bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis of the transcription termination factor Rho engagement with transcribing RNA polymerase from
Thermus thermophilus
Authors: Murayama Yuko , Ehara Haruhiko , Aoki Mari , Goto Mie , Yokoyama Takeshi , Sekine Shun-ichi
Published: February 2023

Transcription termination is an essential step in transcription by RNA polymerase (RNAP) and crucial for gene regulation. For many bacterial genes, transcription termination is mediated by the adenosine triphosphate–dependent RNA translocase/helicase Rho, which causes RNA/DNA dissociation from the RNAP elongation complex (EC). However, the structural basis of the interplay between Rho and RNAP remains obscure. Here, we report the cryo–electron microscopy structure of the
Thermus thermophilus
RNAP EC engaged with Rho. The Rho hexamer binds RNAP through the carboxyl-terminal domains, which surround the RNA exit site of RNAP, directing the nascent RNA seamlessly from the RNA exit to its central channel. The β-flap tip at the RNA exit is critical for the Rho-dependent RNA release, and its deletion causes an alternative Rho-RNAP binding mode, which is irrelevant to termination. The Rho binding site overlaps with the binding sites of other macromolecules, such as ribosomes, providing a general basis of gene regulation.
Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance
Authors: Danielli Sara G. , Porpiglia Ermelinda , De Micheli Andrea J. , Navarro Natalia , Zellinger Michael J. , Bechtold Ingrid , Kisele Samanta , Volken Larissa , Marques Joana G. , Kasper Stephanie , Bode Peter K. , Henssen Anton G. , Gürgen Dennis , Delattre Olivier , Surdez Didier , Roma Josep , Bühlmann Peter , Blau Helen M. , Wachtel Marco , Schäfer Beat W.
Published: February 2023

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.
Compact holographic sound fields enable rapid one-step assembly of matter in 3D
Authors: Melde Kai , Kremer Heiner , Shi Minghui , Seneca Senne , Frey Christoph , Platzman Ilia , Degel Christian , Schmitt Daniel , Schölkopf Bernhard , Fischer Peer
Published: February 2023

Acoustic waves exert forces when they interact with matter. Shaping ultrasound fields precisely in 3D thus allows control over the force landscape and should permit particulates to fall into place to potentially form whole 3D objects in “one shot.” This is promising for rapid prototyping, most notably biofabrication, since conventional methods are typically slow and apply mechanical or chemical stress on biological cells. Here, we realize the generation of compact holographic ultrasound fields and demonstrate the one-step assembly of matter using acoustic forces. We combine multiple holographic fields that drive the contactless assembly of solid microparticles, hydrogel beads, and biological cells inside standard labware. The structures can be fixed via gelation of the surrounding medium. In contrast to previous work, this approach handles matter with positive acoustic contrast and does not require opposing waves, supporting surfaces or scaffolds. We envision promising applications of 3D holographic ultrasound fields in tissue engineering and additive manufacturing.
Terrestrial amplification of past, present, and future climate change
Authors: Seltzer Alan M. , Blard Pierre-Henri , Sherwood Steven C. , Kageyama Masa
Published: February 2023

Terrestrial amplification (TA) of land warming relative to oceans is apparent in recent climatic observations. TA results from land-sea coupling of moisture and heat and is therefore important for predicting future warming and water availability. However, the theoretical basis for TA has never been tested outside the short instrumental period, and the spatial pattern and amplitude of TA remain uncertain. Here, we investigate TA during the Last Glacial Maximum (LGM; ~20 thousand years) in the low latitudes, where the theory is most applicable. We find remarkable consistency between paleotemperature proxies, theory, and climate model simulations of both LGM and future climates. Paleoclimate data thus provide crucial new support for TA, refining the range of future low-latitude, low-elevation TA to

1.37

−
0.23

+
0.27

(95% confidence interval), i.e., land warming ~40% more than oceans. The observed data model theory agreement helps reconcile LGM marine and terrestrial paleotemperature proxies, with implications for equilibrium climate sensitivity.
Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function
Authors: Lei Ienglam , Huang Wei , Noly Pierre Emmanuel , Naik Suyash , Ghali Miriyam , Liu Liu , Pagani Francis D. , Abou El Ela Ashraf , Pober Jordan S. , Pitt Bertram , Platt Jeffrey L. , Cascalho Marilia , Wang Zhong , Chen Y. Eugene , Mortensen Richard M. , Tang Paul C.
Published: February 2023

Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation.
Irg1
transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the
IRG1
enhancer and
IRG1
transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that
Irg1
transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of
Irg1
in mice (Irg1
−/−
) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate’s ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased
IRG1
expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation.
Hypervirulent Klebsiella pneumoniae Causing Neonatal Bloodstream Infections: Emergence of NDM-1-Producing Hypervirulent ST11-K2 and ST15-K54 Strains Possessing pLVPK-Associated Markers
Authors: Mukherjee Subhankar , Bhadury Punyasloke , Mitra Shravani , Naha Sharmi , Saha Bijan , Dutta Shanta , Basu Sulagna
Published: February 2023

Klebsiella pneumoniae
is a leading cause of sepsis in newborns and adults. Among the 2 major pathotypes of
K. pneumoniae
, classical (cKP) and hypervirulent (hvKP), hvKP causes community-acquired severe fatal invasive infections in even healthy individuals, as it possesses several virulence factors.
Interplay between Porphyromonas gingivalis Hemophore-Like Protein HmuY and Kgp/RgpA Gingipains Plays a Superior Role in Heme Supply
Authors: Śmiga Michał , Ślęzak Paulina , Wagner Mateusz , Olczak Teresa
Published: February 2023

Altered or disturbed mutualism between oral microbiome members results in dysbiosis with local injuries and subsequently in systemic diseases. Periodontitis belongs to a group of multifactorial infectious diseases, characterized by inflammation and destruction of tooth-supporting tissues.
Porphyromonas gingivalis
is considered the main etiologic agent and keystone pathogen responsible for developing advanced periodontitis.
Relative importance of magmatic and hydrothermal processes for economic Nb-Ta-W-Sn mineralization in a peraluminous granite system: The Zhaojinggou rare-metal deposit, northern China
Authors: Zhang Lu , Jiang Shao-Yong , Romer Rolf L. , Su Hui-Min
Published: February 2023

Highly evolved granitic melts typically experience late-stage melt-melt and fluid-melt immiscibility as well as fluid-melt and fluid-rock interaction. These processes are particularly important in the formation of deposits of the rare metals Nb, Ta, W, and Sn. We document the relation between immiscibility and alteration processes and the partitioning behavior of rare metals for the Zhaojinggou rare-metal deposit of northern China. This deposit shows a systematic change from a magmatic to a hydrothermal system, including the reaction of the exsolved fluid with earlier crystallized granite and the formation of late-stage quartz veins. The magmatic stage (Stage I) includes biotite alkali-feldspar granite (BAG) with moderate Nb-Ta mineralization. Extreme fractional crystallization of BAG eventually resulted in melt-melt immiscibility and the separation of a hydrosaline melt. Fractional crystallization of this hydrosaline albite granite (AG) melt finally exsolved a magmatic fluid. Therefore, the magmatic-hydrothermal transition (Stage II) includes a melt-dominated Stage IIa with strong Nb-Ta-Sn mineralization in AG and a fluid-dominated Stage IIb with minor Nb-Ta-Sn mineralization in muscovite and biotite greisen. Late hydrothermal processes (Stage III) formed quartz veins with important W mineralization.

There are several texturally and chemically distinct generations of cassiterite and columbite-group minerals (CGM) in BAG and AG reflecting crystallization from an evolving magma. The porous and patchy-zoned reaction rims of tantalite-(Mn) and wodginite on CGM in AG are the result of fluid-melt interaction. Texture and compositions show that wolframite in AG is hydrothermal and formed through interaction of early exsolved magmatic fluids with the host granite. CGM and cassiterite in the biotite greisen and Ta-rutile in the muscovite greisen, as well as wolframite and scheelite in quartz veins that formed when fluid-rock interaction reduced the availability of H+ or F− or the temperature of the fluid decreased.

The distribution and importance of mineralization demonstrate that Nb, Ta, W, and Sn strongly partitioned into the hydrosaline melt during melt-melt immiscibility and that W partitioned into the magmatic fluid during fluid-melt immiscibility. Exsolved magmatic fluids interacted with earlier crystallized rocks mobilizing rare (Nb, Ta, and Sn) and base (Fe and Ti) metals from Li-Fe mica, providing the ore elements for subordinate Nb-Ta-Sn mineralization in AG and in biotite and muscovite greisen. Thus, magmatic processes (with later metal redistribution by magmatic fluids) dominantly control economic Nb-Ta-Sn mineralization, whereas hydrothermal processes mainly control the formation of economic W mineralization.
Crystal Chemistry of Titanates and Zirconates of Rare Earths—Possible Matrices for Actinide Isolation
Authors: Yudintsev S. V. , Nickolsky M. S. , Stefanovskaya O. I. , Nikonov B. S.
Published: February 2023

