bluuebunny/crossref_metadata_2025 huggingface dataset:
Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network
Authors: Tang Qijun , Godschall Elizabeth , Brennan Charles D. , Zhang Qi , Abraham-Fan Ruei-Jen , Williams Sydney P. , Güngül Taha Buğra , Onoharigho Roberta , Buyukaksakal Aleyna , Salinas Ricardo , Sajonia Isabelle R. , Olivieri Joey J. , Calhan O. Yipkin , Deppmann Christopher D. , Campbell John N. , Podyma Brandon , Güler Ali D.
Published: August 2023

Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor–expressing (DMH
LepR
) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemogenetic stimulation of DMH
LepR
neurons disrupts the development of molecular and behavioral food entrainment. Repetitive DMH
LepR
neuron activation leads to the partitioning of a secondary bout of circadian locomotor activity that is in phase with the stimulation and dependent on an intact suprachiasmatic nucleus (SCN). Last, we found a DMH
LepR
neuron subpopulation that projects to the SCN with the capacity to influence the phase of the circadian clock. This direct DMH
LepR
-SCN connection is well situated to integrate the metabolic and circadian systems, facilitating mealtime anticipation.
ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy
Authors: Bround Michael J. , Havens Julian R. , York Allen J. , Sargent Michelle A. , Karch Jason , Molkentin Jeffery D.
Published: August 2023

Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 (
Slc25a4
) or CypD (
Ppif
) in a δ-sarcoglycan (
Sgcd
) gene–deleted mouse model of MD, revealing that dystrophic mice lacking
Slc25a4
were partially protected from cell death and MD pathology. Dystrophic mice lacking both
Slc25a4
and
Ppif
together were almost completely protected from necrotic cell death and MD disease. This study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell death, suggesting a previously unrecognized therapeutic approach in MD and other necrotic diseases.
Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension
Authors: Sturm Lukas , Hirose Misa , Stolz Laura , Schultheiss Michael , Zoldan Katharina , Reincke Marlene , Huber Jan Patrick , Kaeser Rafael , Boettler Tobias , Thimme Robert , Albert Elisabeth , Busch Hauke , Künstner Axel , Bettinger Dominik
Published: August 2023

Recent studies have linked proton pump inhibitor (PPI) treatment to increased complications of cirrhosis, such as bacterial infections and hepatic encephalopathy. However, the underlying pathophysiological mechanisms remain unclear. The present study investigated the hypothesis that PPI treatment may promote adverse effects in patients with advanced cirrhosis by affecting subclinical bacterial translocation (BT) from the gut into the portal venous bloodstream. Blood samples from the portal vein were obtained during implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in a total of 80 cirrhosis patients with PPI treatment (PPI group,
n
= 57) and without PPI treatment (no-PPI group,
n
= 23). BT was identified using a 16S ribosomal RNA gene (V1V2 region) polymerase chain reaction. The microbiota composition in the portal venous blood samples was further analyzed by deep amplicon sequencing. Indeed, the prevalence of BT was significantly higher in the PPI group compared to the no-PPI group (86.0% vs 52.2%,
P
= 0.001). Importantly, this effect was not attributable to group differences in the severity of cirrhosis, parameters of portal hypertension, or medication. Microbiome analyses showed significantly increased alpha-diversity (Shannon) in the portal venous blood of the PPI group. Taxonomic analyses revealed significantly increased
Streptococcus
abundances in these patients. The present study reveals aggravated BT in patients with advanced cirrhosis and portal hypertension receiving PPI therapy. Increased BT could be an important pathomechanism contributing to the adverse effects of PPI treatment in patients with cirrhosis.

IMPORTANCE

Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.
The timing of transcription of RpoS-dependent genes varies across multiple stresses in
Escherichia coli
K-12
Authors: Adams Josephine , Hoang Johnson , Petroni Emily , Ashby Ethan , Hardin Johanna , Stoebel Daniel M.
Published: August 2023

The alternative sigma factor RpoS regulates transcription of over 1,000 genes in
Escherichia coli
in response to many different stresses. RpoS levels rise continuously after exposure to stress, and the consequences of changing levels of RpoS for the temporal patterns of expression of RpoS-regulated genes have not been described. We measured RpoS levels at various times during the entry to stationary phase, or in response to high osmolarity or low temperature, and found that the time required to reach maximum levels varied by several hours. We quantified the transcriptome across these stresses using RNA-seq. The number of differentially expressed genes differed among stresses, with 1,379 DE genes identified in stationary phase, 633 in high osmolarity, and 302 in cold shock. To quantify the timing of gene expression, we fit sigmoid or double sigmoid models to differentially expressed genes in each stress. During the entry into stationary phase, genes whose expression rose earlier tended to be those that had been found to respond most strongly to low levels of RpoS. The timing of individual gene’s expression was not correlated across stresses. Taken together, our results demonstrate
E. coli
activates RpoS with different timing in response to different stresses, which in turn generates a unique pattern of timing of the transcription response to each stress.

