , Rymaszewski Klaudia , Sabic Ksenija , Sands Bruce , Schumm L Philip , Schwartz Marc B , Silverberg Mark S , Simpson Claire L , Stempak Joanne M , Stevens Christine , Targan Stephan R , Xavier Ramnik
Published: June 2021

Background

Crohn’s disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the study was to identify circulating markers associated with CD and/or disease location in CD patients.

Methods

We tested 49 cytokines, chemokines, and growth factors in serum samples from 300 patients with CD and 300 controls. After quality control, analyte levels were tested for association with CD and disease location.

Results

We identified 13 analytes that were higher in CD patients relative to healthy controls and that remained significant after conservative Bonferroni correction (P < 0.0015). In particular, CXCL9, CXCL1, and interleukin IL-6 had the greatest effect and were highly significant (P < 5 × 10–7). We also identified 9 analytes that were associated with disease location, with VEGF, IL-12p70, and IL-6 being elevated in patients with colorectal disease (P < 3 × 10–4).

Conclusions

Multiple serum analytes are elevated in CD. These implicate the involvement of multiple cell types from the immune, epithelial, and endothelial systems, suggesting that circulating analytes reflect the inflammatory processes that are ongoing within the gut. Moreover, the identification of distinct profiles according to disease location supports the existence of a biological difference between ileal and colonic CD, consistent with previous genetic and clinical observations.
Factors associated with the intention of community pharmacists to report adverse drug reactions to regulatory authority in Malaysia: application of the theory of planned behaviour
Authors: Raghvan Hari Pretha Nair , Fatokun Omotayo
Published: June 2021

Objectives

It is known that community pharmacists in Malaysia underreport adverse drug reactions (ADRs). In order to improve ADR reporting, a theory-based understanding of the factors associated with the community pharmacists’ reporting behaviour is important. This study used the theory of planned behaviour (TPB) to identify the predictors of behavioural intention to report ADRs to the regulatory authority among community pharmacists in Malaysia and to assess the relative importance of the predictors.

Methods

A questionnaire-based study was conducted among 188 randomly selected community pharmacists in the state of Johor, Malaysia. The questionnaire included four main TPB constructs (intention, attitude, subjective norms and perceived behavioural control) and related measures, including perceived moral obligation, past reporting behaviour and sociodemographic variables. Descriptive and hierarchical regression analyses were conducted.

Key findings

A total of 164 questionnaires were collected. The mean score of intention to report ADRs was 15.43 (SD = 2.99). The final model of the hierarchical regression analysis showed that attitude towards ADR reporting (P = 0.004), subjective norm (P = 0.010) and perceived moral obligation (P = 0.014) were significant predictors of intention to report ADRs. Attitude was the most significant predictor, followed by subjective norm and perceived moral obligation.

Conclusions

Interventions targeting community pharmacists’ attitude, subjective norms and perceived moral obligations towards ADR reporting, with a specific focus on attitude would likely have a positive impact on improving ADR reporting in Malaysia.
Strong uniform consistency with rates for kernel density estimators with general kernels on manifolds
Authors: Wu Hau-Tieng , Wu Nan
Published: June 2021

When analyzing modern machine learning algorithms, we may need to handle kernel density estimation (KDE) with intricate kernels that are not designed by the user and might even be irregular and asymmetric. To handle this emerging challenge, we provide a strong uniform consistency result with the $L^\infty $ convergence rate for KDE on Riemannian manifolds with Riemann integrable kernels (in the ambient Euclidean space). We also provide an $L^1$ consistency result for kernel density estimation on Riemannian manifolds with Lebesgue integrable kernels. The isotropic kernels considered in this paper are different from the kernels in the Vapnik–Chervonenkis class that are frequently considered in statistics society. We illustrate the difference when we apply them to estimate the probability density function. Moreover, we elaborate the delicate difference when the kernel is designed on the intrinsic manifold and on the ambient Euclidian space, both might be encountered in practice. At last, we prove the necessary and sufficient condition for an isotropic kernel to be Riemann integrable on a submanifold in the Euclidean space.
α2-3 Sialic acid binding and uptake by human monocyte-derived dendritic cells alters metabolism and cytokine release and initiates tolerizing T cell programming
Authors: Lübbers Joyce , Eveline Li Rui-Jún , Gorki Friederike S , Bruijns Sven C M , Gallagher Ashley , Kalay Hakan , Ambrosini Martino , Molenaar Douwe , Van den Bossche Jan , van Vliet Sandra J , van Kooyk Yvette
Published: June 2021

Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolution phase of inflammation and are able to induce tolerance after receiving anti-inflammatory cytokines or upon encounter of self-associated molecular patterns, such as α2-3 linked sialic acid (α2-3sia).

