bluuebunny/crossref_metadata_2025 huggingface dataset:
5-Methyl-cytosine stabilizes DNA but hinders DNA hybridization revealed by magnetic tweezers and simulations
Authors: Zhao Xiao-Cong , Dong Hai-Long , Li Xiao-Lu , Yang Hong-Yu , Chen Xue-Feng , Dai Liang , Wu Wen-Qiang , Tan Zhi-Jie , Zhang Xing-Hua
Published: December 2022

5-Methyl-cytosine (5mC) is one of the most important DNA modifications and plays versatile biological roles. It is well known that 5mC stabilizes DNA duplexes. However, it remains unclear how 5mC affects the kinetics of DNA melting and hybridization. Here, we studied the kinetics of unzipping and rezipping using a 502-bp DNA hairpin by single-molecule magnetic tweezers. Under constant loading rates, 5mC increases the unzipping force but counterintuitively decreases the rezipping force at various salt and temperature conditions. Under constant forces, the non-methylated DNA hops between metastable states during unzipping and rezipping, which implies low energy barriers. Surprisingly, the 5mC DNA can’t rezip after fully unzipping unless much lower forces are applied, where it rezips stochastically in a one-step manner, which implies 5mC kinetically hinders DNA hybridization and high energy barriers in DNA hybridization. All-atom molecular dynamics simulations reveal that the 5mC kinetically hinders DNA hybridization due to steric effects rather than electrostatic effects caused by the additional methyl groups of cytosines. Considering the possible high speed of DNA unzipping and zipping during replication and transcription, our findings provide new insights into the biological roles of 5mC.
Hierarchical DNA branch assembly-encoded fluorescent nanoladders for single-cell transcripts imaging
Authors: Cao Xiaowen , Chen Feng , Xue Jing , Zhao Yue , Bai Min , Zhao Yongxi
Published: December 2022

Spatial visualization of single-cell transcripts is limited by signal specificity and multiplexing. Here, we report hierarchical DNA branch assembly-encoded fluorescent nanoladders, which achieve denoised and highly multiplexed signal amplification for single-molecule transcript imaging. This method first offers independent RNA-primed rolling circle amplification without nonspecific amplification based on circular DNAzyme. It then executes programmable DNA branch assembly on these amplicons to encode virtual signals for visualizing numbers of targets by FISH. In theory, more virtual signals can be encoded via the increase of detection spectral channels and repeats of the same sequences on barcode. Our method almost eliminates nonspecific amplification in fixed cells (reducing nonspecific spots of single cells from 16 to nearly zero), and achieves simultaneous quantitation of nine transcripts by using only two detection spectral channels. We demonstrate accurate RNA profiling in different cancer cells, and reveal diverse localization patterns for spatial regulation of transcripts.
Structural transitions during the cooperative assembly of baculovirus single-stranded DNA-binding protein on ssDNA
Authors: Yin Jiayi , Fu Yan , Rao Guibo , Li Zhiqiang , Tian Kexing , Chong Tingting , Kuang Kai , Wang Manli , Hu Zhihong , Cao Sheng
Published: December 2022

Single-stranded DNA-binding proteins (SSBs) interact with single-stranded DNA (ssDNA) to form filamentous structures with various degrees of cooperativity, as a result of intermolecular interactions between neighboring SSB subunits on ssDNA. However, it is still challenging to perform structural studies on SSB–ssDNA filaments at high resolution using the most studied SSB models, largely due to the intrinsic flexibility of these nucleoprotein complexes. In this study, HaLEF-3, an SSB protein from Helicoverpa armigera nucleopolyhedrovirus, was used for in vitro assembly of SSB–ssDNA filaments, which were structurally studied at atomic resolution using cryo-electron microscopy. Combined with the crystal structure of ssDNA-free HaLEF-3 octamers, our results revealed that the three-dimensional rearrangement of HaLEF-3 induced by an internal hinge-bending movement is essential for the formation of helical SSB–ssDNA complexes, while the contacting interface between adjacent HaLEF-3 subunits remains basically intact. We proposed a local cooperative SSB–ssDNA binding model, in which, triggered by exposure to oligonucleotides, HaLEF-3 molecules undergo ring-to-helix transition to initiate continuous SSB–SSB interactions along ssDNA. Unique structural features revealed by the assembly of HaLEF-3 on ssDNA suggest that HaLEF-3 may represent a new class of SSB.
Salmonella antibacterial Rhs polymorphic toxin inhibits translation through ADP-ribosylation of EF-Tu P-loop
Authors: Jurėnas Dukas , Rey Martial , Byrne Deborah , Chamot-Rooke Julia , Terradot Laurent , Cascales Eric
Published: December 2022

