bluuebunny/crossref_metadata_2025 huggingface dataset:
Picosecond laser drilling grids in aluminium foil at 532 and 355 nm wavelengths
Authors: Tojinazarov Furkat , Sobirov Bekhzod , Ibragimova Elvira , Iskandarov Nurmukhammad , Nazarov Khamdam
Published: January 2024

Ultra-short laser drilling technique enables production of filters, membranes, microfluidic, photonic, and biomedical devices. Micro-hole grids were drilled in aluminum foil using a 28 picosecond Nd:YAG laser operated at wavelength of 532 and 355 nm with energy up to 18 and 12 mJ, respectively. Varying pulse energy and number, micro-holes obtained at 355 nm and 3.6–9 mJ had the appropriate mean diameter of 36–86 μm. However, the circularity changed in 0.5–0.94. For the 2nd harmonic the mean diameter varied 15–61 μm at 0.36–9 mJ with the circularity of 0.81–0.92. The morphology of the area surrounding micro-holes investigated by scanning electron microscopy exhibited distribution of droplets dominated size 0.9–10 μm, which is feasible for filtration of contaminated liquids. Local elemental composition of the area determined by energy dispersive spectroscopy discovered significant increase in the concentration of C and O, and also emergency of F, depending on laser fluence under vapor-dominated ablation mode, where nuclear reactions are excited in hot plasma.
Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis
Authors: Li Yuanyuan , Xu Chan , Zhao Feng , Liu Qinghong , Qiu Xiaojian , Li Min , Yang Yonghui , Yu Shentong , Tong Huajuan , Zhang Lifang , Chen Bing , Qu Lijuan , Yu Zihua
Published: January 2024

More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS.
A liftedℓ1 framework for sparse recovery
Authors: Rahimi Yaghoub , Kang Sung Ha , Lou Yifei
Published: January 2024

We introduce a lifted $\ell _1$ (LL1) regularization framework for the recovery of sparse signals. The proposed LL1 regularization is a generalization of several popular regularization methods in the field and is motivated by recent advancements in re-weighted $\ell _1$ approaches for sparse recovery. Through a comprehensive analysis of the relationships between existing methods, we identify two distinct types of lifting functions that guarantee equivalence to the $\ell _0$ minimization problem, which is a key objective in sparse signal recovery. To solve the LL1 regularization problem, we propose an algorithm based on the alternating direction method of multipliers and provide proof of convergence for the unconstrained formulation. Our experiments demonstrate the improved performance of the LL1 regularization compared with state-of-the-art methods, confirming the effectiveness of our proposed framework. In conclusion, the LL1 regularization presents a promising and flexible approach to sparse signal recovery and invites further research in this area.
Super-Networks Shaping International Agreements: Comparing the Climate Change and Nuclear Weapons Arenas
Authors: Schapper Andrea , Dee Megan
Published: January 2024

While research on transnational advocacy networks (TANs) is well established in international relations, knowledge gaps remain concerning TAN collaboration across policy fields. To address this gap, this article highlights how super-networks (networks above individual TANs) emerge across issue areas and explores the tactics utilized to achieve their objectives and shape international agreements. We develop an analytical framework that emphasizes the important interplay between political opportunity structures, mobilizing structures, and tactics in understanding how super-networks operate. We apply this framework via a comparative case study approach, analyzing the Inter-Constituency Alliance, whose advocacy brought about the inclusion of human rights language in the 2015 Paris Climate Agreement, and the International Campaign for the Abolition of Nuclear Weapons, whose activities based on humanitarian principles resulted in the 2017 Treaty on the Prohibition of Nuclear Weapons. Contributing new knowledge to TANs research, we identify that super-networks utilize multilevel advocacy activities that draw upon a package approach tactic. Via the package approach, super-networks synthesize multiple voices from different issue areas into one key message grounded in humanitarian framing, thereby enhancing their moral leverage and legitimacy, making it more difficult for states to neglect their concerns.
IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification
Authors: Zhao Yuanlin , Yang Ying , Yang Risheng , Sun Chao , Gao Xing , Gu Xiwen , Yuan Yuan , Nie Yating , Xu Shenhui , Han Ruili , Zhang Lijun , Li Jing , Hu Peizhen , Wang Yingmei , Chen Huangtao , Cao Xiangmei , Wu Jing , Wang Zhe , Gu Yu , Ye Jing
Published: January 2024

Isocitrate dehydrogenase (IDH) mutations frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) was a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH resulted in the accumulation of α-KG and promoted astrocyte maturation. However, IDH1 mutation significantly reduced α-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-KG and increasing glutaminolysis. Finally, we found that l-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.
AGREE: a new benchmark for the evaluation of distributional semantic models of ancient Greek
Authors: Stopponi Silvia , Peels-Matthey Saskia , Nissim Malvina
Published: January 2024