Titanates and zirconates of light rare earth elements (REE): REE2TiO5, REE2Ti2O7, REE4Ti9O24, and REE2Zr2O7, are of interest as matrices for isolating the REE actinide fraction of high-level waste from the reprocessing of irradiated nuclear fuel. Data on the incorporation of impurities (Zr, U, Ca) into Nd and La titanates are examined. They display limited isomorphism toward these elements, including by the reaction 2REE3+ ↔ Ca2+ + U4+, which is common for minerals and their synthetic analogues. The reasons for the low solubility of Zr and U in Nd titanates and the role of the crystal chemical factor in the choice of crystalline matrices for the immobilization of the REE actinide fraction are considered.
Sorption of Protactinium, Thorium, and Other Actinides from the LiF–NaF–KF Melt by Activated Carbon
Authors: Fedorov Yu. S. , Samonin V. V. , Zotov A. S. , Khrylova E. D. , Spiridonova E. A. , Miroslavov A. E. , Akatov A. A.
Published: February 2023

The sorption of uranium and thorium fluorides by activated carbon from the eutectic was studied. The sorption isotherms of both fluorides at a temperature of 650°C have a pronounced convex character and are described by the Langmuir equation. Experiments were carried out on the sorption of protactinium by activated carbon AG-3 at 650°С from a melt of alkali metal fluorides LiF–NaF–KF containing thorium and neodymium fluorides. It was found that with an increase in the concentrations of neodymium or thorium fluorides, the value of protactinium sorption diminishes, and in the case of thorium fluoride, the decrease occurs to a greater extent. When protactinium is sorbed by activated carbon with metallic sodium, the sorption enhances by a factor of 20 at the 30% sodium content in the carbon. The separation factors of protactinium from other actinides rise with increasing sodium content in the carbon.
Norbornene-Substituted Cationic Iridium(III) Complex and Water-Soluble Luminescent Polymers Based on It: Synthesis, Photophysical and Cytotoxic Properties
Authors: Parshina Yu. P. , Kovylina T. A. , Konev A. N. , Belikov A. A. , Baber P. O. , Komarova A. D. , Romaeva E. A. , Bochkarev L. N.
Published: February 2023

A norbornene-substituted cationic iridium(III) complex containing 1-phenylisoquinoline cyclometalating ligands and an additional phenylimidazophenanthroline ligand was synthesized. On the base of this complex, water-soluble polymers were obtained by ring-opening metathesis polymerization (ROMP). The resulting polymers showed oxygen-dependent phosphorescence in the orange spectral region and high cytotoxicity against HCT116 cancer cells.
Barriers to home exercise for patients with Parkinson’s disease: a qualitative study
Authors: Wang Qiaohong , Chen Yiping , Li Linbo , Li Chao , Li Li , Cao Huili , Yang Hui
Published: February 2023

Objective

This study aimed to explore the barriers to home exercise for patients with Parkinson’s disease (PwPDs) and to provide guidelines for healthcare providers to build and implement home exercise strategies for PwPDs.

Design

A qualitative descriptive method was used. Semistructured interviews were conducted and thematic analysis was employed.

Setting

The study was conducted at the Department of Neurology at a grade 3 Class A general hospital in China.

Participants

A total of 24 participants were interviewed, including 10 PwPDs, 7 caregivers, 4 nurses, 1head nurse, and 2 Parkinson’s clinicians.

Results

Five themes were identified in this analysis. (1) Psychosomatic stress and low activity; (2) Lack of early rehabilitation authorisation; (3) Poor ‘flow’ state of home exercise; (4) iInaccessibility of continued service; (5) Sociocultural impact on family coping.

Conclusion

PwPDs, caregivers and specialised medical staff raised the challenges faced by patients' home exercises from different perspectives. We can improve services and integrate resources through the management of multi-disciplinary, early rehabilitation authorisation, exercise experience, continuous service mode, and family coping strategies under different cultures to gradually adjust the home exercise behaviour of PwPDs.
Impact of the Controlling Nutritional Status (CONUT) score as a prognostic factor for all-cause mortality in older patients without cancer receiving home medical care: hospital ward-based observational cohort study
Authors: Miura Hisayuki , Goto Yuko
Published: February 2023

Objectives

Malnutrition in cancer-free older patients receiving home medical care may affect prognosis, but indicators of long-term nutrition-related prognosis have not been developed. This study investigated the utility of the Controlling Nutritional Status (CONUT) score as a prognostic factor for older patients without cancer receiving home medical care.

Design

This was a single-centre, hospital ward-based observational cohort study.

Setting and participants

In total, 625 cancer-free older patients (median age, 81.0 years; 47.4% males) receiving continuous home medical care through clinics were enrolled on admission to a hospital ward from March 2011 to September 2018.

