bluuebunny/crossref_metadata_2025 huggingface dataset:
Frond orientations with independent current indicators demonstrate the reclining rheotropic mode of life of several Ediacaran rangeomorph taxa
Authors: Pérez-Pinedo Daniel , Neville Jenna M. , Pasinetti Giovanni , McKean Christopher , Taylor Rod , McIlroy Duncan
Published: February 2023

Fossils from the deep-sea Ediacaran biotas of Newfoundland are among the oldest architecturally complex soft-bodied macroorganisms on Earth. Most organisms in the Mistaken Point–type biotas of Avalonia—particularly the fractal-branching frondose Rangeomorpha— have been traditionally interpreted as living erect within the water column during life. However, due to the scarcity of documented physical sedimentological proxies associated with fossiliferous beds, Ediacaran paleocurrents have been inferred in some instances from the preferential orientation of fronds. This calls into question the relationship between frond orientation and paleocurrents. In this study, we present an integrated approach from a newly described fossiliferous surface (the “Melrose Surface” in the Fermeuse Formation at Melrose, on the southern portion of the Catalina Dome in the Discovery UNESCO Global Geopark) combining: (1) physical sedimentological evidence for paleocurrent direction in the form of climbing ripple cross-lamination and (2) a series of statistical analyses based on modified polythetic and monothetic clustering techniques reflecting the circular nature of the recorded orientation ofFractofusus misraispecimens. This study demonstrates the reclining rheotropic mode of life of the Ediacaran rangeomorph taxonFractofusus misraiand presents preliminary inferences suggesting a similar mode of life forBradgatiasp. andPectinifrons abyssalisbased on qualitative evidence. These results advocate for the consideration of an alternative conceptual hypothesis for position of life of Ediacaran organisms in which they are interpreted as having lived reclined on the seafloor, in the position that they are preserved.
Against Evidential Pluralism in Pharmaceutical Regulation
Authors: Sung Doohyun , Holman Bennett
Published: February 2023

We examine arguments regarding the use of mechanistic evidence in assessing treatment efficacy and find that advocates and critics of EBM+ have largely been talking past each other due to a difference in focus. We explore aducanumab for the treatment of Alzheimer’s disease as a case that may speak to the role of EBM+ in pharmaceutical regulation. The case suggests the debate may be more fruitful if philosophers confine debates to particular domains of medicine and weigh in prospectively instead of relying on historical cases in which outcomes are known and that are susceptible to hindsight bias.
On the Logical Structure of Best Explanations
Authors: Schupbach Jonah N.
Published: February 2023

Standard articulations of Inference to the Best Explanation (IBE) imply the uniqueness claim that exactly one explanation should be inferred in response to an explanandum. This claim has been challenged as being both too strong (sometimes agnosticism between candidate explanatory hypotheses seems the rational conclusion) and too weak (in cases where multiple hypotheses might sensibly be conjointly inferred). I propose a novel interpretation of IBE that retains the uniqueness claim while also allowing for agnostic and conjunctive conclusions. I then argue that a particular probabilistic explication of explanatory goodness helpfully guides us in navigating such options when using IBE.
Intermittent fasting promotes adipocyte mitochondrial fusion through Sirt3-mediated deacetylation of Mdh2
Authors: Li Yizhou , Liang Juntong , Tian Xin , Chen Qi , Zhu Longbo , Wang Han , Liu Zunhai , Dai Xulei , Bian Chenqi , Sun Chao
Published: February 2023

Fat deposition and lipid metabolism are closely related to the morphology, structure and function of mitochondria. The morphology of mitochondria between fusion and fission processes is mainly regulated by protein posttranslational modification. Intermittent fasting (IF) promotes high expression of Sirtuin 3 (Sirt3) and induces mitochondrial fusion in high-fat diet (HFD)-fed mice. However, the mechanism by which Sirt3 participates in mitochondrial protein acetylation during IF to regulate mitochondrial fusion and fission dynamics remains unclear. This article demonstrates that IF promotes mitochondrial fusion and improves mitochondrial function in HFD mouse inguinal white adipose tissue. Proteomic sequencing revealed that IF increased protein deacetylation levels in HFD mice and significantly increased Sirt3 mRNA and protein expression. After transfecting with Sirt3 overexpression or interference vectors into adipocytes, we found that Sirt3 promoted adipocyte mitochondrial fusion and improved mitochondrial function. Furthermore, Sirt3 regulates the JNK-FIS1 pathway by deacetylating malate dehydrogenase 2 (MDH2) to promote mitochondrial fusion. In summary, our study indicates that IF promotes mitochondrial fusion and improves mitochondrial function by upregulating the high expression of Sirt3 in HFD mice, promoting deacetylation of MDH2 and inhibiting the JNK-FIS1 pathway. This research provides theoretical support for studies related to energy limitation and animal lipid metabolism.
Health technology assessment 2025 and beyond: lifecycle approaches to promote engagement and efficiency in health technology assessment
Authors: Trowman Rebecca , Migliore Antonio , Ollendorf Daniel A.
Published: February 2023