Objective: We here investigated whether α2-3sia, that bind immune inhibitory Siglec receptors, would alter signaling and reprogramming of LPS-stimulated human monocyte-derived DCs (moDCs).

Methods and Results: Transcriptomic analysis of moDCs stimulated with α2-3sia-conjugated dendrimers revealed differentially expressed genes related to metabolic pathways, cytokines, and T cell differentiation. An increase in genes involved in ATPase regulator activity, oxidoreductase activity, and glycogen metabolic processes was detected. Metabolic extracellular flux analysis confirmed a more energetic moDC phenotype upon α2-3sia binding as evidenced by an increase in both glycolysis and mitochondrial oxidative phosphorylation. TH1 differentiation promoting genes IFNL and IL27, were significantly downregulated in the presence of α2-3sia. Functional assays confirmed that α2-3sia binding to moDCs induced phosphorylation of Siglec-9, reduced production of inflammatory cytokines IL-12 and IL-6, and increased IL-10. Surprisingly, α2-3sia-differentiated moDCs promoted FoxP3+CD25+/-CD127- regulatory T cell differentiation and decreased FoxP3-CD25-CD127- effector T cell proliferation.

Conclusions: In conclusion, we demonstrate that α2-3sia binding to moDCs, phosphorylates Siglec-9, alters metabolic pathways, cytokine signaling, and T cell differentiation processes in moDCs and promotes regulatory T cells. The sialic acid-Siglec axis on DCs is therefore, a novel target to induce tolerance and to explore for immunotherapeutic interventions aimed to restore inflammatory processes.
Multiplicative and Linear Dependence in Finite Fields and on Elliptic Curves Modulo Primes
Authors: Barroero Fabrizio , Capuano Laura , Mérai László , Ostafe Alina , Sha Min
Published: June 2021

For positive integers $K$ and $L$, we introduce and study the notion of $K$-multiplicative dependence over the algebraic closure ${\overline{{\mathbb{F}}}}_p$ of a finite prime field ${\mathbb{F}}_p$, as well as $L$-linear dependence of points on elliptic curves in reduction modulo primes. One of our main results shows that, given non-zero rational functions $\varphi _1,\ldots ,\varphi _m, \varrho _1,\ldots ,\varrho _n\in{\mathbb{Q}}(X)$ and an elliptic curve $E$ defined over the rational numbers ${\mathbb{Q}}$, for any sufficiently large prime $p$, for all but finitely many $\alpha \in{\overline{{\mathbb{F}}}}_p$, at most one of the following two can happen: $\varphi _1(\alpha ),\ldots ,\varphi _m(\alpha )$ are $K$-multiplicatively dependent or the points $(\varrho _1(\alpha ),\cdot ), \ldots ,(\varrho _n(\alpha ),\cdot )$ are $L$-linearly dependent on the reduction of $E$ modulo $p$. As one of our main tools, we prove a general statement about the intersection of an irreducible curve in the split semiabelian variety ${\mathbb{G}}_{\textrm{m}}^m \times E^n$ with the algebraic subgroups of codimension at least $2$.

