bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of restricted sleep: mood and neurobehavioral outcomes in healthy sleepers
Authors: Dang Rammy , Feng Xiaoming , Haack Monika , Mullington Janet M
Published: March 2023

Study Objective

To evaluate how nocturnal timing of sleep restriction affects vigilant attention and mood in healthy controls with normal sleep–wake patterns.

Methods

A convenience sample from two controlled sleep restriction protocols were used to investigate the difference between 4 hours of sleep early in the night, versus 4 hours late in the night. Volunteers stayed in a hospital setting and were randomized to one of the three conditions: a control (8 hours of sleep each night), an early short sleep (ESS, 2300–0300 hours), and a late short sleep (LSS, 0300–0700 hours). Participants were evaluated with psychomotor vigilance task (PVT) and mood ratings via visual analog scales.

Results

Short sleep conditions led to greater performance decrements than control on PVT. LSS performance impairments were greater than control (lapses, p = 0.011; median RT, p = 0.029; fastest 10%, p = 0.038; reciprocal RT, p = 0.014; and reciprocal 10%, p = 0.005), but had higher positive mood ratings (p = 0.005). LSS also had higher positive mood ratings compared with ESS (p < 0.001).

Conclusions

The data underscore the negative mood impact of waking at an adverse circadian phase, for healthy controls. In addition, the paradoxical relationship between mood and performance seen in LSS raises concerns that staying up late and waking at the usual rise time may be rewarding in terms of mood, but nonetheless have performance consequences that may not be fully recognized.
Category 2 blessing applications: developing trends
Authors: Walker Nathaniel , Trezise Joanna
Published: March 2023

A successful application under Public Trustee v Cooper category 2 (a “blessing” application) will protect the trustee(s) from future claims of breach of duty. Given the broad scope of that protection, the role of the court when considering such an application, and the test that is required to be met, has been subject to scrutiny. In this article, the authors reflect on recent developments and encourage a broad, flexible approach by the courts when determining blessing applications.
Neuroendocrine Transdifferentiation in Cutaneous Melanoma: A Case Report and Review of the Literature
Authors: Pisani David , Micallef Daniel , Scerri Jeanesse , Betts Alexandra , Degaetano James , Baldacchino Shawn
Published: March 2023

Neuroendocrine transdifferentiation refers to the progressive transformation of a nonneuroendocrine tumor to the one showing evidence of neuroendocrine differentiation on morphological and immunohistochemical grounds. Although this phenomenon has been well-documented in certain malignancies, particularly prostatic adenocarcinoma after androgen deprivation, cases of neuroendocrine transdifferentiation in melanomas are exceptionally rare. Herein, we report a case of a conventional superficial spreading melanoma occurring on the skin of the leg in a young male which showed progressive neuroendocrine transdifferentiation as it progressed through 2 in-transit metastases and a nodal metastatic deposit over a 4-year period. The tumor retained theBRAFV600E mutation throughout the disease process, and disease control was achieved through dual BRAF inhibition therapy. The possibility of melanoma masquerading as a high-grade neuroendocrine malignancy when investigating tumors of unknown primary should be kept in the mind of clinicians and histopathologist alike as a potential diagnostic pitfall, thus helping avoid misdiagnosis and guide appropriate treatment strategies.
Delayed Thoracodorsal Artery Perforator Free Flap for Calcaneal Degloving Injury Reconstruction
Authors: Huff Mallorie L. , Mansour Ahmed M. , Raj Mamtha S. , Allen Robert J. , Wallace Sean J.
Published: March 2023

The thoracodorsal artery perforator (TDAP) flap has a long vascular pedicle that is ideal for lower extremity reconstruction, but it generally relies on the presence of a dominant septocutaneous perforator vessel. Surgical delay optimizes flap survival by creating relative ischemia to augment perforator vessels. In this report, we describe the use of a delayed free TDAP flap in the setting of an absent dominant perforator vessel for the reconstruction of a calcaneal degloving injury. A 22-year-old actively smoking patient with a body mass index of 33.5 presented with a nonhealing left heel wound with overlying necrotic changes after traumatic degloving injury. The entire weight-bearing portion of the calcaneal fat pad and the flanking regions were debrided. The TDAP flap was elevated, revealing three small thoracodorsal artery perforators. Given that a dominant perforator was absent, the flap was surgically delayed. Free-tissue transfer occurred 8 days later. This operation was conducted entirely in left lateral decubitus with simultaneous wound preparation and flap harvest. The flap was elevated on two perforators to elongate the pedicle’s length and inset to cover exposed calcaneus and pad the heel. Six months postoperatively, the patient is doing well without flap compromise or ulceration. The TDAP flap is a versatile microsurgical tool, and surgical delay extends the utility of this flap when a dominant septocutaneous perforator is unavailable. Recipient site debridement may occur simultaneously with the TDAP delay procedure. Importantly, only one position is required for flap elevation, microsurgical anastomosis, and insetting, thus obviating intraoperative repositioning.
The Neuroma Startle Sign: A Surgical Indicator of Proximity to an Injured Nerve
Authors: Karinja Sarah J. , Gorky Jonathon , Valerio Ian L. , Ruscic Katarina J. , Eberlin Kyle R.
Published: March 2023