The last years have seen the application of Natural Language Processing, in particular, language models, to the study of the Semantics of ancient Greek, but only a little work has been done to create gold data for the evaluation of such models. In this contribution we introduce AGREE, the first benchmark for intrinsic evaluation of semantic models of ancient Greek created from expert judgements. In the absence of native speakers, eliciting expert judgements to create a gold standard is a way to leverage a competence that is the closest to that of natives. Moreover, this method allows for collecting data in a uniform way and giving precise instructions to participants. Human judgements about word relatedness were collected via two questionnaires: in the first, experts provided related lemmas to some proposed seeds, while in the second, they assigned relatedness judgements to pairs of lemmas. AGREE was built from a selection of the collected data.
Digitizing the USPTO patent backfile
Authors: Rowberry Simon
Published: January 2024

The digitization of the US Patent and Trademark Office’s (USPTO) backfile of six million patents undertaken between 1951 and 2001 was a five-decade struggle, featuring several media transitions from print and microfilm to CD-ROMs and, finally, the Web. This mass digitization project is on a similar scale to Google Books and the Internet Archive, but it is rarely discussed within critical digitization scholarship or for its significance as a tool for knowledge production. In this article, I focus on the USPTO’s patent document’s digital and physical material form and how the current paradigm of access and storage of the digital backfile emerged. Through this case study, I build upon Ian Milligan’s distinction between the ‘text’ and ‘platform’ layers of a digitization project to demonstrate how historical decisions regarding format and metadata continue to influence how users retrieve and interpret documents, such as patents, online.
Trajectory maps: molecular dynamics visualization and analysis
Authors: Kožić Matej , Bertoša Branimir
Published: January 2024

Molecular dynamics simulations generate trajectories that depict system's evolution in time and are analyzed visually and quantitatively. Commonly conducted analyses include RMSD, Rgyr, RMSF, and more. However, those methods are all limited by their strictly statistical nature. Here we present trajectory maps, a novel method to analyze and visualize protein simulation courses intuitively and conclusively. By plotting protein's backbone movements during the simulation as a heatmap, trajectory maps provide new tools to directly visualize protein behavior over time, compare multiple simulations, and complement established methods. A user-friendly Python application developed for this purpose is presented, alongside detailed documentation for easy usage and implementation. The method's validation is demonstrated on three case studies. Considering its benefits, trajectory maps are expected to adopt broad application in obtaining and communicating meaningful results of protein molecular dynamics simulations in many associated fields such as biochemistry, structural biology, pharmaceutical research etc.
Gastroesophageal reflux disease increases the risk of essential hypertension: results from the Nationwide Readmission Database and Mendelian randomization analysis
Authors: Yao Zhenyu , Zhao Chunhui , Zhang Yue , Fan Xiude , Zhao Dong , Gao Ling
Published: January 2024

Background

The link between gastroesophageal reflux disease (GERD) and essential hypertension (EH) and its causal nature remains controversial. Our study examined the connection between GERD and the risk of hypertension and assessed further whether this correlation has a causal relationship.

Methods

First, we utilized the National Readmission Database including 14 422 183 participants to conduct an observational study. Dividing the population into GERD and non-GERD groups, we investigated the correlation between GERD and EH using multivariate logistic regression. Next, bidirectional two-sample Mendelian randomization was adopted. The summary statistics for GERD were obtained from a published genome-wide association study including 78 707 cases and 288 734 controls. We collected summary statistics for hypertension containing 70 651 cases and 223 663 controls from the FinnGen consortium. We assessed causality primarily by the inverse-variance weighted method with validation by four other Mendelian randomization approaches as well as an array of sensitivity analyses.

Results

In the unadjusted model, GERD patients had a higher risk of EH than the non-GERD group, regardless of gender (odds ratio, 1.43; 95% confidence interval: 1.42–1.43; P < .001). Further adjusting for critical confounders did not change this association. For Mendelian randomization, we found that genetically predicted GERD was causally linked to an enhanced risk of EH in inverse-variance weighted technique (odds ratio, 1.52; 95% confidence interval: 1.39–1.67; P = 3.51 × 10−18); conversely, EH did not raise the risk of GERD causally.

Conclusions

GERD is a causal risk factor for EH. Further research is required to probe the mechanism underlying this causal connection.
Amelioration of nonylphenol-induced anxiety/depression-like behaviors in male rats using green tea and Zn-Se tea interventions
Authors: Yu Jie , Li Shengnan , Li Mizhuan , Zhang Yujie , Tong Dayan , Xu Yuzhu , Wang Chengxing , Xu Jie
Published: January 2024

Objective

This study aimed to investigate the effects of exposure to nonylphenol (NP) on anxiety/depression-like behaviors in rats and alleviation of those effects via green tea and zinc selenium (Zn-Se) tea interventions.