As an application of our results, we improve a result of M. C. Chang and extend a result of J. F. Voloch about elements of large order in finite fields in some special cases.
The German Federal Constitutional Court Ruling and the European Central Bank’s Strategy
Authors: Feld Lars P , Wieland Volker
Published: June 2021

The ruling of the German Federal Constitutional Court and its call for conducting and communicating proportionality assessments regarding monetary policy have been the subject of some controversy. However, it can also be understood as a way to strengthen the de facto independence of the European Central Bank (ECB). This article shows how a regular proportionality check could be integrated in the ECB’s strategy, which is currently undergoing a systematic review. In particular, it proposes that quantitative benchmarks for policy rates and the central bank balance sheet should be included. Deviations from such benchmarks can have benefits in terms of the intended path for inflation while involving costs in terms of risks and side effects that need to be balanced. Practical applications to the euro area are provided.
Treatment outcomes of erlotinib plus gemcitabine as late-line chemotherapy in unresectable pancreatic cancer
Authors: Mie Takafumi , Sasaki Takashi , Takeda Tsuyoshi , Okamoto Takeshi , Mori Chinatsu , Furukawa Takaaki , Yamada Yuto , Kasuga Akiyoshi , Matsuyama Masato , Ozaka Masato , Sasahira Naoki
Published: June 2021

Objective

With the introduction of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy for unresectable pancreatic cancer, erlotinib plus gemcitabine therapy is now occasionally used as late-line therapy. This study investigates outcomes of treatment with erlotinib plus gemcitabine for unresectable pancreatic cancer.

Methods

We retrospectively analysed consecutive patients with unresectable pancreatic cancer treated with erlotinib plus gemcitabine as the third or later-line chemotherapy between March 2014 and December 2020 in our hospital.

Results

A total of 56 patients were included (third line/fourth or later line = 42/14). All patients were previously treated with gemcitabine plus nab-paclitaxel and 45 patients were previously treated with modified FOLFIRINOX. The median progression-free survival (PFS) and overall survival (OS) were 1.6 and 4.6 months, respectively. The disease control rate was 21.4%. Performance status, modified Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify patients into good (n = 32) and poor (n = 24) prognostic groups. The median PFS and OS were longer in good than in poor prognostic group, but the difference in PFS was very small (PFS: 2.1 vs. 1.4 months, P = 0.01. OS: 6.8 vs. 2.4 months, P < 0.01). Interstitial pneumonia occurred in one patient (1.8%).

Conclusions

Benefits of erlotinib plus gemcitabine as late-line chemotherapy were limited, particularly with respect to PFS. Development of more effective third-line treatment options is desirable in the future.
The role of soil-borne fungi in driving the coexistence ofPinus massonianaandLithocarpus glaberin a subtropical forest via plant–soil feedback
Authors: Pan Yumei , Yao Zhongyuan , Zhang Naili , Veen G F
Published: June 2021

Aims

Plant–soil feedback (PSF) is a key mechanism that can facilitate tree species coexistence and diversity. Substantial evidence suggests that species-specific soil-borne pathogens around adult trees limit the performance of home (conspecific) seedlings relative to foreign (heterospecific) seedlings. However, the underlying mechanism remains largely elusive.

Methods

Here, we conducted a reciprocal transplant pot experiment using seedlings and from two tree species, Pinus massoniana and Lithocarpus glaber that are dominant and coexist in a subtropical, evergreen, broad-leaf forest in Gutianshan, Zhejiang Province of eastern China. We examined how seedlings from the two tree species responded to soils originating from underneath their own versus the other tree species, using a full-factorial design. Additionally, we added a fungicide (benomyl) to half of the pots to evaluate the role of soil-borne fungi on seedling growth.

Important Findings

We found that the seedlings from L. glaber grew better in soils that were collected from beneath the canopy of P. massoniana, while seedling growth of P. massioniana was not affected by soil origin. The addition of fungicide benomyl resulted in a shift towards more positive PSF effects for L. glaber, indicating that L. glaber seedlings performed better in their own soils than in soils from P. massoniana in the absence of fungi. Our findings highlight the importance of soil-borne pathogenic and ectomycorrhizal fungi in driving PSF, and indicate that PSF may promote the coexistence of two subtropical tree species by reducing the performance of L. glaber in own soils.
Infarcted wandering spleen: A case report from Saudi Arabia
Authors: Alghamdi Raid , Alzahrnai Amer , Alosaimi Abdulaziz , Albabtain Ibrahim
Published: June 2021