Rearrangement hot spot (Rhs) proteins are members of the broad family of polymorphic toxins. Polymorphic toxins are modular proteins composed of an N-terminal region that specifies their mode of secretion into the medium or into the target cell, a central delivery module, and a C-terminal domain that has toxic activity. Here, we structurally and functionally characterize the C-terminal toxic domain of the antibacterial Rhsmain protein, TreTu, which is delivered by the type VI secretion system of Salmonella enterica Typhimurium. We show that this domain adopts an ADP-ribosyltransferase fold and inhibits protein synthesis by transferring an ADP-ribose group from NAD+ to the elongation factor Tu (EF-Tu). This modification is specifically placed on the side chain of the conserved D21 residue located on the P-loop of the EF-Tu G-domain. Finally, we demonstrate that the TriTu immunity protein neutralizes TreTu activity by acting like a lid that closes the catalytic site and traps the NAD+.
Science battles viral diseases: a roundtable discussion with leading experts on COVID-19, hepatitis and AIDS
Authors: Zhu He
Published: December 2022

The Science Popularization and Education Committee of the Academic Divisions of the Chinese Academy of Sciences (CASAD) invited the CAS Institutes of Science and Development (CASISD) and National Science Review (NSR) to organize a roundtable discussion of viral infectious diseases on 11 October 2022. During this extensive discussion, experts introduced the history and background of virus and viral infectious diseases. They explained the function of human's immune system. In addition, they answered frequently asked questions by the public such as the efficacy and safety of COVID vaccines, the cost of disease treatment and the threat of latest monkey pox outbreak.

Chen Dong (董晨)

Professor, director of Shanghai Immune Therapy Institute

Fu-Sheng Wang (王福生)

MD., director of the Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases

George Fu Gao (高福)

Professor, former director-general of Chinese Center for Disease Control and Prevention (China CDC)

Zhonghe Zhou (周忠和, Chair)

Associate director of the Science Popularization and Education Committee of CASAD, professor of CAS Institute of Vertebrate Paleontology and Paleoanthropology and associate editor-in-chief of NSR

Yiming Shao (邵一鸣)

Professor, deputy director of State Key Laboratory for Infectious Disease Control and Prevention, former chief expert on AIDS, China CDC
Prebiotics improve osteoporosis indicators in a preclinical model: systematic review with meta-analysis
Authors: Artoni de Carvalho João Alberto , Magalhães Leticia Rocha , Polastri Laryssa Mayara , Batista Ingrid Eloise Trombine , de Castro Bremer Sophia , Caetano Heliard Rodrigues dos Santos , Rufino Marcos Natal , Bremer-Neto Hermann
Published: December 2022

Context

Studies using experimental models have demonstrated that prebiotics are involved in antiosteoporotic mechanisms.

Objective

This study was conducted to determine the impact of supplementation with prebiotics in the basal diet of ovariectomized rats with induced osteoporosis as a preclinical model.

Methods

A comprehensive systematic search was carried out in the electronic databases PubMed, Science Direct, Web of Science, Scielo, and Google through March 2022 for studies that investigated the impact of prebiotics on bone mineral density (BMD), bone mineral content (BMC), and bone biomechanics.

Results

The search returned 844 complete articles, abstracts, or book chapters. After detailed screening, 8 studies met the inclusion criteria. Rats (n = 206), were randomly divided between control and treatment groups. Weighted mean differences (WMDs) with the 95%CIs were used to estimate the combined effect size. Compared with the control group, dietary intake of prebiotics significantly increased bone density in the BMD subgroups, with WMDs as follows: 0.03 g/cm3, 95%CI, 0.01–0.05, P < 0.00001, n = 46; and 0.00 g/cm2, 95%CI, 0.00–0.02, P < 0.00001, n = 81; total BMD: WMD, 0.01, 95%CI, 0.01–0.02, P < 0.00001, n = 127; bone content in BMC: WMD, 0.02 g, 95%CI, 0.00–0.04, P = 0.05, n = 107; and the 3-point-bend test: WMD, 15.20 N, 95%CI, 5.92–24.47, P = 0.00001, n = 120.

Conclusion

Prebiotics improve indicators of osteoporosis, BMD, BMC, and bone biomechanics in ovariectomized rats. More studies are needed to increase the level of evidence.

Systemic Review Registration

Systematic Review Protocol for Animal Intervention Studies
Tall, heterogeneous forests improve prey capture, delivery to nestlings, and reproductive success for Spotted Owls in southern California
Authors: Wilkinson Zachary A , Kramer H Anu , Jones Gavin M , Zulla Ceeanna J , McGinn Kate , Barry Josh M , Sawyer Sarah C , Tanner Richard , Gutiérrez R J , Keane John J , Peery M Zachariah
Published: December 2022

