bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral and cellular telomerase RNAs possess host-specific anti-apoptotic functions
Authors: Kheimar Ahmed , Trapp-Fragnet Laetitia , Conradie Andelé M. , Bertzbach Luca D. , You Yu , Sabsabi Mohammad A. , Kaufer Benedikt B.
Published: September 2023

Human telomerase RNA (hTR) is overexpressed in many cancers and protects T cells from apoptosis in a telomerase-independent manner. The most prevalent cancer in the animal kingdom is caused by the highly oncogenic herpesvirus Marek’s disease virus (MDV). MDV encodes a viral telomerase RNA (vTR) that plays a crucial role in MDV-induced tumorigenesis and shares all four conserved functional domains with hTR. In this study, we assessed whether hTR drives tumor formation in this natural model of herpesvirus-induced tumorigenesis. Therefore, we replaced vTR with hTR in the genome of a highly oncogenic MDV. Furthermore, we investigated the anti-apoptotic activity of vTR, hTR, and their counterpart in the chicken [chicken telomerase RNA (cTR)]. hTR was efficiently expressed and did not alter replication of the recombinant virus. Despite its conserved structure, hTR did not complement the loss of vTR in virus-induced tumorigenesis. Strikingly, hTR did not inhibit apoptosis in chicken cells, but efficiently inhibited apoptosis in human cells. Inverse host restriction has been observed for vTR and cTR in human cells. Our data revealed that vTR, cTR, and hTR possess conserved but host-specific anti-apoptotic functions that likely contribute to MDV-induced tumorigenesis.

IMPORTANCE

hTR is overexpressed in many cancers and used as a cancer biomarker. However, the contribution of hTR to tumorigenesis remains elusive. In this study, we assessed the tumor-promoting properties of hTR using a natural virus/host model of herpesvirus-induced tumorigenesis. This avian herpesvirus encodes a telomerase RNA subunit (vTR) that plays a crucial role in viral tumorigenesis and shares all conserved functional domains with hTR. Our data revealed that vTR and cellular TRs of humans and chickens possess host-specific anti-apoptotic functions. This provides important translational insights into therapeutic strategies, as inhibition of apoptosis is crucial for tumorigenesis.
Efflux pump inhibitory potential of indole derivatives as an arsenal against
norA
over-expressing
Staphylococcus aureus
Authors: Chandal Nishtha , Tambat Rushikesh , Kalia Ritu , Kumar Gautam , Mahey Nisha , Jachak Sanjay , Nandanwar Hemraj
Published: September 2023

NorA, an extensively studied efflux pump in
Staphylococcus aureus
, has been connected to fluoroquinolone, antiseptic, and disinfection resistance. Several studies have also emphasized how efflux pumps, including NorA, function as the first line of defense of
S. aureus
against antibiotics. In this study, we have screened some chemically synthesized indole derivatives for their activity as efflux pump inhibitors (EPIs). The derivative SMJ-5 was found to be a potent NorA efflux pump inhibitor among the screened indole derivatives, owing to increased ethidium bromide and norfloxacin accumulation in
norA
over-expressing
S. aureus
. The combination of SMJ-5 and ciprofloxacin demonstrated the eradication of
S. aureus
biofilm and prolonged the post-antibiotic effect more than ciprofloxacin alone. SMJ-5 was able to inhibit staphyloxanthin virulence. In
in vitro
time-kill trials and
in vivo
efficacy investigations, the combination enhanced the bactericidal activity of ciprofloxacin against
S. aureus
. Additionally, reverse transcription PCR results revealed that SMJ-5 also inhibits the NorA efflux pump indirectly at the transcriptional level.

IMPORTANCE

The NorA efflux pump is the most effective resistance mechanism in
S. aureus
. The clinical importance of NorA efflux pumps is demonstrated by the expression of pump genes in
S. aureus
strains in response to fluoroquinolones and biocides. Along with the repercussions of decreased fluoroquinolone sensitivity, increasing expression of efflux pump genes by their substrate necessitates the importance of efflux pump inhibitors. Reserpine and verapamil are clinically used to treat ailments and have proven NorA inhibitors, but, unfortunately, the concentration needed for these drugs to inhibit the pump is not safe in clinical settings. In the current study, we have screened some indole derivatives, and among them, SMJ-5 was reported to potentiate norfloxacin and ciprofloxacin at their sub-inhibitory concentration by inhibiting the
norA
gene transcriptionally. Here we highlight the promising points of this study, which could serve as a model to design a therapeutic EPI candidate against
norA
over-expressing
S. aureus
.
Cesin, a short natural variant of nisin, displays potent antimicrobial activity against major pathogens despite lacking two C-terminal macrocycles
Authors: Guo Longcheng , Wambui Joseph , Wang Chenhui , Muchaamba Francis , Fernandez-Cantos Maria Victoria , Broos Jaap , Tasara Taurai , Kuipers Oscar P. , Stephan Roger
Published: September 2023