Spleen is normally positioned in the left upper quadrant. Abnormal location where it is not found in its normal anatomical position is called wandering spleen (WS). Wandering spleen is a rare medical condition that occurs due to developmental abnormality or acquired laxity of the ligaments that hold the spleen in its normal anatomical position. It affects children and young adults, especially childbearing age women. Patients affected with this condition may present with nonspecific symptoms requiring a high index of suspicion. Here, we are presenting a 20-year-old female known to have WS ended up with infarcted WS requiring emergency splenectomy.
The Sw-5b NLR nucleotide-binding domain plays a role in oligomerization, and its self-association is important for activation of cell death signaling
Authors: Zhao Xiaohui , Chen Zhengqiang , Wu Qian , Cai Yazhen , Zhang Yu , Zhao Ruizhen , Yan Jiaoling , Qian Xin , Li Jia , Zhu Min , Hong Lizhou , Xing Jincheng , Khan Nasr Ullah , Ji Yinghua , Wu Peijun , Huang Changjun , Ding Xin Shun , Zhang Hui , Tao Xiaorong
Published: June 2021

Plant and animal intracellular nucleotide-binding and leucine-rich repeat (NLR) receptors play important roles in sensing pathogens and activating defense signaling. However, the molecular mechanisms underlying the activation of host defense signaling by NLR proteins remain largely unknown. Many studies have determined that the coil–coil (CC) or Toll and interleukin-1 receptor/resistance protein (TIR) domain of NLR proteins and their dimerization/oligomerization are critical for activating downstream defense signaling. In this study, we demonstrated that, in tomato, the nucleotide-binding (NB) domain Sw-5b NLR alone can activate downstream defense signaling, leading to elicitor-independent cell death. Sw-5b NB domains can self-associate, and this self-association is crucial for activating cell death signaling. The self-association was strongly compromised after the introduction of a K568R mutation into the P-loop of the NB domain. Consequently, the NBK568R mutant induced cell death very weakly. The NBCΔ20 mutant lacking the C-terminal 20 amino acids can self-associate but cannot activate cell death signaling. The NBCΔ20 mutant also interfered with wild-type NB domain self-association, leading to compromised cell death induction. By contrast, the NBK568R mutant did not interfere with wild-type NB domain self-association and its ability to induce cell death. Structural modeling of Sw-5b suggests that NB domains associate with one another and likely participate in oligomerization. As Sw-5b-triggered cell death is dependent on helper NLR proteins, we propose that the Sw-5b NB domain acts as a nucleation point for the assembly of an oligomeric resistosome, probably by recruiting downstream helper partners, to trigger defense signaling.
A Backwards-step for Gillick: Trans Children’s Inability to Consent to Treatment for Gender Dysphoria—Quincy Bell & Mrs A v The Tavistock and Portman NHS Foundation Trust and Ors [2020] EWHC 3274 (Admin)
Authors: Moreton Kirsty L.
Published: June 2021

The case of Quincy Bell & Mrs A v The Tavistock and Portman NHS Foundation Trust and Ors is a judicial review into the treatment practices of the Gender Identity Development Service (GIDS) run by Tavistock and Portman NHS Foundation Trust (Tavistock). The Divisional Court considered whether children and young people with Gender Dysphoria (GD) can ever be Gillick competent to consent to treatment with Puberty Blockers (PBs), and if so whether GIDS provided sufficient information to support an informed consent. This commentary examines the six key areas of the judgment: the nature of GD and its treatment with PBs; the categorisation of PBs as experimental treatment; the high bar set to achieve Gillick competence; the convergence of information provision and competence; the role of parental consent; and finally the protective jurisdiction of the court. The conclusion of the court that transgender children aged under 16 years will find ‘enormous difficulties’ in reaching the Gillick threshold to be able to consent to PBs, and that even 16- to 17-year olds would benefit from a ‘best interests determination’ from the court, signals judicial thinking which is markedly protectionist. Considering the broad contemporary stance in healthcare of facilitating competence, valuing patient participation, and respecting rights, I argue that this judgment is out of step. It has implications not only for transgender children, but it may also be a worrying signal of a greater general retreat from Gillick and a corresponding advance in emphasis on judicially determined best interests.
Galaxy clustering in harmonic space from the dark energy survey year 1 data: compatibility with real-space results
Authors: Andrade-Oliveira F , Camacho H , Faga L , Gomes R , Rosenfeld R , Troja A , Alves O , Doux C , Elvin-Poole J , Fang X , Friedrich O , Kokron N , Lima M , Miranda V , Pandey S , Porredon A , Sanchez J , Aguena M , Allam S , Annis J , Avila S , Bertin E , Brooks D , Burke D L , Carrasco Kind M , Carretero J , Cawthon R , Chang C , Choi A , Costanzi M , Crocce M , da Costa L N , Pereira M E S , Desai S , Diehl H T , Doel P , Drlica-Wagner A , Everett S , Evrard A E , Ferrero I , Frieman J , García-Bellido J , Gaztanaga E , Gerdes D W , Gruen D , Gruendl R A , Hinton S R , Hollowood D L , Jain B , James D J , Kuropatkin N , Lahav O , MacCrann N , Maia M A G , March M , Melchior P , Menanteau F , Miquel R , Morgan R , Myles J , Ogando R L C , Palmese A , Paz-Chinchón F , Plazas Malagón A A , Rodriguez-Monroy M , Sanchez E , Scarpine V , Serrano S , Sevilla-Noarbe I , Smith M , Soares-Santos M , Suchyta E , Tarle G , To C ,   DES Collaboration
Published: June 2021