Predator–prey interactions can be profoundly influenced by vegetation conditions, particularly when predator and prey prefer different habitats. Although such interactions have proven challenging to study for small and cryptic predators, recent methodological advances substantially improve opportunities for understanding how vegetation influences prey acquisition and strengthen conservation planning for this group. The California Spotted Owl (Strix occidentalis occidentalis) is well known as an old-forest species of conservation concern, but whose primary prey in many regions—woodrats (Neotoma spp.)—occurs in a broad range of vegetation conditions. Here, we used high-resolution GPS tracking coupled with nest video monitoring to test the hypothesis that prey capture rates vary as a function of vegetation structure and heterogeneity, with emergent, reproductive consequences for Spotted Owls in Southern California. Foraging owls were more successful capturing prey, including woodrats, in taller multilayered forests, in areas with higher heterogeneity in vegetation types, and near forest-chapparal edges. Consistent with these findings, Spotted Owls delivered prey items more frequently to nests in territories with greater heterogeneity in vegetation types and delivered prey biomass at a higher rate in territories with more forest-chaparral edge. Spotted Owls had higher reproductive success in territories with higher mean canopy cover, taller trees, and more shrubby vegetation. Collectively, our results provide additional and compelling evidence that a mosaic of large tree forest with complex canopy and shrubby vegetation increases access to prey with potential reproductive benefits to Spotted Owls in landscapes where woodrats are a primary prey item. We suggest that forest management activities that enhance forest structure and vegetation heterogeneity could help curb declining Spotted Owl populations while promoting resilient ecosystems in some regions.
Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma
Authors: Xue Yizheng , Wang Bingran , Tao Yiying , Xia Jun , Yuan Kedi , Zheng Junhua , Zhai Wei , Xue Wei
Published: December 2022

To investigate the role of patient-derived organoid (PDO) model in the precision medicine of advanced clear cell renal cell carcinoma (ccRCC), we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022. The seven patients were diagnosed with advanced ccRCC with or without remote metastasis. Cytoreductive and radical nephrectomy was performed respectively. To predict the response to immunotherapy and provide personalized medicine recommendation, a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed. Hematoxylin and eosin (H&E) staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor. Immunofluorescence staining identified that CD3+ T cells, SMA+ cancer associated fibroblasts, and CD31+ endothelial cells were preserved in PDO models. Fluorescence activated cell sorter (FACS) revealed an evidently increased ratio of CD8+/CD4+ T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4. The results showed that toripalimab is able to rescue the excessive death of CD8+ T cells by critically reversing the immune exhaustion state of ccRCC in PDO model. This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC.
Unique opportunities for future research on the alternative oxidase of plants
Authors: McDonald Allison E
Published: December 2022

Alternative oxidase (AOX) is a terminal oxidase present in the electron transport system of all plants examined to date that plays an important role in the responses to abiotic and biotic stresses. Due to recent advances in cell and tissue culture, genetic engineering, and bioinformatic resources for nonmodel plants, it is now possible to study AOX in a broader diversity of species to investigate the full taxonomic distribution of AOX in plants. Additional functions of AOX should be investigated in thermogenic, carnivorous, and parasitic plants with atypical life histories. Recent methodological improvements in oxygen sensing, clustered regularly interspaced short palindromic repeats technology, and protein biochemistry will allow for considerable advancement on questions that have been long standing in the field due to experimental limitations. The role of AOX in secondary metabolism and mitochondrial metabolic pathways should also be examined due to recent discoveries in analogous systems in other organelles and fungi.
A deep-learning model of prescient ideas demonstrates that they emerge from the periphery
Authors: Vicinanza Paul , Goldberg Amir , Srivastava Sameer B
Published: December 2022

Where do prescient ideas—those that initially challenge conventional assumptions but later achieve widespread acceptance—come from? Although their outcomes in the form of technical innovation are readily observed, the underlying ideas that eventually change the world are often obscured. Here, we develop a novel method that uses deep learning to unearth the markers of prescient ideas from the language used by individuals and groups. Our language-based measure identifies prescient actors and documents that prevailing methods would fail to detect. Applying our model to corpora spanning the disparate worlds of politics, law, and business, we demonstrate that it reliably detects prescient ideas in each domain. Moreover, counter to many prevailing intuitions, prescient ideas emanate from each domain’s periphery rather than its core. These findings suggest that the propensity to generate far-sighted ideas may be as much a property of contexts as of individuals.
Researching Protest Policing in South Africa: A Discourse Analysis of the Police–Researcher Encounter
Authors: Cornell Josephine , Malherbe Nick , Seedat Mohamed , Suffla Shahnaaz
Published: December 2022

Researchers have played a significant role in influencing the public’s critical engagement with the South African Police Service (SAPS). Resultantly, SAPS officers tend to be wary and/or untrusting of researchers. In the present study, we sought to understand how this climate of suspicion impacts policing research in South Africa. To do so, we employed a Foucauldian Discourse Analysis on emails leading up to a study with SAPS officers, and on the transcripts of three focus group discussions with SAPS officers. We identified three discursive strategies that SAPS employed: Security Stall (i.e. blocking research through bureaucratic procedure), Eliciting Sympathy (i.e. winning sympathy for the struggles of SAPS officers) and Undermining the Researcher Subjectivity (i.e. rendering legitimate knowledge on protest violence the sole product of police officers). These strategies destabilize police research while challenging the broader discursive terrain within which SAPS is located. We conclude by offering some insights for police research.
The Later Wittgenstein on Expressive Moral Judgements
Authors: Fairhurst Jordi
Published: December 2022