Nisin is a widely used lantibiotic owing to its potent antimicrobial activity and its food-grade status. Its mode of action includes cell wall synthesis inhibition and pore formation, which are attributed to the lipid II binding and pore-forming domains, respectively. We discovered cesin, a short natural variant of nisin, produced by the psychrophilic anaerobe
Clostridium estertheticum
. Unlike other natural nisin variants, cesin lacks the two terminal macrocycles constituting the pore-forming domain. The current study aimed at heterologous expression and characterization of the antimicrobial activity and physicochemical properties of cesin. Following the successful heterologous expression of cesin in
Lactococcus lactis
, the lantibiotic demonstrated a broad and potent antimicrobial profile comparable to that of nisin. Determination of its mode of action using lipid II and lipoteichoic acid binding assays linked the potent antimicrobial activity to lipid II binding and electrostatic interactions with teichoic acids. Fluorescence microscopy showed that cesin lacks pore-forming ability in its natural form. Stability tests have shown the lantibiotic is highly stable at different pH values and temperature conditions, but that it can be degraded by trypsin. However, a bioengineered analog, cesin R15G, overcame the trypsin degradation, while keeping full antimicrobial activity. This study shows that cesin is a novel (small) nisin variant that efficiently kills target bacteria by inhibiting cell wall synthesis without pore formation.

IMPORTANCE

The current increase in antibiotic-resistant pathogens necessitates the discovery and application of novel antimicrobials. In this regard, we recently discovered cesin, which is a short natural variant of nisin produced by the psychrophilic
Clostridium estertheticum
. However, its suitability as an antimicrobial compound was in doubt due to its structural resemblance to nisin(1–22), a bioengineered short variant of nisin with low antimicrobial activity. Here, we show by heterologous expression, purification, and characterization that the potency of cesin is not only much higher than that of nisin(1–22), but that it is even comparable to the full-length nisin, despite lacking two C-terminal rings that are essential for nisin’s activity. We show that cesin is a suitable scaffold for bioengineering to improve its applicability, such as resistance to trypsin. This study demonstrates the suitability of cesin for future application in food and/or for health as a potent and stable antimicrobial compound.
Erasmus syndrome: role of specialist palliative care
Authors: Kuriakose Jyothsna , Sundararaj Jenifer Jeba , Joseph Jewell , Gladys Anitha , Kurien Richu Bob , Manoharan Aishwarya , AS Chandhu
Published: September 2023

Occupational exposure to silica has been seldom implicated to cause systemic sclerosis. Erasmus syndrome is a rare condition where there is development of systemic sclerosis following silicosis. Early diagnosis is essential for appropriate treatment and symptom control. We describe a 42-year-old stone cutter with silicosis who was subsequently diagnosed to have diffuse pattern of systemic sclerosis. A multidisciplinary team including pulmonologists, specialist palliative care physicians, rheumatologists and radiologists were involved in diagnosis and management. Timely diagnosis and a multidisciplinary team management with pharmacological and non-pharmacological measures was essential in holistic care provision. This is the first report of specialist palliative care team facilitating diagnosis of this rare syndrome and promoting integration in the overall care and management.
Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort
Authors: Mabo Axelle , Borie Raphael , Wemeau-Stervinou Lidwine , Uzunhan Yurdagül , Gomez Emmanuel , Prevot Gregoire , Reynaud-Gaubert Martine , Traclet Julie , Bergot Emmanuel , Cadranel Jacques , Marchand-Adam Sylvain , Bergeron Anne , Blanchard Elodie , Bondue Benjamin , Bonniaud Philippe , Bourdin Arnaud , Burgel Pierre Regis , Hirschi Sandrine , Marquette Charles Hugo , Quétant Sébastien , Nunes Hilario , Chenivesse Cécile , Crestani Bruno , Guirriec Yoann , Monnier Delphine , Ménard Cédric , Tattevin Pierre , Cottin Vincent , Luque Paz David , Jouneau Stéphane
Published: September 2023

Background

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking.

Research question

Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections.

Methods

We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data.

Results

We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7–6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections.Nocardiaspp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316–1591) vs 580 (200–1190), p=0.01). Nine patients had died (9%), but only one death was related to infection.

Interpretation

Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.
Management impacts on organic carbon under continuous perennial grass, perennial grass-legume mixture, and annual cereals on a thick Black Chernozemic soil
Authors: Mapfumo E. , Baron V.S. , Lemke R. , Naeth M.A. , Chanasyk D.S. , Dick Campbell
Published: September 2023