IMPORTANCE

Bacteria adapt to changing environments by altering the transcription of their genes. Specific proteins can regulate these changes. This study explored how a single protein called RpoS controls how many genes change expression during adaptation to three stresses. We found that: (i) RpoS is responsible for activating different genes in different stresses; (ii) that during a stress, the timing of gene activation depends on the what stress it is; and (iii) that how much RpoS a gene needs in order to be activated can predict when that gene will be activated during the stress of stationary phase.
Identification of a common secondary mutation in the
Neurospora crassa
knockout collection conferring a cell fusion-defective phenotype
Authors: Montenegro-Montero Alejandro , Goity Alejandra , Canessa Paulo F. , Larrondo Luis F.
Published: August 2023

Gene-deletion mutants represent a powerful tool to study gene function. The filamentous fungus
Neurospora crassa
is a well-established model organism, and features a comprehensive gene knockout strain collection. While these mutant strains have been used in numerous studies, resulting in the functional annotation of many Neurospora genes, direct confirmation of gene-phenotype relationships is often lacking, which is particularly relevant given the possibility of background mutations, sample contamination, and/or strain mislabeling. Indeed, spontaneous mutations resulting in phenotypes resembling many cell fusion mutants have long been known to occur at relatively high frequency in
N. crassa
, and these secondary mutations are common in the Neurospora deletion collection. The identity of these mutations, however, is largely unknown. Here, we report that the Δ
ada-3
strain from the
N. crassa
knockout collection, which exhibits a cell fusion defect, harbors a secondary mutation responsible for this phenotype. Through whole-genome sequencing and genetic analyses, we found a ~30-Kb deletion in this strain affecting a known cell fusion-related gene,
so
/
ham-1
, and show that it is the absence of this gene—and not of
ada-3
—that underlies its cell fusion defect. We additionally found three other knockout strains harboring the same deletion, suggesting that this mutation may be common in the collection and could have impacted previous studies. Our findings provide a cautionary note and highlight the importance of proper functional validation of strains from mutant collections. We discuss our results in the context of the spread of cell fusion-defective cheater variants in
N. crassa
cultures.

IMPORTANCE

This study emphasizes the need for careful and detailed characterization of strains from mutant collections. Specifically, we found a common deletion in various strains from the
Neurospora crassa
gene knockout collection that results in a cell fusion-defective phenotype. This is noteworthy because this collection is known to contain background mutations—of a largely unclear nature—that produce cell fusion-defective phenotypes. Our results describe an example of such mutations, and highlight how this common genetic defect could have impacted previous studies that have used the affected strains. Furthermore, they provide a cautionary note about the use of Neurospora strains with similar phenotypes. Lastly, these findings offer additional details relevant to our understanding of the origin and spread of cell fusion-defective cheater variants in
N. crassa
cultures.
Boiling-induced extreme Cu isotope fractionation in sulfide minerals forming by active hydrothermal diffusers at the Aegean Kolumbo volcano: Evidence from in situ isotope analysis
Authors: Zegkinoglou Nikolaos N. , Mathur Ryan , Kilias Stephanos P. , Godfrey Linda , Pletsas Vasilios , Nomikou Paraskevi , Zaronikola Nina
Published: August 2023

We analyzed the first Cu isotopes in primary cupreous pyrite and orpiment, from modern CO2-degassing, seafloor massive sulfide diffuser vents (“KCO2Ds”), from the Kolumbo submarine volcano, Hellenic volcanic arc. Samples came from six KCO2Ds that are actively boiling. Pyrite comprises colloform pyrite-I and euhedral pyrite-II, which occur erratically distributed within the KCO2Ds and are contemporaneous with barite and spatially concurrent with the chalcopyrite that is lining narrow internal conduits, respectively. Orpiment occurs on the outer walls of the KCO2Ds with barite and stibnite. The δ65Cupyrite-I values show high variability, ranging from +2.93‰ to +6.38‰, whereas the δ65Cupyrite-II and δ65Cuchalcopyrite values vary from −0.94‰ to +0.25‰ and −0.45‰ to –0.09‰, respectively. The range of δ65Cuorpiment between +1.90‰ and +25.73‰ is the most extreme ever reported from any geological setting. Pyrite-I is concentrically layered, with a core comprising random crystallites, whereas the mantle crystallites have grain-size, shape, and orientation variability between layers. Pyrite-II forms aggregates of uniform euhedral pyrite crystals. Pyrite-I has higher concentrations of Cu (≤21,960 ppm) compared to pyrite-II (≤4963 ppm), and both have incompatible and volatile metal(loid)-rich composition and low Sb/Pb (<0.5) and Tl/Pb (<0.03) ratios. When combined with evidence for significant magmatic contributions at Kolumbo and geochemical and micro-textural evidence for recurrent intense boiling and/or flashing or gentle and/or non-boiling, the measured extreme δ65Cu values are consistent with transport of Cu by vapor that is preferentially enriched by heavy 65Cu and controlled by continuous Rayleigh distillation–type Cu fractionation. Boiling-induced Cu vapor transport can generate extreme Cu isotope fractionation.
Impact of lifestyle risk factors on admission to nursing home care: a cohort study of 127 108 people aged 60 years and over
Authors: Gibson Alice A , Gale Joanne , Stamatakis Emmanuel , Lindley Richard I , Fontana Luigi , Cistulli Peter A , Nassar Natasha
Published: August 2023