This paper shows that Wittgenstein's later explorations of the meaning of expressive moral judgements reach far deeper than has so far been noticed. It is argued that an adequate description of the meaning of expressive moral judgements requires engaging in a grammatical investigation that focuses on three interwoven components within specific language-games. First, the ethical reactions expressed by moral words and the additional purpose they may fulfil. Second, the features of the actions which are bound up with moral words and are constitutive of our moral evaluations. And, finally, the forms of life in which expressive moral judgements and moral language-games are embedded.
Ethics and Moral Agency for a Postpandemic Era: Beyond the Storm
Authors: Swisher Laura Lee
Published: December 2022

Laura Lee (Dolly) Swisher, PT, MDiv, PhD, FAPTA, the 53rd Mary McMillan Lecturer, is professor emerita and former director of the school of physical therapy and rehabilitation sciences at the University of South Florida in the USF Health Morsani College of Medicine. Dr Swisher received a bachelor of arts degree from Wilson College and is a 1986 physical therapy graduate of the University of Tennessee Health Science Center, Memphis. She received the M.Div. from Andover Newton Theological School and a doctoral degree in public administration from Tennessee State University. Dr Swisher is a highly regarded expert on professionalism, ethics, and interprofessional education and has been a featured speaker at local, state, and national conferences. She is the coauthor of Rehabilitation Ethics for Professional Practice, Professionalism in Physical Therapy and Legal and Ethical Issues in Physical Therapy and is a lead author or coauthor of multiple peer reviewed articles and individual book chapters. She served as a member and chair of the Commission on Accreditation for Physical Therapy Education, was former chair and member of the APTA Ethics and Judicial Committee, and served as co-chair of the Task Force to Revise the Core Ethics Documents. Dr Swisher served on the Editorial Board of the Journal of Physical Therapy Education and is a member of the Editorial Board of the Journal of Humanities in Rehabilitation. She is the recipient of APTA's Lucy Blair Service Award and the Polly Cerasoli Lecture Award and is a Catherine Worthingham Fellow of the APTA.
The Effect of Anesthetic Agent and Mean Arterial Pressure on Functional Outcome After General Anesthesia for Endovascular Thrombectomy
Authors: Crimmins Danielle , Ryan Elizabeth , Shah Darshan , Lwin Thar-Nyan , Ayotte Steven , Redmond Kendal , Highton David
Published: December 2022

Background:

The optimal general anesthetic (GA) technique for stroke patients undergoing endovascular thrombectomy (ET) is unclear. We compared favorable outcomes and mortality in patients receiving propofol or volatile GA during ET and assessed associations between mean arterial pressure (MAP) and outcome.

Methods:

Ninety-three patients with anterior circulation stroke who received propofol or volatile GA during ET between February 2015 and February 2018 were included in this retrospective study. Ninety-day modified Rankin scores were compared and mortality was adjusted for intravenous thrombolysis and diabetes. We performed ordinal logistic regression analyses containing MAP time/exposure thresholds.

Results:

There was no difference in the rate of favorable outcome (modified Rankin scores 0-2) in the volatile and propofol groups (48.8% vs. 55.8%, respectively; P=0.5). Ninety-day mortality was lower in patients receiving propofol (11.5%) than in those receiving volatile GA (29.3%) (odds ratio, 0.32; 95% confidence interval, 0.11 to 0.94; P=0.03); this mortality benefit was greater in patients that did not receive intravenous thrombolysis before ET (odds ratio for survival, 6; 95% confidence interval, 1.13 to 31.74). There was no difference in MAP between groups and a (nonsignificant) trend towards the benefit of MAP <90 mm Hg but not <70 mm Hg.

Conclusions:

Favorable outcome rates were similar in stroke patients receiving propofol or volatile GA during ET. Propofol was associated with lower mortality, an effect magnified in patients that did not receive intravenous thrombolysis. MAP time/exposure thresholds were associated with outcome but independent of the anesthetic agent. Our data suggest that a difference in outcome related to an anesthetic agent may exist; this hypothesis needs to be tested in a prospective study.
The Association of Low CD4 Expression on Monocytes and Low CD8+ T-Cell Count at Hospital Admission Predicts the Need for Mechanical Ventilation in Patients With COVID-19 Pneumonia: A Prospective Monocentric Cohort Study
Authors: Allardet-Servent Jérôme , Ait Belkacem Ines , Miloud Tewfik , Benarous Lucas , Galland Franck , Halfon Philippe , Mège Jean-Louis , Penaranda Guillaume , Busnel Jean-Marc , Malergue Fabrice
Published: December 2022

OBJECTIVES:

To identify COVID-19-associated immunophenotyping patterns at hospital admission and to determine if some patterns could predict the need for mechanical ventilation (MV).

DESIGN:

Prospective observational monocentric cohort study.

SETTING:

A university-affiliated hospital in Marseille, France.