We perform an analysis in harmonic space of the Dark Energy Survey Year 1 Data (DES-Y1) galaxy clustering photometric data using products obtained for the real-space analysis. We test our pipeline with a suite of lognormal simulations, which are used to validate scale cuts in harmonic space as well as to provide a covariance matrix that takes into account the DES-Y1 mask. We then apply this pipeline to DES-Y1 data taking into account survey property maps derived for the real-space analysis. We compare with real-space DES-Y1 results obtained from a similar pipeline. We show that the harmonic space analysis we develop yields results that are compatible with the real-space analysis for the bias parameters. This verification paves the way to performing a harmonic space analysis for the upcoming DES-Y3 data.
SNe and their impact during the early evolution of Type I Globular Clusters
Authors: Jiménez Santiago , Tenorio-Tagle Guillermo , Silich Sergiy
Published: June 2021

The iron composition of globular clusters (GCs) is homogeneous in all but a few massive clusters, despite the presence of multiple stellar populations. Hence, most if not all the supernovae (SN) ejecta was not used to form stars. Here by means of semi-analytic and numerical studies we address this issue considering both stellar winds and supernovae feedback during the early evolution of proto-globular clusters. We calculate the ability of stellar winds to form a global wind that removes the gas left over from star formation. The innermost radius from which such a global wind can be formed, the superwind radius RSW, is a function of the cloud parameters and the star formation efficiency. In the case of complete gas expulsion (RSW = 0), the SN ejecta merge with shock-heated winds and exit the cluster. On the other hand, when RSW > 0, supernova remnants (SNRs) become pressure-confined if evolving within a critical radius Rblow, and mix their products with the residual gas. However, outside of this central zone the SNRs experience blowout. In such cases, the thermalized ejecta escapes the cluster, making the SN products unavailable for the formation of new stars. We estimated the metallicity enhancement (Δ[Fe/H]) of the leftover gas and discuss the conditions required to produce secondary stellar populations with Δ[Fe/H] in the range observed in the majority of GCs.
The origins of off-centre massive black holes in dwarf galaxies
Authors: Bellovary Jillian M , Hayoune Sarra , Chafla Katheryn , Vincent Donovan , Brooks Alyson , Christensen Charlotte R , Munshi Ferah D , Tremmel Michael , Quinn Thomas R , Van Nest Jordan , Sligh Serena K , Luzuriaga Michelle
Published: June 2021