Background

Little is known on how lifestyle factors, individually or in combination, may relate to nursing home admission, an outcome of great societal and economic importance with increased population ageing. The aim of this study was to determine the association of lifestyle risk factors with nursing home admission.

Methods

This prospective cohort study linked data from the 45 and Up Study, Australia, to health records. 127 108 men and women, aged ≥60 years, were recruited between 2006 and 2009. A healthy lifestyle score categorised participants into three risk groups based on five equally contributing risk factors: smoking status, physical activity, sedentary behaviour, sleep duration and diet quality. HRs for incident nursing home admission were estimated using multivariable Cox proportional hazards model.

Results

One-quarter of participants were in the low-risk lifestyle group, 62% were in the medium-risk group and 14% in the high-risk (least healthy) group. During a median (IQR) follow-up of 11.3 years, 23 094 (18%) participants were admitted to a nursing home. Compared with those in the low-risk group, risk of nursing home admission was 43% higher among participants in the high-risk group (multivariable adjusted HR (aHR) 1.43; 95% CI 1.36 to 1.50); and participants in the medium-risk group had an intermediate 12% greater risk (aHR 1.12; 95% CI 1.08 to 1.16). Participants aged 60–64 years in the high-risk (aHR 2.15; 95% CI 1.82 to 2.54) lifestyle group had the greatest risk of nursing home admission.

Conclusion

An unhealthy lifestyle was associated with a marked increased risk of admission to a nursing home in adults aged 60+ years. Interventions focused on lifestyle modifications may prevent or delay nursing home admission.
Effect of oculomotor exercises in patients with non-specific chronic neck pain and associated visual complaints
Authors: Aggarwal Amita , Thakur Jidnyasa , Palekar Tushar J
Published: August 2023

Background: Neck pain is a common musculoskeletal disorder, the most common type being non-specific chronic neck pain. It usually involves postural or mechanical causes. In Individuals with neck pain, a notable prevalence of visual complaints has been predominantly reported. It can be linked to the mismatch in the cervical afferent output.

Objective: This study aimed to assess the effect of oculomotor exercises on neck pain, neck disability, gaze stability and visual complaints among individuals with non-specific chronic neck pain and associated visual complaints.

Methods: A total of 32 individuals with non-specific chronic neck pain and associated visual complaints were equally randomised into two groups. To receive either: stretching to the sternocleidomastoid and anterior scalene along with neck Isometric exercises (Group A, conventional) or the conventional protocol along with oculomotor exercises (Group B, experimental). The protocol was given for three alternate days a week for three weeks, a total of nine sessions. The outcome measures were the Visual Analogue Scale (VAS) for pain, Neck Disability Index (NDI) for disability, Dynamic Visual Acuity (DVA) test for gaze stability and Visual Complaints Index (VCI) for visual complaints.

Results: Significant results were seen for the DVA ([Formula: see text]) and VCI ([Formula: see text]), suggesting improvements in gaze stability and visual complaints using oculomotor exercises.

Conclusion: From this study, we highlighted that oculomotor exercises along with conventional treatment led to improvement in visual complaints and gaze stability in patients with non-specific chronic neck pain and associated visual complaints.
That Ship Has Sailed: China’s Belt and Road Initiative and the Marcos Administration
Authors: MISALUCHA-WILLOUGHBY Charmaine , TOLENTINO Elaine
Published: August 2023

What are the prospects for the Belt and Road (BRI) in the Philippines? How will Marcos’ foreign policy impact BRI projects in the country? The authors argue that the BRI’s prospects are less optimistic now because (i) the Philippines’ experience with Chinese infrastructure projects during Duterte’s time was not overwhelmingly positive and (ii) China continues to occupy the West Philippine Sea. China’s BRI missed its chance of capitalising on the political climate during the Duterte administration.
Indo-Pacific Economic Framework: Biden’s New Institutional Instrument in the Asia-Pacific Region
Authors: LI Wei
Published: August 2023

US President Joe Biden has launched the Indo-Pacific Economic Framework (IPEF) to maintain US leadership role in the Asia-Pacific region. IPEF composes of “four pillars”: interconnected economy, resilient economy, clean economy and fair economy. The Biden administration actively seeks the support of allies around these four key areas to build an economic “united front” against China and form the main institutional instrument for the United States to compete with China in the region.
Effects on Cancer Prevention from the COVID-19 Pandemic
Authors: Duffy Stephen W. , de Jonge Lucie , Duffy Thomas E.
Published: August 2023