PATIENTS:

Thirty patients presenting with laboratory-confirmed COVID-19 pneumonia were enrolled within the first 48 hours of hospital admission and compared with 18 healthy controls.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Whole-blood leukocytes were immunophenotyped with a rapid and simplified one-step flow cytometry method. Thirty-eight immune and five laboratory parameters were compared first between COVID-19 patients and controls and then between the COVID-19 patients who received or not MV during their stays. The variables that significantly discriminated MV from non-MV patients in univariate analysis were entered into a multiple stepwise logistic regression analysis. The COVID-19 patients were predominantly male (87%), aged 61 years (50–71 yr), and 93% received early corticosteroid therapy. Sixteen patients (53%) were managed with noninvasive respiratory support, and 14 (47%) required MV. Compared with controls, COVID-19 patients were characterized by an immune signature featuring: 1) decreased HLA-DR expression on monocytes; 2) reduced basophils, eosinophils, T-cells, NK cells, and nonclassical monocyte count; and 3) up regulation of CD169 on monocytes, CD64 on neutrophils, the adhesion/migration markers (CD62L and CD11b), and the checkpoint inhibitor CD274 on myeloid cells. Among the COVID-19 patients, those who received MV had lower level of CD4 and HLA-DR on monocytes, lower CD8+ T-cell count, and higher lactate dehydrogenase at hospital admission. In multivariate analysis, only CD4 on monocytes (p = 0.032) and CD8+ T-cell count (p = 0.026) were associated with MV requirement. The model combining these two variables provided an area under curve of 0.97 (95% CI, 0.83–0.99).

CONCLUSIONS:

The association of low CD4 on monocytes and low CD8+ T-cell count at hospital admission was highly predictive of the need for MV in hospitalized patients with COVID-19 pneumonia.
Clinical Outcome in Children With Cancer With Two or More Microorganisms Isolated From Blood Cultures During Episodes of Fever and Neutropenia
Authors: Ibáñez Carolina , Torres Juan Pablo , De La Maza Verónica , Rivera Salome , Valenzuela Romina , Simian Maria Elvira , Payá Ernesto , Álvarez Ana María , Contardo Verónica , Martínez Daniela , Claverie Ximena , Santolaya María Elena
Published: December 2022

Background:

Bacterial bloodstream infections are a major cause of morbidity and mortality in children with cancer and episodes of fever and neutropenia (FN). The aim of this study was to evaluate the clinical outcome in children with cancer with 2 or more microorganisms isolated from blood cultures during their episodes of FN.

Methods:

Between 2016 and 2021, children presenting with high-risk FN, admitted to any of the 6 participating hospitals in Santiago, Chile, were included in this study if they have positive blood cultures. We compared the clinical outcome of children with 2 or more microorganisms versus those with single agent isolation.

Results:

A total of 1074 episodes of high-risk FN were enrolled in the study period, of which 27% (298) had positive blood cultures and 3% (32) had 2 or more microorganisms isolated from blood cultures. The most frequent identified agents were Viridans group streptococci and Escherichia coli in 20%, followed by Coagulase negative staphylococci in 14%. Children with 2 or more microorganisms presented more days of fever (7 vs. 4 days, P = 0.02), needed longer courses of antimicrobial therapy (16 vs. 14 days, P = 0.04) and had higher mortality at day 30 (13% vs. 1%, P = 0.003).

Conclusions:

Children with cancer and FN with 2 or more microorganisms isolated from blood cultures had a worse clinical outcome than children with single agent isolation.
A Cross-Sectional Study of the Association Between Telecommuting Environments and Shoulder Pain Among Japanese Telecommuting Workers
Authors: Sato Hideyuki , Matsugaki Ryutaro , Ando Hajime , Odagami Kiminori , Mafune Kosuke , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork project
Published: December 2022

Objective

The aim of this study was to investigate the association between telecommuting environments and shoulder pain in Japanese telecommuters.

Methods

We conducted an Internet-monitored, cross-sectional study and analyzed 2537 participants who mainly telecommuted at least 4 days per week. We assessed the presence of shoulder pain using a numerical rating scale and the characteristics of the telecommuting environment by asking eight questions. We used multilevel logistic regression analysis with the city of residence as a random effect.

Results

Inadequate desk brightness (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.09–1.78), inadequate foot space (OR, 1.27; 95% CI, 1.02–1.58), and uncomfortable temperature and humidity (OR, 1.41; 95% CI, 1.16–1.72) were associated with shoulder pain in multilevel logistic regression analysis.

Conclusions

Inappropriate telecommuting environments were associated with an increase in the prevalence of shoulder pain in Japanese telecommuters.
Mobilizing Domestic Funds for the HIV/AIDS Response in Nigeria: Estimating the Potential Contribution of the National Health Insurance Scheme
Authors: Oladele Tolulope T. , Olakunde Babayemi O. , Mao Wenhui , Oladele Edward Adekola , Ogundipe Alex , Yamey Gavin , Ogbuoji Osondu
Published: December 2022

Background:

Amid the dwindling donor support for HIV in Nigeria, there is an urgent need for additional domestic HIV funding. This study estimates the required financial resources for people living with HIV (PLHIV) and the potential magnitude of domestic resources for HIV through the National Health Insurance Scheme (NHIS) and by prioritizing HIV within the health budget.