Massive black holes often exist within dwarf galaxies, and both simulations and observations have shown that a substantial fraction of these may be off-centre with respect to their hosts. We trace the evolution of off-centre massive black holes (MBHs) in dwarf galaxies using cosmological hydrodynamical simulations, and show that the reason for off-centre locations is mainly due to galaxy–galaxy mergers. We calculate dynamical time-scales and show that off-centre MBHs are unlikely to sink to their galaxys’ centres within a Hubble time, due to the shape of the hosts’ potential wells and low stellar densities. These wandering MBHs are unlikely to be detected electromagnetically, nor is there a measurable dynamical effect on the galaxy’s stellar population. We conclude that off-centre MBHs may be common in dwarfs, especially if the mass of the MBH is small or the stellar mass of the host galaxy is large. However, detecting them is extremely challenging, because their accretion luminosities are very low and they do not measurably alter the dynamics of their host galaxies.
Chemical signatures of a warped protoplanetary disc
Authors: Young Alison K , Alexander Richard , Walsh Catherine , Nealon Rebecca , Booth Alice , Pinte Christophe
Published: June 2021

Circumstellar discs may become warped or broken into distinct planes if there is a stellar or planetary companion with an orbit that is misaligned with respect to the disc. There is mounting observational evidence for protoplanetary discs with misaligned inner discs and warps that may be caused by such interactions with a previously undetected companion, giving us a tantalizing indication of possible planets forming there. Hydrodynamical and radiative transfer models indicate that the temperature varies azimuthally in warped discs due to the variable angle at which the disc surface faces the star and this impacts the disc chemistry. We perform chemical modelling based on a hydrodynamical model of a protoplanetary disc with an embedded planet orbiting at a 12° inclination to the disc. Even for this small misalignment, abundances of species including CO and HCO+ vary azimuthally and this results in detectable azimuthal variations in submillimetre line emission. Azimuthal variations in line emission may therefore indicate the presence of an unseen embedded companion. Non-axisymmetric chemical abundances should be considered when interpreting molecular line maps of warped or shadowed protoplanetary discs.
Establishment of a specific in vivo Cu(Ⅰ) reporting system based on metallothionein screening
Authors: Ma Mingjun , Qiu Botao , Jin Jing , Wang Jiaru , Nie Yuzhe , Liang Yang , Yu Ze , Teng Chun-Bo
Published: June 2021

Copper is one of the indispensable trace metal elements in organisms, but excess copper means cytotoxicity. Cells protect themselves by storing excess copper in copper-binding proteins. Metallothioneins (MTs) are a group of low-molecular-weight, cysteine-rich proteins, which are well known in sensing and binding the overcharged Zn(Ⅱ), Cd(Ⅱ), and Cu(Ⅰ) in cells. However, there are few reports on MTs that can specifically respond to intracellular copper ions in mammals in real-time. Here, we screened copper-response MTs in pancreatic cancer cells through data-mining, RNA-seq, and qPCR analysis. We found that MT1E, MT1F, and MT1X mRNA were significantly upregulated after exogenous copper ions induction. By constructing the stable cell lines with MT1E, MT1F, or MT1X promoter-driven EGFP as reporters, we found that only PMT1F-EGFP could specifically and stably report the intracellular Cu(Ⅰ) changes in multiple cell lines, including Panc-1, 8988T, 293T, HepG2, and normal hepatic cells, indicating that PMT1F-EGFP is an ideal in vivo Cu(Ⅰ) reporter. Using the PMT1F-EGFP reporter, we found that MEK inhibitors (U0126) and Astragaloside IV could significantly increase intracellular copper ions. According to these results, that PMT1F-EGFP reporter can sense intracellular copper change and can be used to screen copper-target drugs and study copper-related cellular physiology and pathology.
INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells
Authors: Yu Hongyao , Wang Jiajia , Lackford Brad , Bennett Brian , Li Jian-liang , Hu Guang
Published: June 2021

The INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role in pluripotency and cell fate transition is not fully defined. We examined the impact of Ino80 deletion in the naïve and primed pluripotent stem cells. We found that Ino80 deletion had minimal effect on self-renewal and gene expression in the naïve state, but led to cellular differentiation and de-repression of developmental genes in the transition toward and maintenance of the primed state. In the naïve state, INO80 pre-marked gene promoters that would adopt bivalent histone modifications by H3K4me3 and H3K27me3 upon transition into the primed state. In the primed state, in contrast to its known role in H2A.Z exchange, INO80 promoted H2A.Z occupancy at these bivalent promoters and facilitated H3K27me3 installation and maintenance as well as downstream gene repression. Together, our results identified an unexpected function of INO80 in H2A.Z deposition and gene regulation. We showed that INO80-dependent H2A.Z occupancy is a critical licensing step for the bivalent domains, and thereby uncovered an epigenetic mechanism by which chromatin remodeling, histone variant deposition and histone modification coordinately control cell fate.
The dynamic cycle of bacterial translation initiation factor IF3
Authors: Nakamoto Jose A , Evangelista Wilfredo , Vinogradova Daria S , Konevega Andrey L , Spurio Roberto , Fabbretti Attilio , Milón Pohl
Published: June 2021