The COVID-19 pandemic led to disruption of health services around the world, including cancer services. We carried out a narrative review of the effect of the pandemic on cancer prevention services, including screening. Services were severely affected in the early months of the pandemic, and in some areas are still recovering. Large numbers of additional cancers or additional late-stage cancers have been predicted to arise over the coming years as a result of this disruption. To minimize the effects on cancer outcomes, it is necessary to return as quickly as possible to prepandemic levels of screening and prevention activity or indeed to exceed these levels. The recovery of services should address health inequalities.
Insulating Characteristics and Ionic Conductivity Properties of the Solid Electrolyte Interface in Lithium-Ion Batteries to Improve a Redox-Mediated Enhanced Coulometry Method
Authors: Medina-Santos Jesús I. , Palma Jesús , Ventosa Edgar , Garcia-Quismondo Enrique
Published: August 2023

The Solid Electrolyte Interface (SEI) in lithium-ion batteries plays a critical role in key performance indicators such as cycle life and the significance of its ionic conductivity and electrically-protecting character. The SEI layer’s chemical composition and structure significantly influence its ionic conductivity, and various strategies exist to enhance its electrically-protecting character while maintaining adequate ionic conductivity. Herein, a Redox-Mediated Enhanced Coulometry method is presented, which enables evaluation of both protecting character and ionic conductivity of the SEI, which allows estimation of cycle life at various temperatures. The method is based on the electrochemical impedance spectroscopy (EIS) technique and coulombic efficiency measurements in the presence of redox mediators. The impact of electrolyte additives at different temperatures has been used to demonstrate the potential of the proposed method.
Improving the Stability of Li Metal Anode/Solid Electrolyte Interfaces via an Li3PO4 Intermediate Layer: An Investigation of Surface Chemistry and Electronic Band Structure
Authors: Iida Shin-ichi , Terashima Masahiro , Mamiya Kazutoshi , Kimoto Takahito , Sasaki Shunsuke
Published: August 2023

Recently, researchers are extensively developing next-generation batteries, including all-solid-state batteries (ASSBs), to meet the increasing demand for electric vehicles (EVs) and renewable energy storage. Li metal has been considered an ideal anode material due to its high theoretical capacity and low redox potential. However, it is highly reactive and severe side reactions occur at the interface between Li metal anode and solid electrolytes (SEs), significantly affecting battery performance. Therefore, Li metal anodes have not yet been commercialized. To obtain a chemically stable Li metal anode, the authors examined the side reactions at the interface between the Li metal anode and oxide-type SE using surface analysis techniques such as time-of-flight secondary ion mass spectrometry (TOF-SIMS), X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS) and low-energy inverse photoelectron spectroscopy (LEIPS). In this paper, we present the results of interface analysis between Li metal anode/SE and discuss how to obtain a stable Li metal anode.
Tracking the Lifecycle of a 21700 Cell: A 4D Tomography and Digital Disassembly Study
Authors: Kok Matt D. R. , Jnawali Anmol , Heenan Thomas M. M. , Tranter Thomas G. , Brett Dan J.L. , Shearing Paul R. , Robinson James B.
Published: August 2023

Extending the lifetime of commercial Li-ion cells is amongst the most important challenge to facilitate the continued electrification of transport as demonstrated by the substantial volume of literature dedicated to identifying degradation mechanisms in batteries. Here, we conduct a long-term study on a cylindrical Li-ion cell, tracking the evolution of the structure of the cell using X-ray computed tomography. By evaluating the internal geometry of the cell over several hundreds of cycles we show a causal relationship between changes in the electrode structure and the capacity fade associated with cell ageing. The rapid aging which occurs as cells reach their end-of-life condition is mirrored in a significant acceleration in internal architecture changes. This work also shows the importance of consistent and accurate manufacturing processes with small defects in the jelly-roll being shown to act as nucleation sites for the structural degradation and by extension capacity fade.
Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss
Authors: George Sharon A. , Kiss Alexi , Trampel Katy Anne , Obaid Sofian N. , Tang Lichao , Efimov Igor R. , Efimova Tatiana
Published: August 2023

We show that p38α and p38β have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38α deletion exhibited mild cardioprotective effects in male mice, p38β deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38α and p38β isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38β-dependent cardioprotection in females.
Helium as a Surrogate for Deuterium in LPI Studies
Authors: Geissel Matthias , Harvey-Thompson Adam J. , Weis Matthew R. , Fein Jeffrey R. , Ampleford David , Bliss David E. , Hansen Aaron M. , Jennings Christopher , Kimmel Mark W. , Rambo Patrick , Shores Jonathon E. , Smith Ian C. , Speas C. Shane , Porter John L. , Consoli Fabrizio
Published: August 2023