Material and Methods

Totally, 40 male specific-pathogen free (SPF) Sprague-Dawley (SD) male rats were randomly divided into four groups (n = 10 rats per group): control group (5 ml/kg corn oil), NP group (40 mg/kg NP), NP + GT group (40 mg/kg NP + 1 g/kg/day green tea), and NP + Zn-Se tea group (40 mg/kg NP + 1 g/kg/day ZST). All dose-based groups received oral gavage of either corn oil or drugs over a 6-month period: NP at a dosage of 40 mg/kg/day was administered to rats for the initial 3 months, followed by a combination of NP with green tea and NP with Zn-Se tea for the subsequent 3 months.

Results

Tea intervention resulted in weight loss in rats. The hippocampal tissue NP level in the tea group was slightly lower than that in the NP group. Following tea intervention, compared with the NP group, the residence time in the light-dark box test was shortened PGT = 0.048, P < 0.001), and the number of entries into the closed arm in the elevated plus maze test in the tea-treated group was significantly reduced. In addition, the immobility time in the central square in the open field test decreased. The sucrose preference index score in the sucrose preference test increased, and the immobility time in the forced swimming test was reduced (PGT = 0.049, PZST < 0.001). The effects of Zn-S e tea were superior to green tea. The damage to the hippocampal tissues in the group treated with tea was less than that in the NP group. The cellular arrangement was tighter with degeneration, deepstaining, and pyknotic nerve cells were visible. The nuclei in the NP group were atrophied, and the cells were sparsely arranged. Compared with the control group, serum brain-derived neurotrophic factor (BDNF) level was lower in the NP group. The serum corticosterone level in the NP group was elevated. Compared with the NP group, serum corticosterone level was reduced in the NP + Zn-Se tea group.

Conclusion

Chronic NP exposure induced anxiety/depression-like behaviors in rats. Green tea effectively reduced the damage to the hippocampus and prefrontal cortex induced by NP. The effects of Zn-Se tea were slightly more noticeable than those of conventional green tea.

Highlights
Clinical characteristics, management, outcome, and cost of stings and bites in patients admitted to a tertiary care teaching hospital
Authors: Patil Amar , Chagi Ayyappa , Poojari Pooja Gopal , Rashid Muhammed , Shivashankar K N , Thunga Girish , Nair Sreedharan
Published: January 2024

Aim: The objective of this study was to identify the clinical epidemiology and medical cost of stings and bites at a tertiary care hospital in South India. Subjects and Methods: The medical records of hospitalized patients in the tertiary care unit between 2016 and 2020 with the history of either being stung or bitten by insects were reviewed retrospectively. The patient’s demographic details, clinical symptoms, treatment chart, expenditure details, and outcomes were collected in pre-structured case report forms. The data were analyzed using SPSS Version 20.0. Results: A total of 66 patients were enrolled, with a mean age of 45.86 ± 23.37 years. The majority of the incidence was due to bee stings (61%). Anaphylaxis was reported in 38% of the cases, followed by acute kidney injury (10.6%). The cost of hospitalization was found to be higher for spider bites at 896.73 ± 1414.95 USD, followed by wasp stings at 989.81 ± 1185.57 USD. In patients with complications, the average cost of stings and bites was 438.81 ± 685.81 USD. Most of the patients received antibiotics (75.8%), followed by steroids (62.1%). Conclusion: Stings and bite injuries may appear harmless initially, but they can cause severe complications in unidentified cases and for those who do not seek urgent medical attention. Antibiotics and corticosteroids can help in the management of envenomation.
Club cell‐specific telomere protection protein 1 (TPP1) protects against tobacco smoke‐induced lung inflammation, xenobiotic metabolic dysregulation, and injurious responses
Authors: Muthumalage Thivanka , Goracci Chiara , Rahman Irfan
Published: January 2024

Inhaling xenobiotics, such as tobacco smoke is a major risk factor for pulmonary diseases, e.g., COPD/emphysema, interstitial lung disease, and pre‐invasive diseases. Shelterin complex or telosome provides telomeric end protection during replication. Telomere protection protein 1 (TPP1) is one of the main six subunits of the shelterin complex supporting the telomere stability and genomic integrity. Dysfunctional telomeres and shelterin complex are associated as a disease mechanism of tobacco smoke‐induced pulmonary damage and disease processes. The airway epithelium is critical to maintaining respiratory homeostasis and is implicated in lung diseases. Club cells (also known as clara cells) play an essential role in the immune response, surfactant production, and metabolism. Disrupted shelterin complex may lead to dysregulated cellular function, DNA damage, and disease progression. However, it is unknown if the conditional removal of TPP1 from Club cells can induce lung disease pathogenesis caused by tobacco smoke exposure. In this study, conditional knockout of Club‐cell specific TPP1 demonstrated the instability of other shelterin protein subunits, such as TRF1, dysregulation of cell cycle checkpoint proteins, p53 and downstream targets, and dysregulation of telomeric genes. This was associated with age‐dependent senescence‐associated genes, increased DNA damage, and upregulated RANTES/IL13/IL33 mediated lung inflammation and injury network by cigarette smoke (CS). These phenomena are also associated with alterations in cytochrome P450 and glutathione transferases, upregulated molecular pathways promoting lung lesions, bronchial neoplasms, and adenocarcinomas. These findings suggest a pivotal role of TPP1 in maintaining lung homeostasis and injurious responses in response to CS. Thus, these data TPP1 may have therapeutic value in alleviating telomere‐related chronic lung diseases.
Fully Automated Analysis of the Anatomic and Mechanical Axes From Pediatric Standing Lower Limb Radiographs Using Convolutional Neural Networks
Authors: Murad Yousif , Chhina Harpreet , Cooper Anthony
Published: January 2024