Primary outcome measures

Continuous cumulative survival curves were obtained using the Kaplan-Meier method after dividing the CONUT score into four groups. The prognostic factors for overall mortality were evaluated using the Cox proportional hazards model. Comparisons with other predictive tools were performed.

Results

The Kaplan-Meier curves of CONUT scores revealed a stepwise shortening of the median survival time with increasing scores. The HR of CONUT scores adjusted by age, sex and other confounding variables was 1.422 (95% CI 1.232 to 1.643, p<0.001). The areas under the receiver operating characteristic curve of the CONUT score for 1-year and 5-year survival were 0.684 and 0.707, respectively. The CONUT score displayed greater predictive utility than other nutrition-related predictive tools.

Conclusions

The CONUT score on hospital admission could be used to predict overall mortality in older patients without cancer receiving home medical care. It is expected to be a simpler and cheaper screening tool for assessing the nutritional status in the field of home medical care.
Association between the number of chronic pain sites and neuropathic-like symptoms in community-dwelling older adults with chronic pain: a cross-sectional study
Authors: Saito Takafumi , Chen Tao , Yatsugi Harukaze , Chu Tianshu , Liu Xin , Kishimoto Hiro
Published: February 2023

Objectives

We investigated the relationship between the number of chronic pain sites and the prevalence and severity of neuropathic-like symptoms in community-dwelling older Japanese adults with chronic pain.

Design

Cross-sectional study.

Setting

The data analysed are from a study conducted in the city of Itoshima, Japan in 2017.

Participants

The study population was 988 participants (age 65–75 years) not in need of long-term care who completed questionnaires assessing sociodemographic factors, psychological factors and chronic pain.

Primary outcome measures

The primary outcome was the participants’ neuropathic-like symptoms evaluated by the PainDETECT Questionnaire (PD-Q). We classified the participants into mild and moderate-to-severe pain groups according to the pain intensity on the PD-Q. The number of chronic pain sites was categorised into groups with 1, 2–3 and ≥4 sites.

Results

The age-adjusted and sex-adjusted prevalence of neuropathic-like symptoms was significantly higher among the participants with 2–3 or ≥4 sites compared with the single-site group. In the binomial logistic regression analyses, the multivariable-adjusted ORs and 95% CIs for neuropathic-like symptoms among the participants with 2–3 and ≥4 sites were 1.94 (1.13 to 3.33) and 3.90 (2.22 to 6.85), respectively compared with the participants with single-site pain. The ORs for moderate-to-severe neuropathic-like symptoms increased significantly with the increase in the number of chronic pain sites.

Conclusions

The number of chronic pain sites was positively associated with the presence and severity of neuropathic-like symptoms in community-dwelling older Japanese adults with chronic pain.
Socioeconomic factors associated with the number of children ever born by married Ghanaian females: a cross-sectional analysis
Authors: Boateng Dennis , Oppong Felix Boakye , Senkyire Ephraim Kumi , Logo Divine Darlington
Published: February 2023

Objective

Most studies in Ghana on determinants of children ever born (CEB) are often conducted among all females of reproductive age and do not adequately report patterns among married females. Considering the importance of marriage to fertility in the Ghanaian context, this study seeks to explore the association of socioeconomic characteristics of married Ghanaian women with CEB.

Design

Data from the 2017 Ghana Maternal Health Survey were used. Three separate models were considered: linear regression model using CEB and two logistic regression models. Bivariate and multivariate analyses were considered for all models.

Setting

The study was conducted in all 10 administrative regions of Ghana.

Participants

Married females aged between 15 and 49 years.

Primary and secondary outcome measures

Socioeconomic factors associated with married females’ CEB.

Results

In all three models, place of residence, zone, wealth index, age, age at marriage, media exposure, level of education, number of abortions and age at first sex were all significantly (p<0.05) associated with CEB. Married females with higher education had lower odds of one or more births and lower odds of giving birth to three or more children. Also, married females from households with the highest wealth index had fewer CEB, lower odds of one or more births and lower odds of giving birth to three or more children.

Conclusion

Socioeconomic characteristics of married females in Ghana, including education and wealth status had a significant influence on the number of CEBs. We recommend governments’ intervention to help bridge the gaps in access to education and income-generating opportunities. The mass media must be used to propagate and counsel married females on the potential of high fertility and its consequences.
Circulating IL-6 is associated with disease progression in BRAFwt metastatic melanoma patients receiving anti-PD-1 therapy
Authors: Mirjačić Martinović Katarina , Vuletić Ana , Tišma Miletić Nevena , Matković Suzana , Gavrilović Dušica , Ninković Aleksandra , Jurišić Vladimir , Babović Nada
Published: February 2023

Aims

Despite efficacy of anti-PD-1 blockade in treatment of metastatic melanoma (MM), many patients achieve rapid disease progression (DP). Therefore, the aim of this study is to better define biomarkers for DP by analysing levels of circulating cytokines TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in MM patients prior to anti-PD-1 therapy.