Lifecycle considerations have always been part of health technology assessment (HTA). However, the concept of taking a fuller, more holistic “lifecycle approach” is gaining interest in the HTA community. The 2022 HTAi Global Policy Forum (GPF) discussed how adopting a lifecycle approach could promote stakeholder engagement and robust evidence generation, and whether it could enhance information sharing and transparency across stakeholder groups. This article summarizes the discussions held at the 2022 HTAi GPF and subsequent HTAi Annual Meeting panel session that debated some of the key challenges and opportunities, with particular focus on the pre- and postmarket and disinvestment phase activities. Core themes and recommendations identified that collaboration and patient involvement are happening but still needs to be strengthened, and moving to disease-based approaches may help, although individual contexts still need to be considered. Appropriately developed and mandated core outcome sets may help with information sharing and efficiency in all lifecycle activities. Further, methods for the appropriate use of big data and digital data collection should be developed and driven by the HTA community. The value of lifecycle activities should be reviewed; in particular, scientific advice appears valuable, but the magnitude of effect is somewhat unknown due to the challenges around the confidential nature of these activities. Not all lifecycle activities can be conducted for every technology, and while there is a move away from disinvestment phase activities, more structured prioritization criteria are required. This article ends with suggested next steps to bring forward some of the priority recommendations.
Which rural settlements have lost the most population? An analysis of a case study of north-east Spain (Aragón) (1900–2001)
Authors: Ayuda María Isabel , Gómez Pablo , Pinilla Vicente
Published: February 2023

The aim of this article is to investigate how the characteristics of the different types of human settlements explain their demographic dynamics and, therefore, which of these have been affected to a greater extent by depopulation processes. For this purpose, we analyse the evolution of the population of Aragón (north-east Spain) in the period 1900–2001, according to the different types of population settlements that exist. Our results show that access to public services has played an essential role, especially when the construction of the welfare state made the rural population feel that there was a penalty for residing in settlements with problems to access them. The main settlements, headquarters of the municipal administration, have had advantages over the secondary settlements. Finally, the scattered population was the most affected and, therefore, emigrated to a greater extent, until this form of residence practically disappeared.
How did COVID-19 affect the labor force participation of older workers in the first year of the pandemic?
Authors: Davis Owen F. , Quinby Laura D. , Rutledge Matthew S. , Wettstein Gal
Published: February 2023

This paper uses the Current Population Survey to study older workers' transitions out of employment and into retirement during the first year of the pandemic. We find that, among workers ages 55 to 79, the likelihood of leaving employment over the course of a year rose by 6.7 percentage points, a 43-percent increase over baseline. Workers without a college degree, Asian–Americans, those whose jobs were not amenable to social distancing, and part-time workers saw disproportionate impacts. In contrast, the likelihood of retiring increased by 1 percentage point, and there was no immediate retirement boom for full-time workers under 70.
Northward Extent of Atmospheric Mercury Transboundary Transport to the Himalayas and Tibetan Plateau Region
Authors: Huang Jie , Kang Shichang , Feng Xinbin , Tang Wenjun , Ram Kirpa , Guo Junming , Zhang Qianggong , Sharma Chhatra Mani , Li Chaoliu , Tripathee Lekhendra , Wang Feiyue
Published: February 2023

Indian monsoon circulation is the primary driver of the long‐range transboundary mercury (Hg) pollution from South Asia to the Himalayas and Tibet Plateau region, yet the northward extent of this transport remains unknown. In this study, a strong δ202Hg signature overlapping was found between Lake Gokyo and Indian anthropogenic sources, which is an indicative of the Hg source regions from South Asia. Most of the sediment samples were characterized with relatively large positive Δ199Hg values (mean = 0.07‰–0.44‰) and small positive Δ200Hg values (mean = 0.03‰–0.08‰). Notably, the Δ199Hg values in the lake sediments progressively increased from southwest to northeast. Moreover, the Δ199Hg values peaked at Lake Tanglha (mean = 0.44‰ ± 0.04‰) before decreased at Lake Qinghai that is under the influence of the westerlies. Our results suggest that transboundary atmospheric transport could transport Hg from South Asia northwards to at least the Tanglha Mountains in the northern Himalaya‐Tibet.
Apparent Low‐Velocity Belt in the Shallow Anninghe Fault Zone in SW China and Its Implications for Seismotectonics and Earthquake Hazard Assessment
Authors: Luo Song , Yao Huajian , Wen Jian , Yang Hongfeng , Tian Baofeng , Yan Mengxuan
Published: February 2023