Background:

Lower limb alignment is the quantification of a set of parameters that are commonly measured radiographically to test for and track a wide range of skeletal pathologies. Determining limb alignment is a commonly performed yet laborious task in the pediatric orthopaedic setting and is therefore an interesting goal for automation.

Methods:

We employ a machine learning approach using convolutional neural networks (CNNs) to segment pediatric weight-bearing lower limb radiographs. The results are then used with custom Matlab code to extract anatomic landmarks and to determine lower limb alignment parameters.

Results:

Measurements obtained from the automated workflow proposed here were compared with manual measurements performed by orthopaedic surgery fellows. Mechanical axis deviation was determined within a mean of 2.02 mm. Lateral distal femoral angle and medial proximal tibial angle were determined with a mean deviation of 1.73 and 2.90 degrees, respectively. The calculation speed for the full set of mechanical and anatomic axis parameters was found to be ~2 seconds per radiograph.

Conclusions:

The CNN-based approach proposed in this work was shown to produce results comparable to orthopaedic surgery fellows at fast calculation speed. Although further work is needed to validate these results against radiographs and measurements from other centers, we see this as a promising start and a functional path that can be employed in further research.

Clinical Relevance:

CNNs are a promising approach to automating commonly performed, repetitive tasks, especially those pertaining to image processing. The time savings are particularly important in clinical research applications where large sets of radiographs are routinely available and require analysis. With further development of these algorithms, we anticipate significantly improved agreement with expert-measured results and the calculation speed.
Masculinizing Chest Reconstruction in Adolescents and Young Adults
Authors: Diaddigo Sarah E. , Asadourian Paul A. , Lavalley Myles N. , Marano Andrew A. , Rohde Christine H.
Published: January 2024

Background

Masculinizing chest reconstruction (MCR) has been shown to improve quality of life and gender dysphoria in transmasculine adult patients. As nationwide access to gender-affirming care expands, more adolescents are seeking MCR. However, there is a paucity of literature examining patient characteristics, safety, and disparities among this population.

Methods

Cases of MCR were selected from the pediatric and adult American College of Surgeons and National Surgical Quality Improvement Program. Adolescent (18 years and older) and young adult (aged 19–25 years) transgender patients were analyzed for differences in demographics, comorbidities, surgical characteristics, and postoperative complications.

Results

A total of 1287 cases were identified, with an adolescent cohort of 189 patients. The proportion of White patients to other races was greater among adolescents than young adults (91.2% vs 82.4%, P = 0.007). Of adolescents and young adults, 6.0% and 11.1% identified as Hispanic/Latino, respectively (P = 0.059). Rates of all-cause postoperative complications were similar between adolescents (4.2%) and young adults (4.1%). Multivariate binary logistic regression showed that Black or African American patients experienced more all-cause postoperative complications than other races after controlling for American Society of Anesthesiologists classification, age group, and body mass index (odds ratio, 2.8; 95% confidence interval, 1.3–5.9; P = 0.008).

Conclusions

Masculinizing chest reconstruction is equally safe for transmasculine adolescent and young adult patients. However, our data point to racial disparities in access to care and postoperative outcomes. An intersectional approach is needed to better understand the unique health care needs and barriers to care of minority transgender youth.
A Guide to Perforator Flap Selection for Buttock Pressure Sore Reconstruction
Authors: Zhou Jian , Mo Xiaojin , Xiao Shune , Chang Shusen , Chen Wei , Wei Zairong
Published: January 2024

Perforator flaps have been increasingly used to repair stage IV buttock pressure ulcers. However, no one has proposed an approach for stage IV buttock pressure ulcers repairing based on the subregion of buttock pressure ulcers. This study aims to evaluate the effect of perforator flaps in the repair of stage IV buttock pressure ulcers, and flap selection was based on the location of the pressure ulcers. Over the past 5 years, we evaluated 65 cases of stage IV buttock pressure ulcers repaired using perforator flaps. Flap selection was based on the subregion of each buttock pressure ulcer, following our approach. A total of 87 perforator flaps were used for 65 cases, including 42 superior gluteal artery perforator flaps, 19 fourth lumbar artery perforator flaps, and 26 descending inferior gluteal artery perforator flaps. All patients showed satisfactory reconstruction. The authors' approach can support surgeons in selecting the appropriate flaps to repair stage IV buttock pressure ulcers and achieve excellent reconstructive outcomes. This method makes the selection of flaps for pressure ulcer repair systematic, simple, and highly feasible and thus is worthy of promotion.
Comparing Outcomes of Traditional Lip Repair Versus Early Cleft Lip Repair on a National Scale
Authors: Stanton Eloise , Roohani Idean , Shakoori Pasha , Fahradyan Artur , Urata Mark M. , Magee William P. , Hammoudeh Jeffrey A.
Published: January 2024