Helium or neopentane can be used as surrogate gas fill for deuterium (D2) or deuterium-tritium (DT) in laser-plasma interaction studies. Surrogates are convenient to avoid flammability hazards or the integration of cryogenics in an experiment. To test the degree of equivalency between deuterium and helium, experiments were conducted in the Pecos target chamber at Sandia National Laboratories. Observables such as laser propagation and signatures of laser-plasma instabilities (LPI) were recorded for multiple laser and target configurations. It was found that some observables can differ significantly despite the apparent similarity of the gases with respect to molecular charge and weight. While a qualitative behaviour of the interaction may very well be studied by finding a suitable compromise of laser absorption, electron density, and LPI cross sections, a quantitative investigation of expected values for deuterium fills at high laser intensities is not likely to succeed with surrogate gases.
TABLE 2 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

The malignant cell lines grown as complex tumor spheroids for this study. The names of both patient-derived and established cell lines are listed along with the tumor type they were derived from and key genetic alterations
TABLE 1 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Drugs and investigational agents used in this study. The agents included DNA-damaging drugs (top) and DNA repair inhibitors (bottom). If available at the time of this study, the clinical Cmax is listed. Also shown are the molecular target and current clinical status of each agent
Supplementary Table 1 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Table S1. Top-ranking drug combinations by mean Bliss matrix score.
Supplementary Figure 4 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Figure S4. Heat maps of Bliss synergy scores across the combination dose-response matrices for all twenty-six cell lines grown as multicellular complex spheroids exposed to each DNA damaging agent (A, TMZ; B, topotecan; C, trabectedin) in combination with ATR inhibitors, berzosertib or elimusertib.
Supplementary Figure 2 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Figure S2. Heat maps of Bliss synergy scores across the combination dose-response matrices for all twenty-six cell lines grown as multicellular complex spheroids exposed to each DNA damaging agent (A, TMZ; B, topotecan; C, trabectedin) in combination with PARP inhibitors, olaparib or talazoparib.
FIGURE 4 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Combination of ATR inhibitors with topotecan or trabectedin. Concentration–response curves (top, mean ± SD, n = 4 technical replicates) with corresponding mean Bliss score plots (bottom, n = 4 technical replicates) showing the scores from each combination's concentration matrix and colored as a heat map (blue indicates synergy; yellow indicates additivity; red indicates antagonism). Combinations of the DNA-damaging drug topotecan with the ATR inhibitors berzosertib (A) and elimusertib (B). Combinations of the DNA-damaging drug trabectedin with either berzosertib (C) or elimusertib (D). Data are shown for complex tumor spheroids grown with the malignant cell lines (from left): 287954-098-R-J1 (Ewing sarcoma), NCI-H841 (SCLC), DMS 114 (SCLC), COR L88 (SCLC), and 425362-245-T-J1 (melanoma).
FIGURE 3 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Combination of AZD-1390 and topotecan or trabectedin. A, Mean Bliss matrix scores (n = 546) were calculated from the concentration matrix [(5 concentrations of drug A) × (6 concentrations of drug B) = (30 combination concentrations)] of each combination tested (n = 21) in all complex tumor spheroid models (n = 26). The mean Bliss matrix scores are highlighted from combinations of the ATM inhibitor AZD-1390 with DNA-damaging drugs topotecan or trabectedin (n = 52, orange), whereas the scores from all other combinations are shown in light gray. B, A scatter plot of the mean Bliss matrix scores from the AZD-1390 combinations with topotecan and trabectedin (Pearson r = 0.77, two-tailed P < 0.0001). Concentration–response curves (top, mean ± SD, n = 4 technical replicates) from combinations of AZD-1390 with either topotecan (C) or trabectedin (D) and corresponding mean Bliss score plots (bottom, n = 4 technical replicates) showing the scores from each combination's concentration matrix and colored as a heat map (blue indicates synergy; yellow indicates additivity; red indicates antagonism). Data are shown for complex tumor spheroids grown with the malignant cell lines (from left): G-401 (rhabdoid tumor), NCI-H841 (SCLC), 287954-098-R-J1 (Ewing sarcoma), ASPS-1 (alveolar soft part sarcoma), and DMS 114 (SCLC).
FIGURE 2 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Authors: Dexheimer Thomas S. , Coussens Nathan P. , Silvers Thomas , Wright John , Morris Joel , Doroshow James H. , Teicher Beverly A.
Published: August 2023