Methods:

We estimated the resource needs for providing antiretroviral therapy (ART) to adults, children, and pregnant women living with HIV under 3 scenarios: current coverage rates, coverage rates based on historical trends, and a rapid scale-up situation. We conducted a fiscal space analysis to estimate the potential contribution from macroeconomic growth, the NHIS, and prioritizing HIV within the health budget from 2020 to 2025.

Results:

At current coverage rates, the annual treatment costs for adults would range between US$ 505 million in 2020 to US$ 655 million in 2025; for children, it ranges from US$ 33.5 million in 2020 to US$ 32 million in 2025. The annual costs of providing PMTCT at current coverage rates range from US$ 65 million in 2020 to US$ 72 million in 2025. An additional US$ 319 million could potentially be generated between 2020 and 2025 through the NHIS for HIV. Prioritizing HIV within the health budget can generate an additional US$ 686 million.

Conclusion:

Substantial domestic funds can be mobilized by these means to sustain the HIV response. However, because this additional funding may not be sufficient to cover all PLHIV, a phased approach, initially prioritizing certain populations such as children or pregnant women, is recommended.
Liver Transplantation Using Allografts With Recent Liver Blunt Trauma: A Nationwide Audit From the French CRISTAL Biomedicine Agency Registry
Authors: Seckler Florian , Turco Célia , Mohkam Kayvan , Addeo Pietro , Robin Fabien , Cauchy François , Maulat Charlotte , Brustia Raffaele , Paquette Brice , Faitot François , Weil Verhoeven Delphine , Minello Anne , Lakkis Zaher , Di Martino Vincent , Latournerie Marianne , Chiche Laurence , El Amrani Mehdi , Bucur Petru , Navarro Francis , Chopinet Sophie , Chirica Mircea , Gagnière Johan , Iannelli Antonio , Cheisson Gaëlle , Chardot Christophe , Sommacale Daniele , Muscari Fabrice , Dondero Federica , Sulpice Laurent , Bachellier Philippe , Scatton Olivier , Mabrut Jean Yves , Heyd Bruno , Doussot Alexandre
Published: December 2022

Background.

In the current setting of organ shortage, brain-dead liver donors with recent liver trauma (RLT) represent a potential pool of donors. Yet, data on feasibility and safety of liver transplantation (LT) using grafts with RLT are lacking.

Methods.

All liver grafts from brain-dead donors with RLT proposed for LT between 2010 and 2018 were identified from the nationwide CRISTAL registry of the Biomedicine Agency. The current study aimed at evaluating 1-y survival as the primary endpoint.

Results.

Among 11 073 LTs, 142 LTs (1.3%) using grafts with RLT were performed. These 142 LTs, including 23 split LTs, were performed from 131 donors (46.1%) of 284 donors with RLT proposed for LT. Transplanted grafts were procured from donors with lower liver enzymes levels (P < 0.001) and less advanced liver trauma according to the American Association for the Surgery of Trauma liver grading system (P < 0.001) compared with not transplanted grafts. Before allocation procedures, 20 (7%) of 284 donors underwent damage control intervention. During transplantation, specific liver trauma management was needed in 19 patients (13%), consisting of local hemostatic control (n = 15), partial hepatic resection on back-table (n = 3), or perihepatic packing (n = 1). Ninety-day mortality and severe morbidity rates were 8.5% (n = 12) and 29.5% (n = 42), respectively. One-year overall and graft survival rates were 85% and 81%, and corresponding 5-y rates were 77% and 72%, respectively.

Conclusions.

Using liver grafts from donors with RLT seems safe with acceptable long-term outcomes. All brain-dead patients with multiorgan trauma, including liver injury, should be considered for organ allocation.
Percutaneous Direct Puncture of Retropancreatic Splenic Vein and Portal Thrombectomy in a Patient With Liver Transplantation and Simultaneous Splenectomy
Authors: Hara Takanobu , Soyama Akihiko , Ishimaru Hideki , Matsushima Hajime , Imamura Hajime , Miyamura Shuto , Hamada Takashi , Matsuguma Kunihito , Fukumoto Masayuki , Tanaka Takayuki , Adachi Tomohiko , Hidaka Masaaki , Eguchi Susumu
Published: December 2022

Portal vein thrombosis following liver transplantation is generally managed by endovascular treatment. Although several techniques are available for portal venous access, trans-splenic access is of interest because it avoids damage to the liver graft. However, the spleen cannot be punctured to access the portal vein after splenectomy. We herein report a case of portal vein thrombosis following living donor liver transplantation with simultaneous splenectomy successfully treated by percutaneous intervention with direct puncture of the retropancreatic splenic vein. The splenic vein was punctured under computed tomography guidance in the prone position. Portal venography revealed a contrast defect due to a thrombus in the extrahepatic to intrahepatic portal vein. The portal vein was reopened after thrombectomy, and the portal vein thrombosis did not recur for 2 y. The technique and advantages of our approach are described.
Atomistic mechanisms of phase nucleation and propagation in a model two-dimensional system
Authors: Shuang Fei , Xiao Penghao , Xiong Liming , Gao Wei
Published: December 2022