Background

Cleft lip (CL) is one of the most common congenital anomalies and has traditionally been repaired surgically when the patient is between 3 and 6 months of age. However, recent single-institutional studies have demonstrated the efficacy and safety of early CL repairs (ECLRs) during the neonatal period. This study seeks to evaluate the outcomes of ECLR (repair <1 month) versus traditional lip repair (TLR) by comparing outcomes on a national scale.

Methods

The American College of Surgeons National Surgical Quality Improvement Program Pediatric Date File was used to query patients who underwent CL repairs between 2012 and 2022. The main outcome measures were anesthesia times and perioperative complications. The main predictive variable was operative group (ECLR vs TLR). Patients were considered to be in the ECLR cohort if they were younger than 30 days after birth at the time of cleft repair. Student t test and χ
2 analyses were used to evaluate categorical and continuous differences, respectively. Multiple logistic regression was performed to model the association of ECLR versus TLR with death within 30 days, overall complication rates, dehiscence rates, readmission within 30 days, and reoperation rates while controlling for various covariates.

Results

Multiple linear regression determined that the ECLR cohort had significantly shorter operative times when controlling for operative complications, sex, cardiac risk factors, and American Society of Anesthesiologists class (coefficient = −34.4; confidence interval, −47.8 to −20.9; P < 0.001). Similarly, multiple linear regression demonstrated ECLR patients to have significantly shorter time of exposure to anesthesia (coefficient = −35.0; 95% confidence interval, −50.3 to −19.7; P < 0.001). Multiple logistic regression demonstrated that ECLR was not significantly associated with an increased likelihood of any postoperative complication when controlling for sex, cardiac risk factors, and American Society of Anesthesiologists class (P = 0.26)

Conclusions

The findings of this study provide nationwide evidence that ECLR does not lead to an increased risk of adverse outcomes or complications. In addition, ECLR patients have shorter surgeries and shorter exposure to anesthesia compared with TLR. The results provide further evidence that ECLR can be done safely where earlier intervention may result in better feeding/weight gain and subsequently improve cleft care. However, longer-term studies are warranted to further elucidate the effects of this protocol.
Impact of Neoadjuvant Therapy for Pancreatic Cancer: Transatlantic Trend and Postoperative Outcomes Analysis
Authors: Davis Catherine H , Augustinus Simone , de Graaf Nine , Wellner Ulrich F , Johansen Karin , Andersson Bodil , Beane Joal D , Björnsson Bergthor , Busch Olivier R , Gleeson Elizabeth M , van Santvoort Hjalmar C , Tingstedt Bobby , Williamsson Caroline , Keck Tobias , Besselink Marc G , Koerkamp Bas Groot , Pitt Henry A ,   for the Global Audits on Pancreatic Surgery Group (GAPASURG)
Published: January 2024

BACKGROUND:

The introduction of modern chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). A recent North American study demonstrated increased use of NAT and improved operative outcomes in patients with PDAC. The aims of this study were to compare the use of NAT and short-term outcomes in patients with PDAC undergoing pancreatoduodenectomy (PD) among registries from the US and Canada, Germany, the Netherlands, and Sweden.

STUDY DESIGN:

Databases from 2 multicenter (voluntary) and 2 nationwide (mandatory) registries were queried from 2018 to 2020. Patients undergoing PD for PDAC were compared based on the use of upfront surgery vs NAT. Adoption of NAT was measured in each country over time. Thirty-day outcomes, including the composite measure (ideal outcomes), were compared by multivariable analyses. Sensitivity analyses of patients undergoing vascular resection were performed.

RESULTS:

Overall, 11,402 patients underwent PD for PDAC with 33.7% of patients receiving NAT. The use of NAT increased steadily from 28.3% in 2018 to 38.5% in 2020 (p < 0.0001). However, use of NAT varied widely by country: the US (46.8%), the Netherlands (44.9%), Sweden (11.0%), and Germany (7.8%). On multivariable analysis, NAT was significantly (p < 0.01) associated with reduced rates of serious morbidity, clinically relevant pancreatic fistulae, reoperations, and increased ideal outcomes. These associations remained on sensitivity analysis of patients undergoing vascular resection.