Combination of PARP inhibitors and temozolomide. A, Mean Bliss matrix scores were calculated from each combination's concentration matrix [(5 concentrations of drug A) × (6 concentrations of drug B) = (30 combination concentrations)]. The scores (n = 546) are graphed for all combinations of DNA-damaging drugs with DNA repair inhibitors tested (n = 21) in all complex tumor spheroid models (n = 26). B, The same data shown in A) but combinations of the DNA-damaging drug temozolomide with either PARP inhibitor olaparib or talazoparib are highlighted in blue (n = 52), whereas all other combinations are shown in light gray. C, A scatter plot of the mean Bliss matrix scores from the temozolomide combinations with olaparib and talazoparib (Pearson r = 0.73, two-tailed P < 0.0001). Concentration–response curves (top, mean ± SD, n = 4 technical replicates) from combinations of temozolomide with either olaparib (D) or talazoparib (E) and corresponding mean Bliss score plots (bottom, n = 4 technical replicates) showing the scores from each combination's concentration matrix and colored as a heat map (blue indicates synergy; yellow indicates additivity; red indicates antagonism). Data are shown for complex tumor spheroids grown with the malignant cell lines (from left): VA-ES-VJ (epithelioid sarcoma), SYO-1 (synovial sarcoma), 287954-098-R-J1 (Ewing sarcoma), 349418-098-R (NSCLC), and DMS 114 (SCLC).
The Application of Teachings by the International Court of Justice, 2016–2022
Authors: Helmersen Sondre Torp
Published: August 2023

This article examines the application of teachings by the International Court of Justice between 2016 and 2022. The Court did not cite teachings in its majority opinions during this period. It did cite works from the International Law Commission, which suggests that these are considered different from teachings and possibly have more weight. Judges cited teachings in their individual opinions. Judge Cançado Trindade stands out as a judge with a particularly high citation rate. Teachings played a wide variety of functions in individual opinions, from the classical functions of aiding the interpretation of a treaty and the ascertainment of a rule of customary international law, to a range of other specialized functions such as the interpretation of other texts, in particular judicial decisions, methodological and historical points, and showing the purpose of a rule of instrument, in addition to providing reflections on the role of the international judiciary itself. The article also examines the demographics of the most-cited writers, finding that most of them are men from Western States. The article compares the judges’ practice with findings from prior to 2016 and other international courts and tribunals.
Fact-Finding by Trade-off: Questions of Evidence and Its Interactions with Valuation in Compensation Cases before the International Court of Justice
Authors: Nakajima Kei
Published: August 2023

This article discusses the evidentiary issues that arise at the compensation phase of the proceedings in the International Court of Justice (‘the Court’), with special reference to the intersection of the rules of evidence and the law of State responsibility concerning reparations. It identifies a sequence of interactions between the two sets of norms throughout the compensation phase and even the prior merits stage. Various notions and approaches indicated by the Court that fall into either of the two sets of rules, such as the reversal of the burden of proof, lowering the standards of proof, equitable considerations and the global sum, should thus be read in conjunction with each other and not in isolation. Such an interplay aims ultimately to bring about a financial outcome that may afford minimum satisfaction to both parties in a dispute, even at the sacrifice of the coherence of judicial reasoning to some extent. In particular, the trade-off between the questions of proof and the reduction of the amount of compensation is seen as a practical adjustment of the financial outcome that could otherwise be unacceptable for the responsible State in the situation of evidentiary uncertainties. The remedies brought to the injured party might be minimal, but an invented alternative to nothing, which could have been the case had the rules of evidence and compensation been ordinarily applied.
Revisiting the Standard of Proof for Charges of Exceptional Gravity before the International Court of Justice
Authors: Bills Amanda
Published: August 2023

The International Court of Justice has consistently required a stricter standard of proof for ‘charges of exceptional gravity’. The Bosnia Genocide and Croatia Genocide cases saw the Court require the high standard of ‘fully conclusive’ evidence across all elements of the allegations of genocide. Despite the difficulties associated with obtaining the necessary evidence of the intent of the perpetrators to destroy, in whole or in part, a protected group to establish the commission of genocide, the Court allowed little flexibility in the application of that standard in what may have been a departure from its previous cases relating to grave charges. The Court emphasized the gravity of the allegations and the high stigmatization attached to a finding of responsibility for genocide, suggesting a strong emphasis on the consequences of a finding of responsibility for the wrongdoing State over other interests that may also have been present in the proceedings. The Court has yet to explain the rationale for the high standard of proof applied to charges of exceptional gravity in international judicial proceedings, or why it required a particularly stringent standard of proof in the Genocide cases. This raises questions about the Court’s approaches to the standard of proof and the process by which it balances different interests in judicial proceedings. As States seek out the Court’s jurisdiction for serious breaches of international law – including, for example, the pending Rohingya Genocide case – the Court’s strict approach to the standard of proof risks imposing a high bar to the enforcement of these obligations.
Load-Displacement and Stiffness Characteristics of Carbon-Fiber Reinforced Polymer (CFRP) Strengthened Reinforced Concrete Beams
Authors: Amin Muhammad Nasir , Ullah Hanif , Khan Kaffayatullah , Iqbal Mudassir
Published: August 2023