Impacts of annual and perennial pasture management on soil organic carbon (SOC) and equivalent SOC stocks (equal soil mass basis) were investigated in two trials [CAESA (1994–1997) and BMP (2008–2012) trials] conducted on the same experimental paddocks at Lacombe, AB. The original site was broken from perennial grass in 1992, and the CAESA trial established in 1993. Between 1994 and 1997, half of the paddocks included winter triticale and a mixture of triticale and spring barley; half included smooth and meadow bromegrass; and each paddock was light, medium, or heavily grazed. The BMP trial (2008–2012) on the same paddocks included fertilized, direct seeded barley as silage; grazing and haying of unfertilized meadow bromegrass, fertilized meadow bromegrass, and meadow bromegrass and alfalfa mixture; and unfertilized oldgrass that was continuous since 1994. Between trials (1998–2007), all paddocks received no fertilizer. In the 0–15 cm depth, SOC under oldgrass was constant between 1994 and 2012 and averaged 88 Mg C ha−1. Under barley silage, SOC decreased from 89 to 72 Mg C ha−1 by 2012. Between 1994 and 2012, SOC decreased in all treatments re-established on original annual forage (1994–1998) but not to the level of barley silage. Light fraction carbon was the highest under oldgrass and the lowest under barley silage. Overall, oldgrass with no fertilizer inputs maintained a constant SOC, although annuals reduced SOC stocks. Re-establishment of perennial grass with grazing may therefore reduce SOC loss, whereas haying perennial grass may not reduce SOC loss.
Direct detection of electroweak dark matter
Authors: Amintaheri Ramtin
Published: September 2023

TeV-scale dark matter is well motivated by notions of naturalness as the new physics threshold is expected to emerge in the TeV regime. We generalise the Standard Model by including an arbitrary SU(2) multiplet of dark matter particles in non-chiral representation. The pseudo-real representations can be viable DM candidates if one considers a higher-dimensional operator which induces mass-splitting, and avoids the tree-level inelastic scattering through Z-boson exchange. These effective operators give rise to sizable contributions from Higgs mediated dark matter interactions with quarks and gluons. A linear combination of the effective couplings named $$\lambda $$
λ
is identified as the critical parameter in determining the magnitude of the cross-section. When $$\lambda $$
λ
is smaller than the critical value, the theory behaves similar to the known renormalisable model, and the scattering rate stays below the current experimental reach. Nevertheless, above the criticality, the contribution from the higher-dimensional operators significantly changes the phenomenology. The scattering amplitude of pseudo-real models will be coherently enhanced, so that it would be possible for next generation large-exposure experiments to fully probe these multiplets. We studied the parameter space of the theory, taking into account both indirect astrophysical and direct search constraints. It is inferred that multi-TeV mass scale remains a viable region, quite promising for forthcoming dark matter experiments.
A bias using the ages of the oldest astrophysical objects to address the Hubble tension
Authors: Costa André A. , Ren Zelin , Yin Zhixiang
Published: September 2023

Recently different cosmological measurements have shown a tension in the value of the Hubble constant, $$H_0.$$

H
0

.

Assuming the $$\Lambda $$
Λ
CDM model, the Planck satellite mission has inferred the Hubble constant from the cosmic microwave background (CMB) anisotropies to be $$H_0 = 67.4 \pm 0.5 \, \text {km} \, \text {s}^{-1} \, \text {Mpc}^{-1}.$$

H
0

=
67.4
±
0.5

km

s

-
1

Mpc

-
1

.

On the other hand, low redshift measurements such as those using Cepheid variables and supernovae Type Ia (SNIa) have obtained a significantly larger value. For instance, Riess et al. reported $$H_0 = 73.04 \pm 1.04 \, \text {km} \, \text {s}^{-1} \, \text {Mpc}^{-1},$$

H
0

=
73.04
±
1.04

km

s

-
1

Mpc

-
1

,

which is $$5\sigma $$

5
σ

apart of the prediction from Planck observations. This tension is a major problem in cosmology nowadays, and it is not clear yet if it comes from systematic effects or new physics. The use of new methods to infer the Hubble constant is therefore essential to shed light on this matter. In this paper, we discuss using the ages of the oldest astrophysical objects (OAO) to probe the Hubble tension. We show that, although this data can provide additional information, the method can also artificially introduce a tension. Reanalyzing the ages of 114 OAO, we obtain that the constraint in the Hubble constant goes from slightly disfavoring local measurements to favoring them.
Forward $$\gamma $$+jet production in proton-proton and proton-lead collisions at LHC within the FoCal calorimeter acceptance
Authors: Ganguli Ishita , Hameren Andreas van , Kotko Piotr , Kutak Krzysztof
Published: September 2023

Using the small-x improved transverse momentum dependent factorization (ITMD), which, for a general two-to-two massless scattering can be proved within the color glass condensate (CGC) theory for transverse momenta of particles greater than the saturation scale, we provide predictions for isolated forward photon and jet production in proton-proton and proton-nucleus collisions within the planned ALICE FoCal detector acceptance. We study azimuthal correlations, $$p_T$$

p
T

spectra, as well as normalized ratios of proton-proton cross sections for different energies. The only TMD distribution needed for that process is the “dipole” TMD gluon distribution, which in our computations is based on HERA data and undergoes momentum space BK evolution equation with DGLAP corrections and Sudakov resummation. We conclude, that the process provides an excellent probe of the dipole TMD gluon distribution in saturation regime.
A tilt instability in the cosmological principle
Authors: Krishnan Chethan , Mondol Ranjini , Sheikh-Jabbari M. M.
Published: September 2023