CONCLUSIONS:

NAT before PD for pancreatic cancer varied widely among 4 Western audits yet increased by 26% during 3 years. NAT was associated with improved short-term outcomes.
Calculation of asymptotic charges at the critical sets of null infinity
Authors: Mohamed Mariem Magdy Ali
Published: January 2024

The asymptotic structure of null and spatial infinities of asymptotically flat spacetimes plays an essential role in discussing gravitational radiation, gravitational memory effect, and conserved quantities in General Relativity (GR). Bondi, Metzner and Sachs (BMS) established that the asymptotic symmetry group for asymptotically simple spacetimes is the infinite-dimensional BMS group. Given that null infinity is divided into two sets: past null infinity

I

−

and future null infinity

I

+

, one can identify two independent symmetry groups:

BMS

−

at

I

−

and

BMS

+

at

I

+

. Associated with these symmetries are the so-called BMS charges. A recent conjecture by Strominger suggests that the generators of

BMS

−

and

BMS

+

and their associated charges are related via an antipodal reflection map near spatial infinity. To verify this matching, an analysis of the gravitational field near spatial infinity is required. This task is complicated due to the singular nature of spatial infinity for spacetimes with non-vanishing ADM mass. Different frameworks have been introduced in the literature to address this singularity, e.g. Friedrich’s cylinder, Ashtekar-Hansen’s hyperboloid and Ashtekar-Romano’s asymptote at spatial infinity. This paper reviews the role of Friedrich’s formulation of spatial infinity in the investigation of the matching of the spin-2 charges on Minkowski spacetime and in the full GR setting.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Conformal geodesics and the evolution of spacetimes with positive Cosmological constant
Authors: Minucci Marica
Published: January 2024

This article provides a discussion on the construction of conformal Gaussian gauge systems to study the evolution of solutions to the Einstein field equations with positive Cosmological constant. This is done by means of a gauge based on the properties of conformal geodesics. The use of this gauge, combined with the extended conformal Einstein field equations, yields evolution equations in the form of a symmetric hyperbolic system for which standard Cauchy stability results can be employed. This strategy is used to study the global properties of de Sitter-like spacetimes with constant negative scalar curvature. It is then adapted to study the evolution of the Schwarzschild–de Sitter spacetime in the static region near the conformal boundary. This review is based on Minucci
et al
. 2021
Class. Quantum Grav
.
38
, 145026. (
doi:10.1088/1361-6382/ac0356
) and Minucci
et al
. 2023
Class. Quantum Grav
.
40
, 145005. (
doi:10.1088/1361-6382/acdb3f
).

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Asymptotic symmetries of projectively compact order one Einstein manifolds
Authors: Borthwick Jack , Herfray Yannick
Published: January 2024

We show that the boundary of a projectively compact Einstein manifold of dimension

n

can be extended by a line bundle naturally constructed from the projective compactification. This extended boundary is such that its automorphisms can be identified with asymptotic symmetries of the compactification. The construction is motivated by the investigation of a new curved orbit decomposition for a

n
+
1

dimensional manifold which we prove results in a line bundle over projectively compact order one Einstein manifolds.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Cosmologies with positive λ: hierarchies of future behaviour
Authors: Friedrich Helmut
Published: January 2024

Smooth Cauchy data on

S

3

for the Einstein-

λ

-vacuum field equations with cosmological constant

λ
>
0

that are sufficiently close to de Sitter data develop into a solution that admits a smooth conformal boundary

J

+

in its future. The
conformal Einstein equations
determine a smooth conformal extension across

J

+

that defines on ‘the other side’ again a

λ

-vacuum solution. In this article, we discuss to what extent these properties generalize to the

future asymptotic behaviour of solutions to the Einstein-

λ

equations with matter

. We study Friedmann–Lemaitre–Robertson–Walker (FLRW) solutions and the Einstein-

λ

equations coupled to conformally covariant matter transport equations, to conformally privileged matter equations, and to conformally non-covariant matter equations. We present recent results on the Einstein-

λ

-perfect-fluid equations with a nonlinear
asymptotic dust
or
asymptotic radiation
equation of state.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Polyhomogeneous spin-0 fields in Minkowski space–time
Authors: Gasperín Edgar
Published: January 2024

The asymptotic behaviour of massless spin-0 fields close to spatial and null infinity in Minkowski space–time is studied by means of Friedrich’s cylinder at spatial infinity. The results are applied to a system of equations called the good–bad–ugly which serves as a model for the Einstein field equations in generalized harmonic gauge. The relation between the logarithmic terms (polyhomogeneity) appearing in the solution obtained using conformal methods and those obtained by means of a heuristic method based on Hörmander’s asymptotic system is discussed. This review article is based on Duarteet al.(Duarteet al.2023Class. Quantum Gravity40, 055002. (doi:10.1088/1361-6382/acb47e)); Gasperín & Pinto (Gasperín & Pinto 2023 Spin-0 fields and the NP-constants close to spatial infinity in Minkowski spacetime.J. Math. Phys.64, 082502. (doi:10.1063/5.0158746)).