The Anninghe fault forms the eastern boundary of the Sichuan‐Yunnan block in Southwest China and has been identified as an earthquake gap zone. This study intends to construct the upper crustal shear wave velocity (Vs) structure beneath the Anninghe fault to understand its seismotectonics and potential large earthquake hazards. We deployed a dense seismic array along the southern central Anninghe fault valley. From the 3‐month continuous records, we calculated vertical‐component cross‐correlation functions (CCFs). However, the surface wave signals in the CCFs are intensely interfered by near zero‐time‐lag noise. We proposed a mode separation method based on the high‐resolution linear Radon transform, which suppressed the interfered noise and greatly enhanced the surface wave signals for ambient noise tomography of the Vs structure. The fine upper crustal structure reveals a distinct narrow low‐velocity belt within a depth of 3 km beneath the Anninghe fault zone. At deeper depths (4.5–8 km), the narrow low‐velocity belt shifts to the east and correlates with the distribution of local earthquakes. Combining previous results with our new findings, we presented a seismotectonic model of the southern central Anninghe fault, which interprets the narrow low‐velocity belt as a water‐contained fracture zone that forms a seismogenic zone at deeper depths under transpression. In addition, we demonstrated through scenario earthquake simulations that fine structures play a significant role in the assessment of earthquake hazards along the Anninghe fault. As such, this study provides a typical window into seismotectonics and large earthquake hazards in the active southeastern Tibetan Plateau.
A Large Winter Chlorophyll‐a Bloom in the Southeastern Bay of Bengal Associated With the Extreme Indian Ocean Dipole Event in 2019
Authors: Li Zhiyuan , Long Yu , Huang Saihua , Xie Huawei , Zhou Yu , Yang Bin , Bai Yu , Zhu Xiao‐Hua
Published: February 2023

A large Chlorophyll‐a (Chla) bloom developed in the southeastern Bay of Bengal (BoB) (4°N–10°N, 88°E−95°E) during winter 2019 and was observed from Moderate Resolution Imaging Spectroradiometer‐Aqua Chla data. By analyzing various observational and reanalysis datasets, we found that remote Equatorial Indian Ocean (EIO) upwelling waves and local Ekman pumping associated with the extreme Indian Ocean Dipole (IOD) event in 2019 were responsible for the Chla bloom. The extreme IOD 2019 favored strong upwelling Kelvin waves propagating from the eastern EIO into the BoB along the eastern boundary. These Kelvin waves were reflected into the central BoB as upwelling Rossby waves manifested by eddylike sea surface height propagating westward approximately along 5°N. In addition, local wind stress curl generated strong Ekman pumping in the southeastern BoB. As a result, upwelling processes associated with westward‐propagating Rossby waves and local Ekman pumping together uplifted the thermocline, breaking the stratification so that subsurface nutrient‐rich water was transported to the surface to cause a large Chla bloom in the southeastern BoB during winter 2019. The Chla bloom had a ring structure and its spatial shape was modulated by westward upwelling Rossby waves and cyclonic eddies. This study highlights the important role of IOD events in the formation of Chla bloom in the southeastern BoB during winter.
Reducing the Uncertainty in the Satellite Altimetry Estimates of Global Mean Sea Level Trends Using Highly Stable Water Vapor Climate Data Records
Authors: Barnoud Anne , Picard Bruno , Meyssignac Benoît , Marti Florence , Ablain Michaël , Roca Rémy
Published: February 2023

The global mean sea level (GMSL) has risen by 3.3 ± 0.2 mm.yr−1 (68% confidence level) over 1993–2021. The wet troposphere correction (WTC) used to compute the altimetry‐based mean sea level data is known to be a large source of error in the GMSL long‐term stability. The WTC is derived from the microwave radiometers (MWR) on board the altimetry missions. In order to improve the long‐term estimates of the GMSL, we propose an alternative WTC computation based on highly stable climate data records (CDRs) of water vapor derived from independent MWR measurements on board meteorological satellites. A polynomial model is applied to convert water vapor to WTC. The CDR‐derived WTC enables reducing the low frequency uncertainty of the WTC applied to the altimetry data, hence reducing the uncertainty of the GMSL trend estimate. Furthermore, over 2016–2021, the comparison of MWR‐based with CDR‐based WTC shows a likely drift of the Jason‐3 MWR WTC on the order of −0.5 mm.yr−1 that would lead to an overestimation of the GMSL trend from 2016.
Longitudinal metabolomics of increasing body-mass index and waist-hip ratio reveals two dynamic patterns of obesity pandemic
Authors: Mäkinen Ville-Petteri , Kettunen Johannes , Lehtimäki Terho , Kähönen Mika , Viikari Jorma , Perola Markus , Salomaa Veikko , Järvelin Marjo-Riitta , Raitakari Olli T. , Ala-Korpela Mika
Published: February 2023

Background/Objective

This observational study dissects the complex temporal associations between body-mass index (BMI), waist-hip ratio (WHR) and circulating metabolomics using a combination of longitudinal and cross-sectional population-based datasets and new systems epidemiology tools.

Subjects/Methods

Firstly, a data-driven subgrouping algorithm was employed to simplify high-dimensional metabolic profiling data into a single categorical variable: a self-organizing map (SOM) was created from 174 metabolic measures from cross-sectional surveys (FINRISK, n = 9708, ages 25–74) and a birth cohort (NFBC1966, n = 3117, age 31 at baseline, age 46 at follow-up) and an expert committee defined four subgroups of individuals based on visual inspection of the SOM. Secondly, the subgroups were compared regarding BMI and WHR trajectories in an independent longitudinal dataset: participants of the Young Finns Study (YFS, n = 1286, ages 24–39 at baseline, 10 years follow-up, three visits) were categorized into the four subgroups and subgroup-specific age-dependent trajectories of BMI, WHR and metabolic measures were modelled by linear regression.