Methods

Cytokine levels were evaluated before therapy with pembrolizumab in peripheral blood of BRAF wild-type (wt) MM patients by ELISA method.

Results

In this study, we give pretherapy levels for circulating TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in BRAFwt MM patients and analyse them according to metastasis stage (M1a+M1 b, M1c, M1d groups), lactate dehydrogenase (LDH) level and occurrence of DP. Increased IL-6 level was found in M1d group (central nervous system metastasis), while LDH+patients (LDH ≥460 IU/L) have increased IL-6 and IL-8 values that correlate with LDH level. Also, IL-6 correlates with C reactive protein values. Furthermore, patients with DP have significantly higher IL-6 level compared with non-DP patients. Conversely, the other analysed cytokines are similar in investigated groups of MM patients. By receiver operating characteristics curve analysis, pretherapy IL-6 level was found to be a biomarker for the occurrence of DP with cut-off value of 3.02 pg/mL. Patients in M1d stage are prevalent in the group with IL-6 ≥3.02 pg/mL that is characterised with reduced progression-free survival and higher pretherapy IL-8 and LDH.

Conclusion

The evidence in this study implies that baseline IL-6 could be a biomarker of DP and poor prognosis in BRAFwt MM patients treated with pembrolizumab.
Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer
Authors: Monge Cecilia , Xie Changqing , Myojin Yuta , Coffman Kelley , Hrones Donna Mabry , Wang Sophie , Hernandez Jonathan M , Wood Bradford J , Levy Elliot B , Juburi Israa , Hewitt Stephen M , Kleiner David E , Steinberg Seth M , Figg William D , Redd Bernadette , Homan Philip , Cam Maggie , Ruf Benjamin , Duffy Austin G , Greten Tim F
Published: February 2023

Background

Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.

Methods

Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.

Results

Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+T cells on treatment.

Conclusion

PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.

Trial registration number

NCT03206073.
Conscientious commitment, professional obligations and abortion provision after the reversal ofRoe v Wade
Authors: Giubilini Alberto , Schuklenk Udo , Minerva Francesca , Savulescu Julian
Published: February 2023

We argue that, in certain circumstances, doctors might beprofessionallyjustified to provide abortions even in those jurisdictions where abortion is illegal. That it is at least professionally permissible does not mean that they have an all-things-considered ethical justification or obligation to provide illegal abortions or that professional obligations or professional permissibility trump legal obligations. It rather means that professional organisations should respect and indeed protect doctors’ positive claims of conscience to provide abortions if they plausibly track what is in the best medical interests of their patients. It is the responsibility of state authorities to enforce the law, but it is the responsibility of professional organisations to uphold the highest standards of medical ethics, even when they conflict with the law. Whatever the legal sanctions in place, healthcare professionals should not be sanctioned by the professional bodies for providing abortions according to professional standards, even if illegally. Indeed, professional organisation should lobby to offer protection to such professionals. Our arguments have practical implications for what healthcare professionals and healthcare professional organisations may or should do in those jurisdictions that legally prohibit abortion, such as some US States after the reversal ofRoe v Wade.
Incidence and mortality from malignant mesothelioma 1982–2020 and relationship with asbestos exposure: the Australian Mesothelioma Registry
Authors: Walker-Bone Karen , Benke Geza , MacFarlane Ewan , Klebe S , Takahashi Ken , Brims Fraser , Sim Malcolm Ross , Driscoll Tim R
Published: February 2023

Objectives

Malignant mesothelioma is an uncommon cancer associated with asbestos exposure, predominantly occupational. Asbestos has been banned in Australia since 2003 but mesothelioma has a long latency and incident cases continue to present. The Australian Mesothelioma Registry was incepted to collect systematic data about incidence and mortality alongside asbestos exposure.

Methods

Benefiting from the Australian national system of cancer notification, all incident cases of mesothelioma in all states and territories are fast-tracked and notified regularly. Notified patients are contacted asking for consent to collect exposure information, initially by postal questionnaire and subsequently by telephone interview. Age-standardised annual incidence rates and mortality rates were calculated. Asbestos exposure was categorised as occupational, non-occupational, neither or, both; and as low, or high, probability of exposure.