We present a computational study on the solid–solid phase transition of a model two-dimensional system between hexagonal and square phases under pressure. The atomistic mechanism of phase nucleation and propagation are determined using solid-state Dimer and nudged elastic band (NEB) methods. The Dimer is applied to identify the saddle configurations and NEB is applied to generate the transition minimum energy path (MEP) using the outputs of Dimer. Both the atomic and cell degrees of freedom are used in saddle search, allowing us to capture the critical nuclei with relatively small supercells. It is found that the phase nucleation in the model material is triggered by the localized shear deformation that comes from the relative shift between two adjacent atomic layers. In addition to the conventional layer-by-layer phase propagation, an interesting defect-assisted low barrier propagation path is identified in the hexagonal to square phase transition. The study demonstrates the significance of using the Dimer method in exploring unknown transition paths without
a priori
assumption. The results of this study also shed light on phase transition mechanisms of other solid-state and colloidal systems.
Stability of an inhomogeneous ferrofluid in a channel, subject to a normal field
Authors: Ferguson Briggs S. H. , Mestel A. J.
Published: December 2022

The stability of a ferrofluid with a fairly arbitrary non-uniform magnetic susceptibility between two parallel walls, subject to a non-uniform magnetic field acting normal to the walls, is investigated. The susceptibility may depend on position and the field strength, and the stationary state is such that the gradient of the susceptibility with respect to the modulus of the field is negative. Previous work suggests that the configuration may be linearly unstable, as regions of higher susceptibility do not coincide with regions of strongest field, and this is proved here. Adding a constant field in the plane of the layer suppresses parallel instabilities, but has no effect on those orthogonal to it. However, it is demonstrated that stability can be achieved by applying a rapidly rotating field.
Interhemispheric communication during haptic self-perception
Authors: Kong Gaiqing , Cataldo Antonio , Nitu Miruna , Dupin Lucile , Gomi Hiroaki , Haggard Patrick
Published: December 2022

During the haptic exploration of a planar surface, slight resistances against the hand's movement are illusorily perceived as asperities (bumps) in the surface. If the surface being touched is one's own skin, an actual bump would also produce increased tactile pressure from the moving finger onto the skin. We investigated how kinaesthetic and tactile signals combine to produce haptic perceptions during self-touch. Participants performed two successive movements with the right hand. A haptic force-control robot applied resistances to both movements, and participants judged which movement was felt to contain the larger bump. An additional robot delivered simultaneous but task-irrelevant tactile stroking to the left forearm. These strokes contained either increased or decreased tactile pressure synchronized with the resistance-induced illusory bump encountered by the right hand. We found that the size of bumps perceived by the right hand was enhanced by an increase in left tactile pressure, but also by a decrease. Tactile event detection was thus transferred interhemispherically, but the sign of the tactile information was not respected. Randomizing (rather than blocking) the presentation order of left tactile stimuli abolished these interhemispheric enhancement effects. Thus, interhemispheric transfer during bimanual self-touch requires a stable model of temporally synchronized events, but does not require geometric consistency between hemispheric information, nor between tactile and kinaesthetic representations of a single common object.
Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes
Authors: Bajema Kristina L. , Berry Kristin , Streja Elani , Rajeevan Nallakkandi , Li Yuli , Yan Lei , Cunningham Francesca , Hynes Denise M. , Rowneki Mazhgan , Bohnert Amy , Boyko Edward J. , Iwashyna Theodore J. , Maciejewski Matthew L. , Osborne Thomas F. , Viglianti Elizabeth M. , Aslan Mihaela , Huang Grant D. , Ioannou George N.
Published: December 2022

Background

Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19.

Methods

We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses.

Results

Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] - 13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI - 16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups.

Conclusions

Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral.
A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese non-human primate model
Authors: Zheng Songmao , Polidori David , Wang Yuanping , Geist Brian , Lin-Schmidt Xiefan , Furman Jennifer L. , Nelson Serena , Nawrocki Andrea R. , Hinke Simon A.
Published: December 2022