Initiation factor IF3 is an essential protein that enhances the fidelity and speed of bacterial mRNA translation initiation. Here, we describe the dynamic interplay between IF3 domains and their alternative binding sites using pre-steady state kinetics combined with molecular modelling of available structures of initiation complexes. Our results show that IF3 accommodates its domains at velocities ranging over two orders of magnitude, responding to the binding of each 30S ligand. IF1 and IF2 promote IF3 compaction and the movement of the C-terminal domain (IF3C) towards the P site. Concomitantly, the N-terminal domain (IF3N) creates a pocket ready to accept the initiator tRNA. Selection of the initiator tRNA is accompanied by a transient accommodation of IF3N towards the 30S platform. Decoding of the mRNA start codon displaces IF3C away from the P site and rate limits translation initiation. 70S initiation complex formation brings IF3 domains in close proximity to each other prior to dissociation and recycling of the factor for a new round of translation initiation. Altogether, our results describe the kinetic spectrum of IF3 movements and highlight functional transitions of the factor that ensure accurate mRNA translation initiation.
Directed evolution of orthogonal RNA–RBP pairs through library-vs-library in vitro selection
Authors: Fukunaga Keisuke , Yokobayashi Yohei
Published: June 2021

RNA-binding proteins (RBPs) and their RNA ligands play many critical roles in gene regulation and RNA processing in cells. They are also useful for various applications in cell biology and synthetic biology. However, re-engineering novel and orthogonal RNA–RBP pairs from natural components remains challenging while such synthetic RNA–RBP pairs could significantly expand the RNA–RBP toolbox for various applications. Here, we report a novel library-vs-library in vitro selection strategy based on Phage Display coupled with Systematic Evolution of Ligands by EXponential enrichment (PD-SELEX). Starting with pools of 1.1 × 1012 unique RNA sequences and 4.0 × 108 unique phage-displayed L7Ae-scaffold (LS) proteins, we selected RNA–RBP complexes through a two-step affinity purification process. After six rounds of library-vs-library selection, the selected RNAs and LS proteins were analyzed by next-generation sequencing (NGS). Further deconvolution of the enriched RNA and LS protein sequences revealed two synthetic and orthogonal RNA–RBP pairs that exhibit picomolar affinity and >4000-fold selectivity.
Discovery of a pre-mRNA structural scaffold as a contributor to the mammalian splicing code
Authors: Saha Kaushik , Fernandez Mike Minh , Biswas Tapan , Joseph Simpson , Ghosh Gourisankar
Published: June 2021

The specific recognition of splice signals at or near exon-intron junctions is not explained by their weak conservation and instead is postulated to require a multitude of features embedded in the pre-mRNA strand. We explored the possibility of 3D structural scaffold of AdML—a model pre-mRNA substrate—guiding early spliceosomal components to the splice signal sequences. We find that mutations in the non-cognate splice signal sequences impede recruitment of early spliceosomal components due to disruption of the global structure of the pre-mRNA. We further find that the pre-mRNA segments potentially interacting with the early spliceosomal component U1 snRNP are distributed across the intron, that there is a spatial proximity of 5′ and 3′ splice sites within the pre-mRNA scaffold, and that an interplay exists between the structural scaffold and splicing regulatory elements in recruiting early spliceosomal components. These results suggest that early spliceosomal components can recognize a 3D structural scaffold beyond the short splice signal sequences, and that in our model pre-mRNA, this scaffold is formed across the intron involving the major splice signals. This provides a conceptual basis to analyze the contribution of recognizable 3D structural scaffolds to the splicing code across the mammalian transcriptome.