Results

Mesothelioma incidence appears to have peaked. The age-standardised incidence rates have declined steadily since the early 2000s (peaking in males at 5.9/100 000 and in all-persons at 3.2/100 000), driven by rates in males, who comprise the majority of diagnosed cases. Rates in women have remained fairly stable since that time. Age-standardised mortality rates have followed similar trends. Mesothelioma remains the most common in those aged over 80 years. Nearly all (94%) cases were linked with asbestos exposure (78% occupational in men; 6.8% in women).

Conclusions

With effective control of occupational asbestos use, the decline in age-standardised incidence and death rates has occurred. Incidence rates among women, in whom occupational asbestos exposure is rarely detectable, remain unchanged, pointing to the role of household and /or environmental asbestos exposure.
Genicular nerve and fracture site chemical neurolysis for distal femoral fracture: a case report
Authors: Dhingra Prateek , McHardy Paul G , Jenkinson Richard , Meng Howard
Published: February 2023

Background

Distal femur fractures account for approximately 3%–6% of all femoral fractures. Non-operative management may be an attractive option for the elderly with significant perioperative mortality risk. Adequate pain control is a major barrier to non-operative fracture management. Chemical neurolysis has been described for analgesic management of proximal hip fractures, however no description of interventional management of distal femur fracture exists in literature. We describe a case of phenol chemical neurolysis of genicular nerves in addition to injection at the site of fracture to provide effective analgesia for distal femur fracture.

Case presentation

A patient in their 90s with a witnessed mechanical fall sustained an intra-articular displaced fracture of the distal right femur shaft with extension into the distal femoral condyle. The patient elected to undergo non-surgical management given the high perioperative mortality risk. Acute pain service was involved and multimodal oral analgesics including opioids were insufficient in managing the patient’s pain. The addition of femoral nerve catheter local anesthetic infusion did not sufficiently improve analgesia. Phenol chemical neurolysis of the superolateral, superomedial, inferomedial genicular nerves and of the fracture site was offered and performed. Resting pain decreased from Numerical Rating Scale 5/10 to 0/10 on postprocedure day 1. This was sustained at the 2-month timepoint.

Conclusions

We report the successful use of phenol neurolysis of genicular nerves and the fracture site in an elderly patient with a conservatively managed distal femur fracture. These interventions resulted in improved analgesia and achieved prolonged duration of effect.
Conifer performance, stand productivity, and understory cover in varying densities of mixed conifer-broadleaf stands in southwestern British Columbia
Authors: Huberman Yudel L. , Eskelson Bianca N.I.
Published: February 2023

There is an increasing interest in mixed conifer-broadleaf stands as a way to increase the diversity and productivity of managed forests. This study examined the impacts of varying densities of planted broadleaf trees on conifer performance, total stand productivity, and understory plant cover 20 years after stand establishment. The study took place in the Malcolm Knapp Research Forest in Maple Ridge, British Columbia. It used a randomized complete block design to compare treatments containing low, moderate, or high broadleaf densities added to a constant conifer density. Each block contained a conifer-only plot as a control. Conifers were composed of equal amounts of western hemlock, western redcedar, and Douglas-fir. Broadleaves were composed of either red alder or paper birch. We found that conifer volume was significantly lower in most broadleaf treatments relative to the control, due to lower hemlock and redcedar volumes. Douglas-fir, on the other hand, had a higher volume—albeit not significant—in the broadleaf treatments. There were no significant differences in total stand volume between any of the treatments and the control. Shrub cover was significantly higher in the low and high alder treatments relative to the control, but there were no differences in shrub cover between birch treatments and the control. The results suggest that low alder density provides a good balance of conifer yield and understory development.
Landscapes of fear and safety: the integration of two different sensory landscapes determines behavioral responses in the crayfish Faxonius rusticus and is mediated by chemical cues
Authors: Ducsai Georgiana , Wagner Madison J. , Moore Paul A.
Published: February 2023

Research into predator–prey interactions has focused on the landscape of fear and nonconsumptive effects that result from prey responses. Prey behavior is influenced by predator presence and the location and quality of foraging resources in habitats. These areas have been fruitful, but the role of prey refuges has lagged. We investigated how refuge spatial distribution and quality influence prey behavior. To determine the role of the landscape of safety (LOS) in prey decision-making, we altered spatial relationships between refuges, refuge quality, and predation threats in mesocosms. Mesocosms were constructed such that prey only received predatory chemical cues. We employed a behavioral assay including largemouth bass ( Micropterus salmoides (Lacepède, 1802): predator) and virile crayfish ( Faxonius rusticus (Girard, 1852): prey). Crayfish shelter use was significantly influenced by quality and spatial relationship of shelters to predatory threats, and the interaction of these two factors. Particularly, crayfish used high-quality shelters more often when located closer to predatory cues than farther away and did not use low-quality shelters more than controls. High-quality shelter usage decreased as threat level (measured by gape ratio) decreased. These results support the idea that prey utilize an LOS, and information contained in these two landscapes may alter behavioral decisions.
Vacuum material properties and Cherenkov radiation in logarithmic electrodynamics
Authors: Gaete Patricio , Helayël-Neto J. A.
Published: February 2023