Results

The four subgroups were characterised at age 39 by high BMI, WHR and dyslipidemia (designated TG-rich); low BMI, WHR and favourable lipids (TG-poor); low lipids in general (Low lipid) and high low-density-lipoprotein cholesterol (High LDL-C). Trajectory modelling of the YFS dataset revealed a dynamic BMI divergence pattern: despite overlapping starting points at age 24, the subgroups diverged in BMI, fasting insulin (three-fold difference at age 49 between TG-rich and TG-poor) and insulin-associated measures such as triglyceride-cholesterol ratio. Trajectories also revealed a WHR progression pattern: despite different starting points at the age of 24 in WHR, LDL-C and cholesterol-associated measures, all subgroups exhibited similar rates of change in these measures, i.e. WHR progression was uniform regardless of the cross-sectional metabolic profile.

Conclusions

Age-associated weight variation in adults between 24 and 49 manifests as temporal divergence in BMI and uniform progression of WHR across metabolic health strata.
The hTERT-p50 homodimer inhibits PLEKHA7 expression to promote gastric cancer invasion and metastasis
Authors: Wu Yu-Yun , Xiao Yu-Feng , Tian Li-Xing , He Bing , Liu Jiao , Li Zhi-Bin , Yang Huan , Chen Yang , Luo Qiang , Li Bo-Sheng , Yang Shi-Ming
Published: February 2023

Although accumulating evidence has highlighted the molecular mechanisms by which hTERT promotes tumour cell invasion and metastasis, the molecular mechanisms of the properties enabling hTERT to contribute to invasion and metastasis have not been clearly illustrated. Here, we report that hTERT promotes gastric cancer invasion and metastasis by recruiting p50 to synergistically inhibit PLEKHA7 expression. We observed that the expression of PLEKHA7 in gastric cancer was significantly negatively associated with the TNM stage and lymphatic metastasis and that decreased PLEKHA7 expression dramatically increased invasion and metastasis in gastric cancer cells. Further mechanistic research showed that hTERT directly regulates PLEKHA7 expression by binding p50 and recruiting the hTERT/p50 complex to the PLEKHA7 promoter. Increased hTERT dramatically decreased PLEKHA7 expression and promoted invasion and metastasis in gastric cancer cells. The hTERT-mediated invasion/metastasis properties at least partially depended on PLEKHA7. Our work uncovers a novel molecular mechanism underlying invasion/metastasis in gastric cancer orchestrated by hTERT and p50.
Genetic propensity, socioeconomic status, and trajectories of depression over a course of 14 years in older adults
Authors: Kosciuszko Martyna , Steptoe Andrew , Ajnakina Olesya
Published: February 2023

Depression is one of the leading causes of disability worldwide and is a major contributor to the global burden of disease among older adults. The study aimed to investigate the interplay between socio-economic markers (education and financial resources) and polygenic predisposition influencing individual differences in depressive symptoms and their change over time in older adults, which is of central relevance for preventative strategies. The sample encompassing n = 6202 adults aged ≥50 years old with a follow-up period of 14 years was utilised from the English Longitudinal Study of Ageing. Polygenic scores for depressive symptoms were calculated using summary statistics for (1) single-trait depressive symptoms (PGS-DSsingle), and (2) multi-trait including depressive symptoms, subjective well-being, neuroticism, loneliness, and self-rated health (PGS-DSmulti-trait). The depressive symptoms over the past week were measured using the eight-item Centre for Epidemiologic Studies Depression Scale. One standard deviation increase in each PGS was associated with a higher baseline score in depressive symptoms. Each additional year of completed schooling was associated with lower baseline depression symptoms (β = −0.06, 95%CI = −0.07 to −0.05, p < 0.001); intermediate and lower wealth were associated with a higher baseline score in depressive symptoms. Although there was a weak interaction effect between PGS-DSs and socio-economic status in association with the baseline depressive symptoms, there were no significant relationships of PGS-DSs, socio-economic factors, and rate of change in the depressive symptoms during the 14-year follow-up period. Common genetic variants for depressive symptoms are associated with a greater number of depressive symptoms onset but not with their rate of change in the following 14 years. Lower socio-economic status is an important factor influencing individual levels of depressive symptoms, independently from polygenic predisposition to depressive symptoms.
PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions
Authors: Chen Jiayi , Li Mei , Liu Yeqing , Guan Tangming , Yang Xiao , Wen Yalei , Zhu Yingjie , Xiao Zeyu , Shen Xiangchun , Zhang Haoxing , Tang Hui , Liu Tongzheng
Published: February 2023