We show that the Friedmann–Lemaître–Robertson–Walker (FLRW) framework has an instability towards the growth of fluid flow anisotropies, even if the Universe is accelerating. This flow (tilt) instability in the matter sector is invisible to Cosmic No-Hair Theorem-like arguments, which typically only flag shear anisotropies in the metric. We illustrate our claims in the setting of “dipole cosmology”, the maximally Copernican generalization of FLRW that can accommodate a flow. Simple models are sufficient to show that the cosmic flow need not track the shear, even in the presence of a positive cosmological constant. We also emphasize that the growth of the tilt hair is fairly generic if the effective equation of state$$w \rightarrow -1$$w→-1at late times (as it does in standard cosmology), irrespective of the precise model of dark energy. The generality of our theoretical result puts various recent observational claims about late time anisotropies and cosmic dipoles in a new light.
Water quality of the southern Tibetan Plateau: hydrogeochemical assessment of the Yarlungzangbo River
Authors: Shi Dongping , Tan Hongbing , Zhang Yu , Cong Peixin , Cao Yucheng
Published: September 2023

The Yarlungzangbo River is the largest river system draining the northern slopes of the Himalayan ranges on the southern Tibetan Plateau and has a crucial role in the supply of water downstream. We investigated the chemical composition of the Yarlungzangbo River and its major tributaries (the Nianchu and Lhasa rivers). Water samples (
n
 = 165) were collected and analysed for major ions and trace elements. Multivariable analyses showed that the geology and climate are the major explanatory variables for the spatiotemporal variations of the water chemistry in this river system. The water chemistry is mainly controlled by carbonate weathering, with Ca
2+
and HCO
3
−
as the dominant ions. Another potential ion source affecting the river water chemistry is the discharge from hot springs, which is rich in Na
+
, Cl
−
, SO
4
2−
and Li, resulting in higher solute concentrations in the source region and upstream, with the total dissolved solids reaching 176.9 mg L
−1
. The concentrations of most trace elements are generally low, although elevated concentrations of As (16.6 

μ

g L
−1
) and Sb (2.08 

μ

g L
−1
) are found in the headwaters and additions from untreated wastewater are evident. These concentrations exceed the national drinking water standard for China and the World Health Organization drinking water guideline, posing a risk to people living in both the local and surrounding areas.

Supplementary material:
The basic field records, water chemical compositions and trace elements of the Yarlungzangbo River and its main tributaries, and concentrations of chemicals of health significance as described by the international guideline (WHO) and the China national guideline (GB) for drinking water quality are available at
https://doi.org/10.6084/m9.figshare.c.6850720
Late Oligocene monsoonal climate in the Lunpola Basin, central Tibetan Plateau: evidence from palaeosol records
Authors: Guo Zengguang , Wu Fuli , Fang Xiaomin , Ye Chengcheng , Yang Yibo , Zan Jinbo , Mao Ziqiang , Shen Maohua
Published: September 2023

The Asian monsoon affects the natural patterns of climate in China and its origin and evolution have been a matter of much debate in palaeoclimatology. Results from recent studies indicate that the Asian monsoon had reached the subtropical zone by at least
c.
41 Ma and expanded to the central Tibetan Plateau during the Late Oligocene, although more geological evidence is required to confirm its spatial and temporal evolution. The well-developed Late Oligocene palaeosol in the Lunpola Basin, central Tibetan Plateau is an ideal material for addressing the issue. Observations of various climatic indicators suggest that these palaeosols were forest cinnamon soils, as shown by the compound Bt and Bk horizons, abundant clay coatings and carbonate nodules, and the diagnostic chemical composition of clays in the Bt horizon. A high chemical weather index, the Rb/Sr ratios and high contents of illite/smectite mixed-layer minerals show that these palaeosols experienced intense weathering and leaching during pedogenesis. The mean annual temperature and mean annual precipitation during the developmental period of the palaeosols were 10.4–14.8°C and 615–1128 mm, respectively, as estimated by empirical formulas, which are comparable with those of cinnamon soils in current monsoon climates. This study provides important independent evidence from palaeosols for studies of the evolution of the Asian monsoon.