GDF15 is a circulating polypeptide associated with cellular stress, and recently linked to metabolic adaptation. GDF15 has a half-life of approximately 3 hours in and acts at the GFRAL receptor selectively expressed in the area postrema. To characterize the effects of sustained GFRAL agonism on food intake (FI) and body weight (BW), we developed a half-life extended analog of GDF15 (Compound H; CpdH) suitable for reduced dosing frequency and tested its effects in obese cynomolgus monkeys. Animals were treated once weekly for 12 weeks with 0.048, 0.16, or 1.6 mg/Kg of CpdH or with 0.02 mg/Kg of the long-acting GLP-1 analog dulaglutide as a positive control. FI was measured daily and BW was measured biweekly. Mechanism-based longitudinal exposure-response (E-R) modeling was performed to characterize the effects of CpdH and dulaglutide on FI and BW. The integrated novel model accounts for both acute, exposure-dependent effects of treatments to reduce FI and the compensatory changes in energy expenditure (EE) and FI that occur over time in response to weight loss. CpdH had approximately linear, dose-proportional pharmacokinetics with a half-life of ≈8 days and treatment with CpdH led to dose- and exposure-dependent reductions in FI and BW. The 1.6 mg/Kg CpdH dose reduced mean FI by 57.5% at 1 week and provided sustained FI reductions of 31.5% from weeks 9-12, leading to a peak reduction in BW of 16±5%. Dulaglutide had more modest effects on FI (reductions between 15-40%) and peak BW loss was 3.8±4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by the exposure-dependent reductions in FI without any increase in EE. Upon verification of pharmacokinetic/pharmacodynamic relationship established in monkeys and human for dulaglutide, we predicted that CpdH could reach double digit BW loss in human. In summary, treatment with a long-acting GDF15 analog led to sustained dose- and exposure-dependent reductions in food intake in a monkey model of obesity and holds potential for effective clinical obesity pharmacotherapy.

Significance Statement

GDF15 activation of GFRAL receptors in the hindbrain controls food intake and body weight. Here we describe the effect and durability of a circulating half-life extended analog of GDF15 (Compound H) on food intake and body weight loss in a spontaneously obese cynomolgus monkey model. Inclusion of a translational treatment arm with a weight loss agent, dulaglutide, permitted pharmacokinetic/pharmacodynamic modeling and comparison of both GDF15 and GLP-1 based weight loss mechanisms, and development of an allometric scaling based mathematical model to estimate the efficacy of Compound H in human obese subjects.
What is learned determines how Pavlovian conditioned fear is consolidated in the brain
Authors: Leake Jessica , Leidl Dana M. , Lay Belinda P. P. , Fam Justine P. , Giles Madeleine C. , Qureshi Omar A. , Westbrook R. Frederick , Holmes Nathan M.
Published: December 2022

Activity in the basolateral amygdala complex (BLA) is needed to encode fears acquired through contact with both innate sources of danger (i.e., things that are painful) and learned sources of danger (e.g., being threatened with a gun). However, within the BLA, the molecular processes required to consolidate the two types of fear are not the same: protein synthesis is needed to consolidate the first type of fear (so-called first-order fear) but not the latter (so-called second-order fear). The present study examined why first- and second-order fears differ in this respect. To do so, it used a range of conditioning protocols in rats and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on fear to first- and second-order conditioned stimuli. The results revealed that the differential protein synthesis requirements for consolidation of first- and second-order fears reflect differences in what is learned in each case. Protein synthesis in the BLA is needed to consolidate fears that result from encoding of relations between stimuli in the environment (stimulus-stimulus associations, typical for first-order fear) but is not needed to consolidate fears that form when environmental stimuli associate directly with fear responses emitted by the animal (stimulus-response associations, typical for second-order fear). Thus, the substrates of Pavlovian fear conditioning in the BLA depend on the way that the environment impinges upon the animal. This is discussed with respect to theories of amygdala function in Pavlovian fear conditioning, and ways in which stimulus-response associations might be consolidated in the brain.
Neurogenic defects underlie functional bladder outflow tract obstruction associated with biallelic variants inLRIG2
Authors: Grenier Celine , Lopes Filipa M. , Cueto-González Anna M , Rovira-Moreno Eulàlia , Gander Romy , Jarvis Benjamin W , McCloskey Karen D. , Gurney Alison M. , Beaman Glenda M. , Newman William G. , Woolf Adrian S. , Roberts Neil A.
Published: December 2022

Urinary tract malformations account for half of all children with kidney failure, and some have defined monogenic causes. One such disorder is urofacial, or Ochoa, syndrome (UFS), an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. Incomplete voiding predisposes to urosepsis and kidney failure. Half of individuals with UFS carry biallelic variants inHPSE2, whereas some carry variants inLRIG2(leucine rich repeats and immunoglobulin like domains 2). We report one new kindred where the index case presented with fetal hydronephrosis and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with urinary tract disease, characterizes UFS. WhileHPSE2sequencing was normal, he carried a homozygous, predicted pathogenic, stop variant (c.1939C>T; p.Arg647*) inLRIG2. Hypothesizing that neurogenic defects underlieLRIG2-associated bladder dysfunction, we studiedLrig2homozygous mutant mice. Juveniles had enlarged bladders andex vivophysiology experiments showed neurogenic defects in outflow tract relaxation. Mutants also displayed abnormal detrusor contractility. Moreover, there were nuanced differences in physiological defects between the sexes. The current case emphasizes that urinary tract disease in UFS begins before birth. Putting this family in the context of all reported urinary tract disease-associatedLRIG2variants, the urinary and facial phenotype of UFS occurs with biallelic putative loss of function variants, but missense variants lead to bladder-limited disease without the grimace. Finally, our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.