During operative intervention for the treatment of symptomatic neuromas, the authors have observed a hypersensitive “startle” response to stimulation in proximity to the painful nerve. This physiologic sign is an indicator of the specific anatomic localization of the painful stimulus, commonly a symptomatic neuroma, that appears to be reproducible. The aim of this article is to describe this “neuroma startle sign,” posit the underlying mechanism for this observation, and propose how this phenomenon could be clinically harnessed for innovation and optimization in both surgery and anesthesia for more effective symptomatic neuroma localization.
The Impact of Nurse Practitioner Care and Accountable Care Organization Assignment on Skilled Nursing Services and Hospital Readmissions
Authors: Meddings Jennifer , Gibbons Jason B. , Reale Bailey K. , Banerjee Mousumi , Norton Edward C. , Bynum Julie P.W.
Published: March 2023

Background:

Accountable care organizations (ACOs) and the employment of nurse practitioners (NP) in place of physicians are strategies that aim to reduce the cost and improve the quality of routine care delivered in skilled nursing facilities (SNF). The recent expansion of ACOs and nurse practitioners into SNF settings in the United States may be associated with improved health outcomes for patients.

Objectives:

To determine the relationship between ACO attribution and NP care delivery during SNF visits and the relationship between NP care delivery during SNF visits and unplanned hospital readmissions.

Methods:

We obtained a sample of 527,329 fee-for-service Medicare beneficiaries with 1 or more SNF stays between 2012 and 2017. We used logistic regression to measure the association between patient ACO attribution and evaluation and management care delivered by NPs in addition to the relationship between evaluation and management services delivered by NPs and hospital readmissions.

Results:

ACO beneficiaries were 1.26% points more likely to receive 1 or more E&M services delivered by an NP during their SNF visits [Marginal Effect (ME): 0.0126; 95% CI: (0.009, 0.0160)]. ACO-attributed beneficiaries receiving most of their E&M services from NPs during their SNF visits were at a lower risk of readmission than ACO-attributed beneficiaries receiving no NP E&M care (5.9% vs. 7.1%; P<0.001).

Conclusions:

Greater participation by the NPs in care delivery in SNFs was associated with a reduced risk of patient readmission to hospitals. ACOs attributed beneficiaries were more likely to obtain the benefits of greater nurse practitioner involvement in their care.
Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia
Authors: Weinreb Ilan , Rooper Lisa M. , Dickson Brendan C. , Hahn Elan , Perez-Ordonez Bayardo , Smith Stephen M. , Lewis James S. , Skalova Alena , Baněčková Martina , Wakely Paul E. , Thompson Lester D.R. , Rupp Niels J. , Freiberger Sandra N. , Koduru Prasad , Gagan Jeffrey , Bishop Justin A.
Published: March 2023

The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors’ relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed “metatypical adenoid cystic carcinoma.” Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.
Venous Thromboembolism Rates After Free Flap Reconstruction of the Head and Neck Region
Authors: Bengur Fuat Baris , Saadoun Rakan , Moroni Elizabeth A. , Khan Nayel I. , Bottegal Matthew T. , Sridharan Shaum , Kubik Mark W. , Solari Mario G.
Published: March 2023

Background

Venous thromboembolism (VTE) is a major concern for the postoperative hospitalized patient, especially after long and complex procedures. Cancer itself also contributes to the hypercoagulable state, further complicating the management of patients. Despite prophylaxis, breakthrough events can occur. We aimed to assess our institutional VTE and bleeding rates after free flap reconstruction of the head and neck (H&N) region and the factors associated with VTE events.

Methods

A retrospective review of the patients who underwent H&N free flap reconstruction at an academic center from 2012 to 2021 was performed from a prospectively maintained database. Data regarding patient demographics, medical history, surgical details, and overall outcomes were collected. Outcomes studied included postoperative 30-day VTE rates and major bleeding events. Patients who had a VTE event were compared with the rest of the cohort to identify factors associated with VTE.

Results

Free flap reconstruction of the H&N region was performed in 949 patients. Reconstruction after cancer extirpation for squamous cell carcinoma was the most common etiology (79%). The most common flap was thigh based (50%), followed by the fibula (29%). The most common postoperative VTE chemoprophylaxis regimen was enoxaparin 30 mg twice daily (83%). The VTE and bleeding rates over the 10-year period were 4.6% (n = 44) and 8.7% (n = 83), respectively. Body mass index (28.7 ± 5.8 vs 26.2 ± 6.6, P = 0.013) and pulmonary comorbidities were found to be significantly higher in patients who had a VTE event (43% vs 27%, P = 0.017). Patients with a VTE event had a prolonged hospital stay of 8 more days (19.2 ± 17.4 vs 11 ± 7, P = 0.003) and a higher incidence of bleeding events (27% vs 8%, P < 0.001).