Supplementary material:
The data about the clay chemical composition and climatic indicators of palaeosol and modern soils are available at
https://doi.org/10.6084/m9.figshare.c.6850703

Thematic collection:
This article is part of the Mesozoic and Cenozoic tectonics, landscape and climate change collection available at:
https://www.lyellcollection.org/topic/collections/mesozoic-and-cenozoic-tectonics-landscape-and-climate-change
Boosting Diversity in Visual Search with Pareto Non-Dominated Re-Ranking
Authors: Lei Si-Chao , Gong Yue-Jiao , Xiao Xiao-Lin , Zhou Yi-cong , Zhang Jun
Published: September 2023

The field of visual search has gained significant attention recently, particularly in the context of web search engines and e-commerce product search platforms. However, the abundance of web images presents a challenge for modern image retrieval systems, as they need to find both relevant and diverse images that maximize users’ satisfaction. In response to this challenge, we propose a non-dominated visual diversity re-ranking (NDVDR) method based on the concept of Pareto optimality. To begin with, we employ a fast binary hashing method as a coarse-grained retrieval procedure. This allows us to efficiently obtain a subset of candidate images for subsequent re-ranking. Fed with this initial retrieved image results, the NDVDR performs a fine-grained re-ranking procedure for boosting both relevance and visual diversity among the top-ranked images. Recognizing the inherent conflict nature between the objectives of relevance and diversity, the re-ranking procedure is simulated as the analytical stage of a multi-criteria decision-making process, seeking the optimal tradeoff between the two conflicting objectives within the initial retrieved images. In particular, a non-dominated sorting mechanism is devised that produces Pareto non-dominated hierarchies among images based on the Pareto dominance relation. Additionally, two novel measures are introduced for the effective characterization of the relevance and diversity scores among different images. We conduct experiments on three popular real-world image datasets and compare our re-ranking method with several state-of-the-art image search re-ranking methods. The experimental results validate that our re-ranking approach guarantees retrieval accuracy while simultaneously boosting diversity among the top-ranked images.
RoboWorld: Verification of Robotic Systems with Environment in the Loop
Authors: Baxter James , Carvalho Gustavo , Cavalcanti Ana , Júnior Francisco Rodrigues
Published: September 2023

A robot affects and is affected by its environment, so that typically its behaviour depends on properties of that environment. For verification, we need to formalise those properties. Modelling the environment is very challenging, if not impossible, but we can capture assumptions. Here, we present RoboWorld, a domain-specific controlled natural language with a process algebraic semantics that can be used to define (a) operational requirements, and (b) environment interactions of a robot. RoboWorld is part of the RoboStar framework for verification of robotic systems. In this article, we define RoboWorld’s syntax and hybrid semantics, and illustrate its use for capturing operational requirements, for automatic test generation, and for proof. We also present a tool that supports the writing of RoboWorld documents. Since RoboWorld is a controlled natural language, it complements the other RoboStar notations in being accessible to roboticists, while at the same time benefitting from a formal semantics to support rigorous verification (via testing and proof).
Fruit Flies: Challenges and Opportunities to Stem the Tide of Global Invasions
Authors: Papadopoulos Nikos T. , De Meyer Marc , Terblanche John S. , Kriticos Darren J.
Published: September 2023

Global trade in fresh fruit and vegetables, intensification of human mobility, and climate change facilitate fruit fly (Diptera: Tephritidae) invasions. Life-history traits, environmental stress response, dispersal stress, and novel genetic admixtures contribute to their establishment and spread. Tephritids are among the most frequently intercepted taxa at ports of entry. In some countries, supported by the rules-based trade framework, a remarkable amount of biosecurity effort is being arrayed against the range expansion of tephritids. Despite this effort, fruit flies continue to arrive in new jurisdictions, sometimes triggering expensive eradication responses. Surprisingly, scant attention has been paid to biosecurity in the recent discourse about new multilateral trade agreements. Much of the available literature on managing tephritid invasions is focused on a limited number of charismatic (historically high-profile) species, and the generality of many patterns remains speculative.
The Fluid Mechanics of Female Reproduction: A Review of the Biofluid Mechanics of Pregnancy and Delivery
Authors: Leftwich Megan C. , Baumer Alexa C.
Published: September 2023

Reproductive biomechanics, a broad and developing field, contains fluid mechanics problems at every stage. In particular, the human female reproductive system is a complex and dynamic fluid-structure system. Until recently, the majority of this research focused on the early moments of reproduction—namely, the transport phenomena that dominate fertilization and implantation. However, in the past two decades, fluid mechanics has begun to be used in investigations of all aspects surrounding pregnancy, labor, and delivery. In this review, we discuss human reproduction starting with the nonpregnant uterus through implantation, delivery, and lactation and breastfeeding. We cover physiologic changes from the transformation of the uterus and the cervical remodeling process to the development of the placenta and the beginning of lactation. We examine the role of reproductive fluids such as amniotic fluid and vernix caseosa, and how force is transferred during labor.
Hypoxic Bone Marrow Stromal Cells Secrete miR-140–5p and miR-28–3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma
Authors: Zhang Hui , Du Zhimin , Tu Chenggong , Zhou Xinyan , Menu Eline , Wang Jinheng
Published: September 2023

Bone marrow stromal cell (BMSC)–derived small extracellular vesicles (sEV) promote drug resistance to bortezomib in multiple myeloma cells. Elucidating the components of BMSC sEV that induce drug resistance in multiple myeloma cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in multiple myeloma cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in multiple myeloma cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140–5p and miR-28–3p were enclosed in hypoxic BMSC-derived sEVs. Both miR-140–5p and miR-28–3p conferred bortezomib resistance in multiple myeloma cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in multiple myeloma cells through activating MAPK-related pathways and significantly promoted multiple myeloma bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to multiple myeloma cells in inducing drug resistance and identify the miR-140–5p/miR-28–3p/SPRED1/MAPK pathway as a potential targetable axis for treating multiple myeloma.