We study some observational signatures of nonlinearities of the electromagnetic field. First to all we show the vital role played by nonlinearities in triggering a material behavior of the vacuum with $$(\varepsilon > 0, \mu <0)$$

(
ε
>
0
,
μ
<
0
)

, which corresponds to a ferrimagnetic material. Secondly, the permittivity and susceptibility induced by nonlinearities are considered in order to obtain the refractive index via the dispersion relation for logarithmic electrodynamics. Finally, we consider the electromagnetic radiation produced by a moving charged particle interacting with a medium characterized by nonlinearities of the electromagnetic field. To this end we consider logarithmic electrodynamics. The result shows that the radiation is driven by the medium through which the particle travels like the one that happens in the Cherenkov effect.
Searching for wormholes with gravitational wave scattering
Authors: Zhang Hong , Hou Shaoqi , Bao Shou-shan
Published: February 2023

We propose using the gravitational wave scattering off spherical wormholes to search for their existence. We carefully calculate the reflected and transmitted waveforms with time-independent scattering theory. Our results quantitatively show the echo signatures in the two universes on both sides of the wormhole. In a certain wormhole mass range, the transmitted wave has a unique isolated chirp without an inspiral waveform, and the reflected wave has the anti-chirp behavior, i.e., the missing of the chirping signal. We also calculate the searching range of the current and projected gravitational wave telescopes. Our method can be adapted to efficiently calculate the templates to search for wormholes.
Observation of two zeros of the real amplitude in pp scattering at LHC energies
Authors: Kohara Anderson Kendi
Published: February 2023

Elastic scattering of charged hadrons is described by the combination of nuclear and Coulomb amplitudes. It is well know that at the very forward range the nuclear real and Coulomb parts interplay a crucial role in the determination of the magnitude of the real part at $$|t|=0$$

|
t
|
=
0

. However, beyond $$|t|=0$$

|
t
|
=
0

the real and imaginary nuclear amplitudes have different t dependencies and we show that at LHC energies the zeros formed by the combination $$T_C(t)+T_R^N(s,t)=0$$

T
C

(
t
)

+

T
R
N

(
s
,
t
)

=
0

in pp process can be potentially observed when the background due to the imaginary part is removed. This observation constrains the real part at this forward range.
An introduction to ice ages, climate dynamics and biotic events: the Late Pennsylvanian world
Authors: Lucas Spencer G. , DiMichele William A. , Opluštil Stanislav , Wang Xiangdong
Published: February 2023

The Late Pennsylvanian was a time of ice ages and climate dynamics that drove biotic changes in the marine and non-marine realms. The apex of late Paleozoic glaciation in southern Gondwana was during the Late Pennsylvanian, rather than the early Permian as inferred from more equatorial Pangaea. Waxing and waning of ice sheets drove cyclothemic sedimentation in the Pangaean tropics, providing an astrochronology tuned to Earth-orbital cycles, tied to climatic changes, reflected in aeolian loess and palaeosol archives. Vegetation change across the Middle–Late Pennsylvanian boundary was not a ‘Carboniferous rainforest collapse’, but instead a complex and drawn out step-wise change from one kind of rainforest to another. Changes in marine invertebrate and terrestrial vertebrate animals occurred across the Middle–Late Pennsylvanian boundary, but these did not lead to substantive changes in the organization of those communities. The base of the Upper Pennsylvanian is the base of the Kasimovian Stage, and this boundary needs a GSSP to standardize and stabilize chronostratigraphic usage. To avoid further chronostratigraphic confusion, the Cantabrian Substage should be abandoned, and the traditional Westphalian–Stephanian boundary should be returned to and recognized as the time of major floristic change, the lycospore extinction event.
Exploring Blockchains Interoperability: A Systematic Survey
Authors: Wang Gang , Wang Qin , Chen Shiping
Published: February 2023