In the current study, the efficiency of the carbon-fiber reinforced polymer (CFRP) strengthening technique is experimentally applied to reinforced concrete (RC) beams. In total, four types of test beam specimens are fabricated and tested, labeled as B-1, B-2, B-3, and B-4 for controlled
specimens; the beams strengthened at high-level bending-moment regions, beams strengthened at bending-moment regions with enhanced development length, and U-wrapped shear plus flexural strengthened beams, respectively. The control specimens were fabricated under-reinforced in order
to exhibit ductile failure according to ACI 318-08. The variation in the CFRP external configuration included a change in the bond length and use of U-shaped strips to limit the CFRP debonding. For strengthening the beams, Sika group CFRP was used in this study. The test specimens were
subjected to three-point loading following seven days of strengthening. The test result includes failure modes, load displacement curves, and stiffness degradation. The proposed CFRP strengthening configuration of the RC beams (B-2, B-3, and B-4) demonstrated improved behavior of their load
response as compared to that of control beam (B-1). The CFRP configuration used of RC beam B-4 exhibited almost double flexural strength to that of control beam B-1. Moreover, the deformability of the CFRP strengthened RC beams was also increased.
Convection-Permitting Simulations of Precipitation over the Peruvian Central Andes: Strong Sensitivity to Planetary Boundary Layer Parameterization
Authors: Huang Yongjie , Xue Ming , Hu Xiao-Ming , Martin Elinor , Novoa Hector Mayol , McPherson Renee A. , Perez Andres , Morales Isaac Yanqui
Published: August 2023

Regional climate dynamical downscaling at convection-permitting resolutions is now practical and has the potential to significantly improve over coarser-resolution simulations, but the former is not necessarily free of systematic biases. The evaluation and optimization of model configurations are therefore important. Twelve simulations at a grid spacing of 3 km using the WRF Model with different microphysics, planetary boundary layer (PBL), and land surface model (LSM) schemes are performed over the Peruvian central Andes during the austral summer, a region with particularly complex terrain. The simulated precipitation is evaluated using rain gauge data and three gridded precipitation datasets. All simulations correctly capture four precipitation hotspots associated with prevailing winds and terrain features along the east slope of the Andes, though they generally overestimate the precipitation intensity. The simulation using Thompson microphysics, Asymmetric Convection Model version 2 (ACM2) PBL, and Noah LSM schemes has the smallest bias. The simulated precipitation is most sensitive to PBL, followed by microphysics, and least sensitive to LSM schemes. The simulated precipitation is generally stronger in simulations using the YSU rather than the MYNN and ACM2 schemes. All simulations successfully capture the diurnal precipitation peak time mainly in the afternoon over the Peruvian central Andes and in the early morning along the east slope. However, there are significant differences over the western Amazon basin, where the precipitation peak occurs primarily in the late afternoon. Simulations using YSU exhibit a 4–8-h delay in the precipitation peak over the western Amazon basin, consistent with their stronger and more persistent low-level jets. These results provide guidance on the optimal configuration of a dynamical downscaling of global climate projections for the Peruvian central Andes.
A Comparison of the Impacts of Inner-Core, In-Vortex, and Environmental Dropsondes on Tropical Cyclone Forecasts during the 2017–20 Hurricane Seasons
Authors: Ditchek Sarah D. , Sippel Jason A.
Published: August 2023

This study conducts the first large-sample comparison of the impact of dropsondes in the tropical cyclone (TC) inner core, vortex, and environment on NWP-model TC forecasts. We analyze six observing-system experiments, focusing on four sensitivity experiments that denied dropsonde observations within annuli corresponding with natural breakpoints in reconnaissance sampling. These are evaluated against two other experiments detailed in a recent parallel study: one that assimilated and another that denied dropsonde observations. Experiments used a basin-scale, multistorm configuration of the Hurricane Weather Research and Forecasting (HWRF) Model and covered active periods of the 2017–20 North Atlantic hurricane seasons. Analysis focused on forecasts initialized with dropsondes that used mesoscale error covariance derived from a cycled HWRF ensemble, as these forecasts were where dropsondes had the greatest benefits in the parallel study. Some results generally support findings of previous research, while others are novel. Most notable was that removing dropsondes anywhere, particularly from the vortex, substantially degraded forecasts of maximum sustained winds. Removing in-vortex dropsondes also degraded outer-wind-radii forecasts in many instances. As such, in-vortex dropsondes contribute to a majority of the overall impacts of the dropsonde observing system. Additionally, track forecasts of weak TCs benefited more from environmental sampling, while track forecasts of strong TCs benefited more from in-vortex sampling. Finally, inner-core-only sampling strategies should be avoided, supporting a change made to the U.S. Air Force Reserve’s sampling strategy in 2018 that added dropsondes outside of the inner core.