Significance:

Hypoxia induces stromal cells to secrete extracellular vesicles with increased miR-140–5p and miR-28–3p that are transferred to multiple myeloma cells and drive drug resistance by increasing the MAPK signaling.
Super Enhancer–Regulated LncRNA LINC01089 Induces Alternative Splicing of DIAPH3 to Drive Hepatocellular Carcinoma Metastasis
Authors: Su Tao , Zhang Nasha , Wang Teng , Zeng Jiajia , Li Wenwen , Han Linyu , Yang Ming
Published: September 2023

Hepatocellular carcinoma (HCC) is one of the most lethal neoplasms and has a 5-year survival rate of only 18% in patients with metastatic diseases. Epigenetic modifiers and alterations, including histone modifications, long noncoding RNAs (lncRNA), RNA alternative splicing, and N6-methyladenosine (m6A) modification, are key regulators of HCC development, highlighting the importance of understanding the cross-talk between these biological processes. In the current study, we identified LINC01089 as a super enhancer (SE)–driven lncRNA that promotes epithelial–mesenchymal transition (EMT), migration, invasion, and metastasis of HCC cells in vivo and in vitro. The transcription factor E2F1 bound to a LINC01089 SE, promoting LINC01089 transcription and overexpression. LINC01089 interacted with heterogeneous nuclear ribonucleoprotein M (hnRNPM) and led to hnRNPM-mediated skipping of DIAPH3 exon 3. Knockdown of LINC01089 increased the inclusion of DIAPH3 exon 3, which contains an important m6A-modification site that is recognized by IGF2BP3 to increase DIAPH3 mRNA stability. Thus, LINC01089 loss increased DIAPH3 protein levels, which suppressed the ERK/Elk1/Snail axis and inhibited EMT of HCC cells. In conclusion, this study revealed cross-talk between different epigenetics modifiers and alterations that drives HCC progression and identified LINC01089 as a potential prognostic marker and therapeutic target for HCC.

Significance:

LINC01089 is a super enhancer–driven long noncoding RNA that induces ERK signaling and epithelial–mesenchymal transition by regulating DIAPH3 alternative splicing that blocks N6-methyladenosine–mediated mRNA stabilization, establishing an epigenetic network that promotes hepatocellular carcinoma metastasis.
Long-Read Sequencing Reveals Alternative Splicing-Driven, Shared Immunogenic Neoepitopes Regardless of SF3B1 Status in Uveal Melanoma
Authors: Yao Tengteng , Zhang Zhe , Li Qian , Huang Rui , Hong Yanhong , Li Chen , Zhang Feng , Huang Yingying , Fang Yan , Cao Qin , Jin Xiaoliang , Li Chunliang , Wang Zefeng , Lin Xinhua (James) , Li Lingjie , Wei Wu , Wang Zhaoyang , Shen Jianfeng
Published: September 2023

Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell–based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.
Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy
Authors: Zhang Huimin , Chen Sanwei , Zhang Yuwei , Tian Chenxi , Pan Jun , Wang Yu , Bai Shiyu , Wu Qielan , Su Miya , Xie Di , Fu Sicheng , Li Shuhang , Zhang Jing , Chen Yusheng , Zhu Shasha , Qian Yeben , Bai Li
Published: September 2023

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.
Combining Polygenic and Proteomic Risk Scores With Clinical Risk Factors to Improve Performance for Diagnosing Absence of Coronary Artery Disease in Patients With de novo Chest Pain
Authors: Møller Peter Loof , Rohde Palle Duun , Dahl Jonathan Nørtoft , Rasmussen Laust Dupont , Schmidt Samuel Emil , Nissen Louise , McGilligan Victoria , Bentzon Jacob F. , Gudbjartsson Daniel F. , Stefansson Kari , Holm Hilma , Winther Simon , Bøttcher Morten , Nyegaard Mette
Published: September 2023

Background:

Patients with de novo chest pain, referred for evaluation of possible coronary artery disease (CAD), frequently have an absence of CAD resulting in millions of tests not having any clinical impact. The objective of this study was to investigate whether polygenic risk scores and targeted proteomics improve the prediction of absence of CAD in patients with suspected CAD, when added to the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) minimal risk score (PMRS).

Methods:

Genotyping and targeted plasma proteomics (N=368 proteins) were performed in 1440 patients with symptoms suspected to be caused by CAD undergoing coronary computed tomography angiography. Based on individual genotypes, a polygenic risk score for CAD (PRS
CAD
) was calculated. The prediction was performed using combinations of PRS
CAD
, proteins, and PMRS as features in models using stability selection and machine learning.