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Characterizations of Kerr-de Sitter in arbitrary dimension from null infinity
Authors: Mars M. , Peón-Nieto C.
Published: January 2024

The Kerr and Kerr-de Sitter metrics share remarkable local geometric properties in four dimensions. Gibbonset al.found a generalization of the Kerr-de Sitter metric to higher dimensions, to which the local characterization above cannot be applied. One viable approach to characterize this family is to understand the behaviour of these metrics at future null infinity. We review Friedrich’s and Fefferman-Graham formalisms to discuss the asymptotic initial value problem of (Λ>0)-vacuum spacetimes in arbitrary dimensions and study their properties: geometric identification and conformal equivalence of data, Killing initial data and conformal equivalence of boundary conformal Killing vectors (CKV). These results are used to review a recent characterization of Kerr-de Sitter in terms of its asymptotic data, namely conformal flatness atItogether with a canonical TT tensor constructed from specific CKV atI. Allowing for arbitrary CKV defines the (larger) Kerr-de Sitter-like class. All these metrics can be obtained explicitly as limits or analytic extensions of Kerr-de Sitter. The Kerr-de Sitter-like class is also characterized by the property of being Kerr-Schild and fulfilling a certain falloff condition. In addition, in five dimensions, this class corresponds to all algebraically special metrics with non-degenerate optical matrix.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Computational and neural evidence for altered fast and slow learning from losses in gambling disorder
Authors: Iigaya Kiyohito , Larsen Tobias , Fong Timothy , O’Doherty John P.
Published: January 2024

Learning occurs across multiple timescales, with fast learning crucial for adapting to sudden environmental changes, and slow learning beneficial for extracting robust knowledge from multiple events. Here we asked if miscalibrated fast vs slow learning can lead to maladaptive decision-making in individuals with gambling disorder. Participants with problem gambling and a recreational gambling control group without any symptoms associated with problem gambling performed a probabilistic decision-making task involving reward-learning and loss-avoidance while being scanned with fMRI. Problem gamblers showed impaired reversal learning from losses compared to the control group, with excessive dependence on slow timescales and reduced reliance on fast timescales. fMRI data implicated the putamen, an area associated with habit, and medial prefrontal cortex (PFC) in slow loss-value encoding, with significantly more robust encoding in medial PFC in problem gamblers compared to controls. Problem gamblers also exhibited stronger loss prediction error encoding in the insular cortex. These findings suggest that individuals with problem gambling have an impaired ability to adjust their predictions following losses, manifested by a stronger influence of slow value learning. This impairment could contribute to the behavioral inflexibility of problem gamblers, particularly the persistence in gambling behavior typically observed in those individuals after incurring loss outcomes.
Integration of genetic and epigenetic data pinpoints autoimmune specific remodelling of enhancer landscape in CD4+ T cells
Authors: Daga Neha , Servaas Nila H. , Kisand Kai , Moonen Dewi , Arnold Christian , Reyes-Palomares Armando , Kaleviste Epp , Kingo Külli , Kuuse Reet , Ulst Katrin , Steinmetz Lars , Peterson Pärt , Nakic Nikolina , Zaugg Judith B.
Published: January 2024

CD4+ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used transcriptomic and epigenomic data from CD4+ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves’ disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harbouring AD-associated single-nucleotide polymorphisms, which we also validated using CRISPRi in primary CD4+ T cells. Our results suggest that alterations in the regulatory landscapes of CD4+ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.
Impact of occluder device configurations in in-silico left atrial hemodynamics for the analysis of device-related thrombus
Authors: Albors Carlos , Mill Jordi , Olivares Andy L. , Iriart Xavier , Cochet Hubert , Camara Oscar
Published: January 2024

Left atrial appendage occlusion devices (LAAO) are a feasible alternative for non-valvular atrial fibrillation (AF) patients at high risk of thromboembolic stroke and contraindication to antithrombotic therapies. However, optimal LAAO device configurations (i.e., size, type, location) remain unstandardized due to the large anatomical variability of the left atrial appendage (LAA) morphology, leading to a 4-6% incidence of device-related thrombus (DRT). In-silico simulations have the potential to assess DRT risk and identify the key factors, such as suboptimal device positioning. This work presents fluid simulation results computed on 20 patient-specific left atrial geometries, analysing different commercially available LAAO occluders, including plug-type and pacifier-type devices. In addition, we explored two distinct device positions: 1) the real post-LAAO intervention configuration derived from follow-up imaging; and 2) one covering the pulmonary ridge if it was not achieved during the implantation (13 out of 20). In total, 33 different configurations were analysed. In-silico indices indicating high risk of DRT (e.g., low blood flow velocities and flow complexity around the device) were combined with particle deposition analysis based on a discrete phase model. The obtained results revealed that covering the pulmonary ridge with the LAAO device may be one of the key factors to prevent DRT. Moreover, disk-based devices exhibited enhanced adaptability to various LAA morphologies and, generally, demonstrated a lower risk of abnormal events after LAAO implantation.
Discriminative histone imputation using chromatin accessibility
Authors: Wen Wen , Zhong Jiaxin , Zhang Zhaoxi , Jia Lijuan , Chu Tinyi , Wang Nating , Danko Charles G. , Wang Zhong
Published: January 2024