Significance Statement

This study uses a regional hurricane model to conduct the most comprehensive assessment to date of the impact of dropsondes at different distances away from the center of a tropical cyclone (TC) on TC forecasts. The main finding is that in-vortex dropsondes are most important for intensity and outer-wind-radii forecasts. Particularly notable is the impact of dropsondes on TC maximum wind speed forecasts, as reducing sampling anywhere would degrade those forecasts.
The Sustainable Library: A retrospective case study of a public library sharing initiative
Authors: Mathiasson Mia Høj , Jochumsen Henrik
Published: August 2023

Sharing initiatives, things collections or libraries of things have become developing features in public libraries within recent years. This article reports on a retrospective case study of The Sustainable Library, a now-concluded Danish sharing initiative from 2016 to 2022. As an early example of a public library sharing initiative, The Sustainable Library is a unique case. Moreover, its explicit focus on sustainability and sharing economy makes it an early example of sustainable librarianship. The study offers empirical insights into the life cycle of the sharing initiative and its different phases. Examining the case from its organizational context, the study asks how and why the sharing initiative was developed, what were its preconditions and drivers, and which barriers were experienced along the way. Finally, the study makes room for hindsight reflections on the role and responsibility of public libraries and sharing initiatives in the sustainability agenda.
A randomized, open-label, cross-over pilot study investigating metabolic product kinetics of the palatable novel ketone ester, bis-octanoyl (R)-1,3-butanediol, and bis-hexanoyl (R)-1,3-butanediol ingestion in healthy adults
Authors: Stubbs Brianna J , Cook Chad , Blonquist Traci M , Taggart Kristen , Beckman Dawn , Kruger Claire , Conze Dietrich , Boileau Amy C
Published: August 2023

Introduction

Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel, palatable ketone ester that, when consumed, is hydrolyzed in the gastrointestinal tract into octanoic acid (OCT) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Metabolism of BO-BD is hypothesized to be similar to bis-hexanoyl (R)-1,3-butanediol (BH-BD), apart from release of octanoic acid instead of hexanoic acid (HEX).

Methods

As part of the safety assessment for BO-BD a randomized, cross-over, open-label study in middle-aged, healthy adults ( n = 12) was undertaken to provide a qualitative comparison of plasma BHB, OCT, HEX and BDO concentrations for 8 h following consumption of 12.5 or 25  g of BO-BD and 12.5  g of BH-BD.

Results

All study products increased plasma BHB and BDO up to 4 h post-consumption. BH-BD increased HEX, whereas BO-BD increased OCT. All kinetic parameters for BHB and BDO were similar between 12.5  g servings of BH-BD and BO-BD while Cmax and AUC for OCT were higher following 12. 5  g servings of BO-BD as compared to HEX with 12.5  g of BH-BD. All metabolites returned to baseline by 8 h post-consumption. BHB, BDO and OCT Cmax and AUC were increased with serving size of BO-BD from 12.5 to 25  g. Sensory acceptability scores of BO-BD were significantly higher than for BH-BD. An in vitro hydrolysis experiment using human blood plasma further confirmed that plasma esterases possess the ability to break down the novel ketone esters into BDO, and OCT or HEX.

Discussion

The two novel ketone ester molecules exhibit similar metabolic breakdown to BHB and BDO and result in transiently higher concentrations of the plasma fatty acids, OCT and HEX, in vivo.

Conclusions

Given the similar ketone delivery with greater acceptability, BO-BD may offer a more broadly translatable tool to induce physiologic ketosis than BH-BD.
Hereditary transthyretin amyloidosis in the era of RNA interference, antisense oligonucleotide, and CRISPR-Cas9 treatments
Authors: Adams David , Algalarrondo Vincent , Echaniz-Laguna Andoni
Published: August 2023

Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant adult-onset disorder caused by point mutations in the transthyretin (TTR) gene encoding TTR, also known as prealbumin. ATTRv survival ranges from 3 to 10 years, and peripheral nervous system and heart are usually the 2 main tissues affected, although central nervous system and eye may also be involved. Because the liver is the main TTR protein secretor organ, it has been the main target of treatments developed these last years, including liver transplantation, which has been shown to significantly increase survival in a subset of patients carrying the so-called “early-onset Val30Met” TTR gene mutation. More recently, treatments targeting hepatic TTR RNA have been developed. Hepatic TTR RNA targeting is performed using RNA interference (RNAi) and antisense oligonucleotide (ASO) technologies involving lipid nanoparticle carriers or N-acetylgalactosamine fragments. RNAi and ASO treatments induce an 80% decrease in TTR liver production for a period of 1 to 12 weeks. ASO and RNAi phase 3 trials in patients with TTR-related polyneuropathy have shown a positive impact on neuropathy clinical scores and quality of life end points, and delayed RNAi treatment negatively affects survival. Clinical trials specifically investigating RNAi therapy in TTR cardiomyopathy are underway. Hepatic RNA targeting has revolutionized ATTRv treatment and may allow for the transforming a fatal disease into a treatable disorder. Because retina and choroid plexus secrete limited quantities of TTR protein, both tissues are now seen as the next targets for fully controlling the disease.