Results:

Prediction of absence of CAD yielded an area under the curve of PRS
CAD
-model, 0.64±0.03; proteomic-model, 0.58±0.03; and PMRS model, 0.76±0.02. No significant correlation was found between the genetic and proteomic risk scores (Pearson correlation coefficient, −0.04;
P
=0.13). Optimal predictive ability was achieved by the full model (PRS
CAD
+protein+PMRS) yielding an area under the curve of 0.80±0.02 for absence of CAD, significantly better than the PMRS model alone (
P
<0.001). For reclassification purpose, the full model enabled down-classification of 49% (324 of 661) of the 5% to 15% pretest probability patients and 18% (113 of 611) of >15% pretest probability patients.

Conclusions:

For patients with chest pain and low-intermediate CAD risk, incorporating targeted proteomics and polygenic risk scores into the risk assessment substantially improved the ability to predict the absence of CAD. Genetics and proteomics seem to add complementary information to the clinical risk factors and improve risk stratification in this large patient group.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02264717
From the Outside in: ASMR Is Characterised by Reduced Interoceptive Accuracy but Higher Sensation Seeking
Authors: Poerio Giulia L. , Osman Fatimah , Todd Jennifer , Kaur Jasmeen , Jones Lovell , Cardini Flavia
Published: September 2023

Autonomous Sensory Meridian Response (ASMR) is a complex sensory-perceptual phenomenon characterised by relaxing and pleasurable scalp-tingling sensations. The ASMR trait is nonuniversal, thought to have developmental origins, and a prevalence rate of 20%. Previous theory and research suggest that trait ASMR may be underlined by atypical multisensory perception from both interoceptive and exteroceptive modalities. In this study, we examined whether ASMR responders differed from nonresponders in interoceptive accuracy and multisensory processing style. Results showed that ASMR responders had lower interoceptive accuracy but a greater tendency towards sensation seeking, especially for tactile, olfactory, and gustatory modalities. Exploratory mediation analyses suggest that sensation-seeking behaviours in trait ASMR could reflect a compensatory mechanism for either deficits in interoceptive accuracy, a tendency to weight exteroceptive signals more strongly, or both. This study provides the foundations for understanding how interoceptive and exteroceptive mechanisms might explain not only the ASMR trait, but also individual differences in the ability to experience complex positive emotions more generally.
Description of two new genera and five new species of clade K92 from Bahia and Espírito Santo, southeastern Brazil (Arachnida, Opiliones, Gonyleptidae)
Authors: KURY ADRIANO B. , BERNABÉ TIAGO
Published: September 2023

The systematics of gonyleptid harvestmen has recently been undergoing critical changes, especially regarding the Pachylinae and the K92 clade. In a recent cladistic analysis of the latter, the authors refrained from describing some of the detected new species to minimize the bulk of the alpha taxonomy in the manuscript. Herein, as a supplement and following the results of that analysis and the dismantlement of the genus Metagonyleptes Roewer, 1913, the formalization of two genera and five species belonging to clade K92 is proposed. Cajango gen. nov. is described in Caelopyginae based on three new species from southern Bahia State. Titanoleptes gen. nov. is proposed in Sodreaninae to include Metagonyleptes calcar Roewer, 1913, Metagonyleptoides cupidensis Soares & Soares, 1946, and two new species from Espírito Santo State.
Preface
Authors: Hillman Rebecca
Published: September 2023

The Preface reflects on Paul Farmer’s book as a bold and timely intervention on political working-class theatre. It places A39’s practice in the context of historical events and theatrical practice, but also in relation to a rich seam of academic enquiry on agitprop theatre, often assumed redundant beyond the end of the 1970s. It invites readers to consider the book as a provocative political analysis, and corrective to that understanding of history. It proposes the significance of returning to this territory at a time of increased class-conscious and materialist critiques from contemporary artists and theatre makers. This is especially in view of the political agency of A39’s approach; moments of which are highlighted here.
2. Into A39
Authors: Farmer Paul
Published: September 2023

After parting with Miracle Theatre comes a period reviewing the significance of that experience in the light of British art, class and culture, and the need to express political commitment and class identity in relation to the developing history of the Miners’ Strike. What is contemporary theatre? How is it so literally exclusive, its institutions and assumptions reserved so determinedly to the middle classes? What is the significance of British state obsession with William Shakespeare? The discovery of the Plen an Gwari and Ordinalia traditions reveal a history of Cornish popular engagement with theatre, and theatre’s possibilities as a medium that can defy dominant power structures and interests are investigated. Two ex-members of Miracle form an alliance with two members of Falmouth-based unemployed workers’ theatre group Roll Up, and A39 Theatre Group is formed. The writings of John McGrath in relation to 7:84 Theatre Company suggest forms for a practice that can disseminate socialist ideas and working-class perspectives to support the Strike.
9. Building the New Show
Authors: Farmer Paul
Published: September 2023

Brecht on Theatre becomes a significant influence at this time. In this A39 was moving against the structuralist/poststructuralist/postmodernist flow of academic fashion, but we have no connection with that world and it has no resonance in ours.