The VHL protein (pVHL) functions as a tumor suppressor by regulating the degradation or activation of protein substrates such as HIF1α and Akt. In human cancers harboring wild-type VHL, the aberrant downregulation of pVHL is frequently detected and critically contributes to tumor progression. However, the underlying mechanism by which the stability of pVHL is deregulated in these cancers remains elusive. Here, we identify cyclin-dependent kinase 1 (CDK1) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) as two previously uncharacterized regulators of pVHL in multiple types of human cancers harboring wild-type VHL including triple-negative breast cancer (TNBC). PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo. Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation. Furthermore, the genetic ablation or pharmacological inhibition of CDK1 by RO-3306 and PIN1 by all-trans retinoic acid (ATRA), the standard care for Acute Promyelocytic Leukemia could markedly suppress tumor growth, metastasis and sensitize cancer cells to chemotherapeutic drugs in a pVHL dependent manner. The histological analyses show that PIN1 and CDK1 are highly expressed in TNBC samples, which negatively correlate with the expression of pVHL. Taken together, our findings reveal the previous unrecognized tumor-promoting function of CDK1/PIN1 axis through destabilizing pVHL and provide the preclinical evidence that targeting CDK1/PIN1 is an appealing strategy in the treatment of multiple cancers with wild-type VHL.
Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals
Authors: Zhang Yulin , Tanabe Yoshiaki , Kuriyama Shogo , Sakata Ken , Nishibayashi Yoshiaki
Published: February 2023

Transition metal-catalyzed enantioselective free radical substitution reactions have recently attracted attention as convenient and important building tools in synthetic chemistry, although construction of stereogenic carbon centers at the propargylic position of propargylic alcohols by reactions with free radicals remains unchallenged. Here we present a strategy to control enantioselective propargylic substitution reactions with alkyl radicals under photoredox conditions by applying dual photoredox and diruthenium catalytic system, where the photoredox catalyst generates alkyl radicals from 4-alkyl-1,4-dihydropyridines, and the diruthenium core with a chiral ligand traps propargylic alcohols and alkyl radicals to guide enantioselective alkylation at the propargylic position, leading to high yields of propargylic alkylated products containing a quaternary stereogenic carbon center at the propargylic position with a high enantioselectivity. The result described in this paper provides the successful example of transition metal-catalyzed enantioselective propargylic substitution reactions with free alkyl radicals.
11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial
Authors: Othonos Nantia , Pofi Riccardo , Arvaniti Anastasia , White Sarah , Bonaventura Ilaria , Nikolaou Nikolaos , Moolla Ahmad , Marjot Thomas , Stimson Roland H. , van Beek André P. , van Faassen Martijn , Isidori Andrea M. , Bateman Elizabeth , Sadler Ross , Karpe Fredrik , Stewart Paul M. , Webster Craig , Duffy Joanne , Eastell Richard , Gossiel Fatma , Cornfield Thomas , Hodson Leanne , Jane Escott K. , Whittaker Andrew , Kirik Ufuk , Coleman Ruth L. , Scott Charles A. B. , Milton Joanne E. , Agbaje Olorunsola , Holman Rury R. , Tomlinson Jeremy W.
Published: February 2023

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation
Authors: Liang Jiale , Inoue Asuka , Ikuta Tatsuya , Xia Ruixue , Wang Na , Kawakami Kouki , Xu Zhenmei , Qian Yu , Zhu Xinyan , Zhang Anqi , Guo Changyou , Huang Zhiwei , He Yuanzheng
Published: February 2023

Lysophosphatidylserine (LysoPS) is a lipid mediator that induces multiple cellular responses through binding to GPR174. Here, we present the cryo-electron microscopy (cryo-EM) structure of LysoPS-bound human GPR174 in complex with Gsprotein. The structure reveals a ligand recognition mode, including the negatively charged head group of LysoPS forms extensive polar interactions with surrounding key residues of the ligand binding pocket, and the L-serine moiety buries deeply into a positive charged cavity in the pocket. In addition, the structure unveils a partially open pocket on transmembrane domain helix (TM) 4 and 5 for a lateral entry of ligand. Finally, the structure reveals a Gsengaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs.
Novel plant–frugivore network on Mauritius is unlikely to compensate for the extinction of seed dispersers
Authors: Heinen Julia H. , Florens F. B. Vincent , Baider Cláudia , Hume Julian P. , Kissling W. Daniel , Whittaker Robert J. , Rahbek Carsten , Borregaard Michael K.
Published: February 2023

Insular communities are particularly vulnerable to anthropogenic extinctions and introductions. Changes in composition of island frugivore communities may affect seed dispersal within the native plant community, risking ecological shifts and ultimately co-extinction cascades. Introduced species could potentially mitigate these risks by replacing ecological functions of extinct species, but conclusive evidence is lacking. Here, we investigate changes in plant–frugivore interactions involving frugivorous birds, mammals and reptiles in Mauritius, an oceanic island with an exceptionally well-specified frugivore community and well-described species introduction history. We demonstrate substantial losses of binary interaction partnerships (at the species level) resulting from native species extinctions, but also gains of equal numbers of novel interactions with introduced species, potentially supporting the idea that non-native species might compensate for lost seed dispersal. However, closer investigation of animal seed handling behaviour reveals that most interactions with seed dispersers are replaced by ecologically different interactions with seed predators. Therefore, restoration of seed dispersal functionality in this novel plant–frugivore community is unlikely.
Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases
Authors: de Klein Niek , Tsai Ellen A. , Vochteloo Martijn , Baird Denis , Huang Yunfeng , Chen Chia-Yen , van Dam Sipko , Oelen Roy , Deelen Patrick , Bakker Olivier B. , El Garwany Omar , Ouyang Zhengyu , Marshall Eric E. , Zavodszky Maria I. , van Rheenen Wouter , Bakker Mark K. , Veldink Jan , Gaunt Tom R. , Runz Heiko , Franke Lude , Westra Harm-Jan
Published: February 2023