The next-generation blockchain ecosystem is expected to integrate both homogeneous and heterogeneous distributed ledgers. These systems require operations across multiple blockchains to enrich advanced functionalities for future applications. However, the development of blockchain interoperability involves much more complexity regarding the variety of underlying architectures. Guaranteeing the properties of ACID (Atomicity, Consistency, Isolation, Durability) across diverse blockchain systems remains challenging. To clear the fog, this article accordingly provides a comprehensive review of the current progress of blockchain interoperability. We explore the general principles and procedures for interoperable blockchain systems to highlight their design commons. Then, we survey practical instances and compare state-of-the-art systems to present their unique features between distinct solutions. Finally, we discuss critical challenges and point out potential research directions. We believe our work can provide an intuitive guideline for newcomers and also promote rapid development in terms of blockchain interoperability.
Assessing the Early Bird Heuristic (for Predicting Project Quality)
Authors: C. Shrikanth N. , Menzies Tim
Published: February 2023

Before researchers rush to reason across all available data or try complex methods, perhaps it is prudent to first check for simpler alternatives. Specifically, if the historical data has the most information in some small region, then perhaps a model learned from that region would suffice for the rest of the project.

To support this claim, we offer a case study with 240 projects, where we find that the information in those projects “clumps” towards the earliest parts of the project. A quality prediction model learned from just the first 150 commits works as well, or better than state-of-the-art alternatives. Using just this “early bird” data, we can build models very quickly and very early in the project life cycle. Moreover, using this early bird method, we have shown that a simple model (with just a few features) generalizes to hundreds of projects.

Based on this experience, we doubt that prior work on generalizing quality models may have needlessly complicated an inherently simple process. Further, prior work that focused on later-life cycle data needs to be revisited, since their conclusions were drawn from relatively uninformative regions.

Replication note: All our data and scripts are available here: https://github.com/snaraya7/early-bird.
A Low-Power mmWave Platform for the Internet of Things
Authors: Mazaheri Mohammad , Abari Omid
Published: February 2023

With the advancement of the Internet of Things (IoT), billions of devices will be connected to the Internet, enabling new applications such as digital twin, augmented reality, and smart home. These applications have placed a huge strain on today's wireless network. mmWave technology is promising to solve this problem by providing a large bandwidth over the very-high-frequency spectrum band. However, most mmWave radios and platforms have much higher power consumption than what IoT devices and their applications can afford. Hence, mmWave networks cannot be utilized in most IoT applications today. In this work, we present a novel low-power mmWave platform, which brings this technology to IoT applications. Our approach to design this platform is to take a holistic view and optimize the whole wireless system by considering practical challenges in mmWave communication. Our lowcost and low-power platform not only brings mmWave communication to IoT applications, but also enables researchers that do not have hardware background to work on mmWave research.
Interaction Dynamics of Intrinsically Disordered Proteins from Single-Molecule Spectroscopy
Authors: Chowdhury Aritra , Nettels Daniel , Schuler Benjamin
Published: February 2023

Many proteins contain large structurally disordered regions or are entirely disordered under physiological conditions. The functions of these intrinsically disordered proteins (IDPs) often involve interactions with other biomolecules. An important emerging effort has thus been to identify the molecular mechanisms of IDP interactions and how they differ from the textbook notions of biomolecular binding for folded proteins. In this review, we summarize how the versatile tool kit of single-molecule fluorescence spectroscopy can aid the investigation of these conformationally heterogeneous and highly dynamic molecular systems. We discuss the experimental observables that can be employed and how they enable IDP complexes to be probed on timescales from nanoseconds to hours. Key insights include the diverse structural and dynamic properties of bound IDPs and the kinetic mechanisms facilitated by disorder, such as fly-casting; disorder-mediated encounter complexes; and competitive substitution via ternary complexes, which enables rapid dissociation even for high-affinity complexes. We also discuss emerging links to aggregation, liquid–liquid phase separation, and cellular processes, as well as current technical advances to further expand the scope of single-molecule spectroscopy.
Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation
Authors: Fu Jianing , Wu Hao
Published: February 2023

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, the active NLRP3-NEK7 (NIMA-related kinase 7)-ASC inflammasome disk, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome.
T Cell Responses to SARS-CoV-2
Authors: Sette Alessandro , Sidney John , Crotty Shane
Published: February 2023

A large body of evidence generated in the last two and a half years addresses the roles of T cells in SARS-CoV-2 infection and following vaccination. Infection or vaccination induces multi-epitope CD4 and CD8 T cell responses with polyfunctionality. Early T cell responses have been associated with mild COVID-19 outcomes. In concert with animal model data, these results suggest that while antibody responses are key to prevent infection, T cell responses may also play valuable roles in reducing disease severity and controlling infection. T cell memory after vaccination is sustained for at least six months. While neutralizing antibody responses are impacted by SARS-CoV-2 variants, most CD4 and CD8 T cell responses are preserved. This review highlights the extensive progress made, and the data and knowledge gaps that remain, in our understanding of T cell responses to SARS-CoV-2 and COVID-19 vaccines.