Brecht, even more than McGrath, insisted that theatre is a virtuoso art. We identify A39 in Brecht’s description of Epic Theatre, and his description of the ‘V-Effekt’ encourages us to deal differently with the formulation and performance of protagonists. Brecht’s demands for ‘pedagogics’ brings him into conflict with McGrath, but experiences with the aspects of One & All! formally most influenced by McGrath bring us down firmly on Brecht’s side. This informs the conception of an aesthetic within which the new show will operate.

The new play will be about the Industrial Revolution as embodied by the Cornish engineer Richard Trevithick, the inventor of the steam locomotive and many other innovations, and why his life ended in poverty and failure while others made fortunes from his works. We will use Trevithick’s story to demonstrate how capitalism came to be what it is and why its time must end.
11. One & All! An unofficial history of Cornish tin mining
Authors: Farmer Paul , Kilburn Mark
Published: September 2023

The complete script of One & All!–an unofficial history of tin mining in Cornwall, revised version (post Tin Crisis), by Paul Farmer and Mark Kilburn.
12. The Tale of Trevithick’s Tower
Authors: Farmer Paul , Kilburn Mark
Published: September 2023

The complete script of The Tale of Trevithick’s Tower by Paul Farmer and Mark Kilburn.
A Spatial Analysis of Decisions Made in Response to Simulated Tornado Warnings in the United States
Authors: DeWinter-Maciag Taylor A. , McPherson Renee A.
Published: September 2023

Although decision-making in response to tornado warnings is well researched, most studies do not examine whether individual responses to these warnings vary across different geographical locations and demographic groups. This gap is addressed by using data from a decision experiment that places participants virtually in a simulated tornado warning and asks them to minimize the costs of their decisions. The authors examine the following: 1) what demographic attributes may contribute to choices to minimize costs to protect assets at a specific location in a tornado warning, 2) whether there is a spatial component to how these attributes influence decision-making, and 3) if there are specific U.S. regions where individuals do not make protective decisions that minimize their overall cost. Multilevel regression analysis and poststratification are applied to data from the simulated decision experiment to estimate which demographic attributes and National Weather Service County Warning Areas are most associated with the costliest protective decisions. The results are then analyzed using spatial autocorrelation to identify spatial patterns. Results indicate that sex, race, and ethnicity are important factors that influence protection decisions. Findings also show that people across the southern portions of the United States tend to make more costly protective decisions, as defined in this work.

Significance Statement

Tornadoes, although rare, threaten both life and property. Studies have shown that certain demographic groups are more negatively impacted by disasters than others and are at higher risk of severe weather hazards. We ask if there are demographic characteristics or geographic locations in common among people who are more prone to making protection decisions during tornado warnings to minimize economic costs. Results can help warning providers, such as the National Weather Service, direct resources and education to specific types of decision-makers or locations to improve sheltering decisions.
Excess suicides in Brazil during the first 2 years of the COVID-19 pandemic: Gender, regional and age group inequalities
Authors: Orellana Jesem Douglas Yamall , de Souza Maximiliano Loiola Ponte , Horta Bernardo Lessa
Published: September 2023

Background:

While the COVID-19 pandemic’s total impact on global mortality is uncertain, an estimated 15 million excess deaths occurred during the first two pandemic years, suggesting that a broad impact, since several causes of death showed a substantial rise.

Aims:

To estimate excess suicides in Brazil and evaluate differences within and between subgroups during the first 2 years of the COVID-19 pandemic.

Method:

Based on suicide data from the mortality information system of the Brazilian Ministry of Health, the expected number of suicides was estimated by age group, gender, 4-month periods and regions through quasi-Poisson generalized additive models. Analyses were performed in R software and RStudio.

Results:

Between March 2020 and February 2022, 29,295 suicides were reported in Brazil, close to what would be expected (30,116; 95% Confidence Interval (95% CI): [28,009, 32,224]), albeit in males and females aged 30 to 59 years and 60 years and over, there were excess suicides in at least one of the six 4-month periods evaluated, especially in the second pandemic year. In the Southeast region, a 28% increase was observed in women 60 years and older during the second year. In the North region, suicide increased 23% and 32% among women aged 30 to 59 years during the first and second pandemic years, respectively. The Northeast region had a 16% excess in suicides among men aged 30 to 59 years and 61% among women 60 years old and older during the second pandemic year, reaching 83% in July to October 2021.

Conclusions:

During the first 2 pandemic years, the pattern of suicides was not homogeneous in Brazil. There were substantial excess suicides in women aged 30 to 59 years from the North and Northeast, while among the elderly and men there was a consistent pattern in several four-month periods throughout Brazil.