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n ≤ 2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. We inferred brain cell types for 3,549 cis-eQTLs by interaction analysis. We prioritized 186 cis-eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis-eQTLs with an inferred cell type, such as a neuron-specific cis-eQTL (CYP24A1) for multiple sclerosis. We further describe 737 trans-eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.
The diachronic trend of female and male stature in Milan over 2000 years
Authors: Biehler-Gomez Lucie , del Bo Beatrice , Petrosino Daniele , Morandini Paolo , Mattia Mirko , Palazzolo Luca , Guerrini Uliano , Cattaneo Cristina
Published: February 2023

Stature is a biological trait directly determined by the interaction of genetic and environmental components. As such, it is often evaluated as an indicator for the reconstruction of skeletal biological profiles, past health, and social dynamics of human populations. Based on the analysis of 549 skeletons from the CAL (Collezione Antropologica LABANOF), a study of the diachronic trend of male and female adult stature in Milan (Italy) is being proposed here, covering a time span of about 2000 years, ranging from the Roman era to present-days. The skeletons, from necropolises dedicated to the less wealthy classes of Milanese society, were assigned to one of following five historical periods: Roman Era (first–fifth centuries AD), Early Middle Ages (sixth–tenth centuries AD), Late Middle Ages (eleventh–fifteenth centuries AD), Modern Era (sixteenth–eighteenth centuries AD) and Contemporary Era (nineteenth–twentieth centuries AD), and their stature was estimated according to the regression formulae of Trotter (1970). The collected data were then subjected to statistical analyses with ANOVA using R software. Although stature values showed an ample standard deviation in all periods, statistical analyses showed that stature did not significantly vary across historical periods in Milan for both sexes. This is one of the rare studies showing no diachronic changes in the trend of stature in Europe.
A multidimensional ODE-based model of Alzheimer’s disease progression
Authors: Bossa Matías Nicolás , Sahli Hichem
Published: February 2023

Data-driven Alzheimer’s disease (AD) progression models are useful for clinical prediction, disease mechanism understanding, and clinical trial design. Most dynamic models were inspired by the amyloid cascade hypothesis and described AD progression as a linear chain of pathological events. However, the heterogeneity observed in healthy and sporadic AD populations challenged the amyloid hypothesis, and there is a need for more flexible dynamical models that accompany this conceptual shift. We present a statistical model of the temporal evolution of biomarkers and cognitive tests that allows diverse biomarker paths throughout the disease. The model consists of two elements: a multivariate dynamic model of the joint evolution of biomarkers and cognitive tests; and a clinical prediction model. The dynamic model uses a system of ordinary differential equations to jointly model the rate of change of an individual’s biomarkers and cognitive tests. The clinical prediction model is an ordinal logistic model of the diagnostic label. Prognosis and time-to-onset predictions are obtained by computing the clinical label probabilities throughout the forecasted biomarker trajectories. The proposed dynamical model is interpretable, free of one-dimensional progression hypotheses or disease staging paradigms, and can account for the heterogeneous dynamics observed in sporadic AD. We developed the model using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative. We illustrate the patterns of biomarker rates of change and the model performance to predict the time to conversion from MCI to dementia.
Novel Bromo and methoxy substituted Schiff base complexes of Mn(II), Fe(III), and Cr(III) for anticancer, antimicrobial, docking, and ADMET studies
Authors: Abdel-Rahman Laila H. , Abdelghani Amani A. , AlObaid Abeer A. , El-ezz Doaa Abou , Warad Ismail , Shehata Mohamed R. , Abdalla Ehab M.
Published: February 2023