Histone modifications (HMs) play a pivot role in various biological processes, including transcription, replication and DNA repair, significantly impacting chromatin structure. These modifications underpin the molecular mechanisms of cell-specific gene expression and complex diseases. However, annotating HMs across different cell types solely using experimental approaches is impractical due to cost and time constraints. Herein, we present dHICA (discriminative histone imputation using chromatin accessibility), a novel deep learning framework that integrates DNA sequences and chromatin accessibility data to predict multiple HM tracks. Employing the Transformer architecture alongside dilated convolutions, dHICA boasts an extensive receptive field and captures more cell-type-specific information. dHICA not only outperforms state-of-the-art baselines but also achieves superior performance in cell-specific loci and gene elements, aligning with biological expectations. Furthermore, dHICA’s imputations hold significant potential for downstream applications, including chromatin state segmentation and elucidating the functional implications of SNPs. In conclusion, dHICA serves as an invaluable tool for advancing the understanding of chromatin dynamics, offering enhanced predictive capabilities and interpretability.
Tviblindi algorithm identifies branching developmental trajectories of human B cell development
Authors: Bakardjieva Marina , Stuchlý Jan , Pelák Ondřej , Wentink Marjolein , Glier Hana , Novák David , Stančíková Jitka , Kužílková Daniela , Janowska Iga , Rizzi Marta , Burg Mirjam van der , Kalina Tomáš
Published: January 2024

Detailed knowledge of the human B-cell development is crucial for proper interpretation of inborn errors of immunity and for malignant diseases. It is of interest to understand the kinetics of protein expression changes during the B cell development, but also to properly interpret the major and possibly alternative developmental trajectories. We have investigated human bone marrow and peripheral blood samples from healthy individuals with the aim to describe all B-cell developmental trajectories across the two tissues. We validated a 30-parameter mass cytometry panel and demonstrated the utility of “vaevictis” visualization of B-cell developmental stages. We used our recently developed trajectory inference tool “tviblindi” to exhaustively describe all trajectories leading to all developmental ends discovered in the data. Focusing on Natural Effector B cells, we demonstrated the dynamics of expression of nuclear factors (PAX-5, TdT, Ki-67, Bcl-2), cytokine and chemokine receptors (CD127, CXCR4, CXCR5) in relation to the canonical B-cell developmental stage markers (CD34, CD10, sIgM, IgD, CD20, CD27). Lastly, we performed analysis of the expression changes related to developmental branching points (Natural Effector versus Switched Memory B cells, marked by up-regulation of CD73).

In conclusion, we developed, validated and presented a comprehensive set of tools for investigation of B-cell development.
TheArabidopsis thalianaTRAPPIII subunit AtTRAPPC8/AtTRS85 is involved in ER functioning and autophagy
Authors: Hoffman-Sommer Marta , Piłka Natalia , Anielska-Mazur Anna , Nowakowska Julita , Dagdas Yasin , Swiezewska Ewa
Published: January 2024

TRAPP (transport protein particle) tethering complexes are known for their function as Rab-GTPase exchange factors (GEFs). Two versions of the complex are considered functionally separate: TRAPPII, an activator of GTPases of the Rab11 family (RabA in plants) which functions in post-Golgi sorting, and TRAPPIII, activating the Rab1 family (RabD in plants) which regulates ER-to-Golgi trafficking and autophagy. InArabidopsis thaliana, the TRAPPIII complex has been identified and its subunit composition established, but little is known about its functions. Here, we found that binary subunit interactions of the plant TRAPPIII complex are analogous to those of metazoan TRAPPIII, with the two large subunits TRAPPC8 and -C11 linking the TRAPP core and the small C12-C13 dimer. To gain insight into the functions of TRAPPIII in plants, we characterized twoA. thaliana trappc8mutants. The mutants display abnormalities in plant morphology, in particular in flower and seed development. They also have autophagic defects, constitutive ER stress response, and elevated levels of the ER lipid dolichol – an indispensable cofactor of protein glycosylation. These results show that plant TRAPPC8 is involved in multiple trafficking steps in the cells and they suggest a novel link between ER membrane turnover and dolichol levels.

HIGHLIGHT

Arabidopsis thalianaTRAPPC8 is necessary for correct functioning of the ER, in particular for its lipid homeostasis. Dysruption ofTRAPPC8leads to defects in secretion, autophagosome formation, and plant development.