In this study, four new Mn(II), Fe(III), and Cr(III) complexes with two Schiff base ligands namely, 4-bromo-2-[(E)-{[4-(2-hydroxyethyl)phenyl]imino}methyl]phenol (HL1) and 2-[(E)-{[4-(2-hydroxyethyl)phenyl]imino}methyl]-4-methoxy phenol (HL2) have been synthesized and characterized. Different analytical and spectral methods have been used to characterize the ligands and their complexes. General formulas of [M(L)Cl2(H2O)2] for FeL1, CrL1 and CrL2, and [M(L)Cl(H2O)3] for MnL2 were proposed. HOMO and LUMO energies, as well as the electrical characteristics, have been calculated using DFT/B3LYP calculations with Gaussian 09 program. The optimized lowest energy configurations of the complexes are proven. The disc diffusion technique was used to test the pharmacological activities' antibacterial efficacy against diverse bacterial and fungus species. The MTT technique was used to assess the in vitro cytotoxicity of the ligands and their metal complexes on the Hep-G2 human liver carcinoma cell line and the MCF-7 human breast cancer cell line. All compounds displayed better activity compared to the free ligands. MnL2 complex showed predominant activity when compared to the other complexes with an IC50 value of 2.6 ± 0.11 μg/ml against Hep-G2, and against MCF-7 the IC50 value was 3.0 ± 0.2 μg/ml which is less than the standard drug cisplatin (4.0 μg/ml). UV–vis electronic spectrum and gel electrophoresis techniques have been used to investigate the compounds’ affinity to bind and cleavage CT-DNA. The interaction’s binding constants, or Kb, have been identified, and it was discovered that the new complexes' binding affinities are in the order of FeL1 > MnL2 > CrL2 > CrL1, and the binding mechanism has been suggested. To assess the kind of binding and binding affinity of the investigated drugs with human DNA, a molecular docking study was carried out (PDB:1bna). The acquired results supported the intercalation binding mechanism proposed in the experimental part and revealed that complexes may be inserted into the DNA molecule to stop DNA replication. According to ADMET data, the synthesized compounds have a high bioavailability profile and their physicochemical and pharmacological features remained within Lipinski's RO5 predicted limitations.
Quantification of the methodological error in kinematic evaluation of the DRUJ using dynamic CT
Authors: Oonk J. G. M. , Dobbe J. G. G. , Strackee S. D. , Strijkers G. J. , Streekstra G. J.
Published: February 2023

Distal radio-ulnar joint (DRUJ) motion analysis using dynamic CT is gaining popularity. Following scanning and segmentation, 3D bone models are registered to (4D-)CT target frames. Imaging errors like low signal-to-noise ratio (SNR), limited Z-coverage and motion artefacts influence registration, causing misinterpretation of joint motion. This necessitates quantification of the methodological error. A cadaver arm and dynamic phantom were subjected to multiple 4D-CT scans, while varying tube charge-time product and phantom angular velocity, to evaluate the effects of SNR and motion artefacts on registration accuracy and precision. 4D-CT Z-coverage is limited by the scanner. To quantify the effects of different Z-coverages on registration accuracy and precision, 4D-CT was simulated by acquiring multiple spiral 3D-CT scans of the cadaver arm. Z-coverage was varied by clipping the 3D bone models prior to registration. The radius position relative to the ulna was obtained from the segmentation image. Apparent relative displacement seen in the target images is caused by registration errors. Worst-case translations were 0.45, 0.08 and 1.1 mm for SNR-, Z-coverage- and motion-related errors respectively. Worst-case rotations were 0.41, 0.13 and 6.0 degrees. This study showed that quantification of the methodological error enables composition of accurate and precise DRUJ motion scanning protocols.
The effect of a brief, unplanned treatment delay on neovascular age-related macular degeneration patients: a retrospective cohort study
Authors: Zehden Jason Adam , Ghosh Arko , Soundararajan Srinath , Tsujimoto Tamy Harumy Moraes , Jiang Huijun , Lin Feng-Chang , Blahnik Tyler , Fleischman David , Zhang Alice Yang
Published: February 2023

Non-compliance to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy can result in increased disease activity in neovascular age-related macular degeneration (nAMD). Our study aims to determine effects of unplanned delay in anti-VEGF injection treatment for nAMD. This retrospective observational study included patients with delays in receiving intravitreal injections for nAMD treatment from March to May 2020 by at least 21 days. Baseline demographic and clinical characteristics, visual acuity (VA), central macular thickness (CMT) measured on optical coherence tomography (OCT), and duration of delayed treatment were analyzed for 3 time points, the pre-delay visit (v1) and post-delay visits (v2 and v3). Data were compared to age-matched controls treated for nAMD in 2019 without delay. Demographic characteristics were compared using two-sample t-tests for continuous variables and Pearson’s chi-square tests for categorical variables. For the two primary outcomes of interest, VA and CMT, means and standard deviations were reported for each combination of group and time. Each outcome was modeled using a linear mixed model with the group, time and group-time interaction as fixed effects. A total of 69 patients (99 eyes) in the treatment delay group and 44 patients (69 eyes) in the control group were identified. Statistically significant differences between control and delayed groups were detected for VA (difference in mean logMAR = 0.16; 95% CI 0.06, 0.27; p = 0.002) and CMT (difference in mean CMT = 29; 95% CI 12, 47; p = 0.001) at v2. No differences were detected for v1 and v3 time points for both outcomes. An unplanned delay in intravitreal injection treatment for nAMD resulted in an increase in CMT and worsening of VA compared to controls observed at v2. At v3, CMT and VA recovered to near v1 levels. This study demonstrates that a one-time, brief interruption in treatment for nAMD results in reversible, temporary worsening.
Design and fabrication of superhydrophobic cellulose nanocrystal films by combination of self-assembly and organocatalysis
Authors: Alimohammadzadeh Rana , Sanhueza Italo , Córdova Armando
Published: February 2023

Cellulose nanocrystals, which have unique properties of high aspect ratio, high surface area, high mechanical strength, and a liquid crystalline nature, constitute a renewable nanomaterial with great potential for several uses (e.g., composites, films and barriers). However, their intrinsic hydrophilicity results in materials that are moisture sensitive and exhibit poor water stability. This limits their use and competitiveness as a sustainable alternative against fossil-based materials/plastics in packaging, food storage, construction and materials application, which cause contamination in our oceans and environment. To make cellulose nanocrystal films superhydrophobic, toxic chemicals such as fluorocarbons are typically attached to their surfaces. Hence, there is a pressing need for environmentally friendly alternatives for their modification and acquiring this important surface property. Herein, we describe the novel creation of superhydrophobic, fluorocarbon-free and transparent cellulose nanocrystal films with functional groups by a bioinspired combination of self-assembly and organocatalytic surface modification at the nanoscale using food approved organic acid catalysts. The resulting film-surface is superhydrophobic (water contact angle > 150°) and has self-cleaning properties (the lotus effect). In addition, the superhydrophobic cellulose nanocrystal films have excellent water stability and significantly decreased oxygen permeability at high relative humidity with oxygen transmission rates better than those of commonly used plastics.
[18F]Tosyl fluoride as a versatile [18F]fluoride source for the preparation of 18F-labeled radiopharmaceuticals
Authors: Zhou Dong , Chu Wenhua , Xu Jinbin , Schwarz Sally , Katzenellenbogen John A.
Published: February 2023

Positron emission tomography (PET) is an in vivo imaging technology that utilizes positron-emitting radioisotope-labeled compounds as PET radiotracers that are commonly used in clinic and in various research areas, including oncology, cardiology, and neurology. Fluorine-18 is the most widely used PET-radionuclide and commonly produced by proton bombardment of 18O-enriched water in a cyclotron. The [18F]fluoride thus obtained generally requires processing by azeotropic drying in order to completely remove H2O before it can be used for nucleophilic radiofluorination. In general, the drying step is important in facilitating the radiofluorination reactions and the preparation of 18F-labeled PET radiotracers. In this communication, we have demonstrated the feasibility of using [18F]tosyl fluoride ([18F]TsF) as a versatile [18F]fluoride source for radiofluorination to bypass the azeotropic drying step, and we have developed a continuous flow solid-phase radiosynthesis strategy to generate [18F]TsF in a form that is excellent for radiofluorination. [18F]TsF shows high reactivity in radiofluorination and provides the features suitable for preparing PET radiotracers on a small scale and exploring novel radiolabeling technologies. Thus, using [18F]TsF as a [18F]fluoride source is a promising strategy that facilitates radiofluorination and provides a convenient and efficient solution for the preparation of 18F-labeled radiopharmaceuticals that is well matched to the emerging trends in PET imaging technologies.
Targeted delivery of paclitaxel drug using polymer-coated magnetic nanoparticles for fibrosarcoma therapy: in vitro and in vivo studies
Authors: Al-Obaidy Rusul , Haider Adawiya J. , Al-Musawi Sharafaldin , Arsad Norhana
Published: February 2023

Fibrosarcoma is a rare type of cancer that affects cells known as fibroblasts that are malignant, locally recurring, and spreading tumor in fibrous tissue. In this work, an iron plate immersed in an aqueous solution of double added deionized water, supplemented with potassium permanganate solution (KMnO4) was carried out by the pulsed laser ablation in liquid method (PLAIL). Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using different laser wavelengths (1064, 532, and 266 nm) at a fluence of 28 J/cm2with 100 shots of the iron plate to control the concentration, shape and size of the prepared high-stability SPIONs. The drug nanocarrier was synthesized by coating SPION with paclitaxel (PTX)-loaded chitosan (Cs) and polyethylene glycol (PEG). This nanosystem was functionalized by receptors that target folate (FA). The physiochemical characteristics of SPION@Cs-PTX-PEG-FA nanoparticles were evaluated and confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-Ray diffraction (XRD), atomic force microscopy (AFM), and dynamic light scattering (DLS) methods. Cell internalization, cytotoxicity assay (MTT), apoptosis induction, and gene expression of SPION@Cs-PTX-PEG-FA were estimated in fibrosarcoma cell lines, respectively. In vivo studies used BALB/c tumor-bearing mice. The results showed that SPION@Cs-PTX-PEG-FA exhibited suitable physical stability, spherical shape, desirable size, and charge. SPION@Cs-PTX-PEG-FA inhibited proliferation and induced apoptosis of cancer cells (P < 0.01). The results of the in vivo study showed that SPION@Cs-PTX-PEG-FA significantly decreased tumor size compared to free PTX and control samples (P < 0.05), leading to longer survival, significantly increased splenocyte proliferation and IFN-γ level, and significantly decreased the level of IL-4. All of these findings indicated the potential of SPION@Cs-PTX-PEG-FA as an antitumor therapeutic agent.