Conclusions

Postoperative VTE is a significant complication associated with increased length of hospitalization in patients undergoing free flap reconstruction of the H&N region. Institutional measures should be implemented on an individualized basis based on patient comorbidities to improve the postoperative VTE rates, while balancing the bleeding events.
Ecological drivers and consequences of torpor in Andean hummingbirds
Authors: Revelo Hernández Diana Carolina , Baldwin Justin W. , Londoño Gustavo A.
Published: March 2023

Daily torpor allows endotherms to save energy during energetically stressful (e.g. cold) conditions. Although studies on avian torpor have mostly been conducted under laboratory conditions, information on the usage of torpor in the wild is limited to few, predominantly temperate-zone species. We studied torpor under seminatural conditions from 249 individuals from 29 hummingbird species across a 1920 m elevational gradient in the western Andes of Colombia using cloacal thermistors. Small birds were more likely to use torpor than large birds, but only at low ambient temperatures, where torpor was prolonged. We also found effects of proxy variables for body condition and energy expenditure on the use of torpor, its characteristics, and impacts. Our results suggest that context-dependency and phylogenetic variation in the probability of deploying torpor can help understand clade-wide patterns of elevational distribution in Andean hummingbirds.
Acoustic activity of bats at power lines correlates with relative humidity: a potential role for corona discharges
Authors: Froidevaux Jérémy S. P. , Jones Gareth , Kerbiriou Christian , Park Kirsty J.
Published: March 2023

With the ever-increasing dependency on electric power, electrical grid networks are expanding worldwide. Bats exhibit a wide diversity of foraging and flight behaviours, and their sensitivity to anthropogenic stressors suggests this group is very likely to be affected by power lines in a myriad of ways. Yet the effects of power lines on bats remains unknown. Here we assessed the responses of insectivorous bats to very high voltage power lines (VHVPL; greater than 220 kV). We implemented a paired sampling design and monitored bats acoustically at 25 pairs, one pair consisting of one forest edge near to VHVPL matched with one control forest edge. Relative humidity mediates the effects of power lines on bats: we detected bat attraction to VHVPL at high relative humidity levels and avoidance of VHVPL by bats at low relative humidity levels. We argue that the former could be explained by insect attraction to the light emitted by VHVPL owing to corona discharges while the latter may be owing to the physical presence of pylons/cables at foraging height and/or because of electromagnetic fields. Our work highlights the response of bats to power lines at foraging habitats, providing new insight into the interactions between power lines and biodiversity.
Black Women’s Maternal Health: Insights from Community Based Participatory Research in Newark, New Jersey
Authors: Kantor Leslie M. , Cruz Naomi , Adams Christiana , Akhimien Constance , Allibay Abdulkadir Fauziyya , Battle Cherriece , Oluwayemi Maria , Salimon Olanike , Hee Won Sang , Lassiter Teri , Niraula Sophee
Published: March 2023

This study on Black women’s maternal health engaged a group of six community members in a community based participatory research project in a state with one of the largest racial disparities in maternal mortality and severe maternal morbidity in the United States. The community members conducted 31 semi-structured interviews with other Black women who had given birth within the past 3 years. Four main themes emerged: (1) challenges related to the structure of healthcare, including insurance gaps, long wait times, lack of co-location of services, and financial challenges for both insured and uninsured people; (2) negative experiences with healthcare providers, including dismissal of concerns, lack of listening, and missed opportunities for relationship building; (3) preference for racial concordance with providers and experiences with discrimination across multiple dimensions; and (4) mental health concerns and lack of social support. CBPR is a research methodology that could be more widely deployed to illuminate the experiences of community members in order to develop solutions to complex problems. The results indicate that Black women’s maternal health will benefit from multi-level interventions with changes driven by insights from Black women.
Unsupervised pattern discovery in spatial gene expression atlas reveals mouse brain regions beyond established ontology
Authors: Cahill Robert , Wang Yu , Xian R. Patrick , Lee Alex J. , Zeng Hongkui , Yu Bin , Tasic Bosiljka , Abbasi-Asl Reza
Published: March 2023

The rapid growth of large-scale spatial gene expression data demands efficient and reliable computational tools to extract major trends of gene expression in their native spatial context. Here, we used stability-driven unsupervised learning (i.e. staNMF) to identify principal patterns (PPs) of 3D gene expression profiles and understand spatial gene distribution and anatomical localization at the whole mouse brain level. Our subsequent spatial correlation analysis systematically compared the PPs to known anatomical regions and ontology from the Allen Mouse Brain Atlas using spatial neighborhoods. We demonstrate that our stable and spatially coherent PPs, whose linear combinations accurately approximate the spatial gene data, are highly correlated with combinations of expert-annotated brain regions. These PPs yield a new brain ontology based purely on spatial gene expression. Our PP identification approach outperforms principal component analysis (PCA) and typical clustering algorithms on the same task. Moreover, we show that the stable PPs reveal marked regional imbalance of brainwide genetic architecture, leading to region-specific marker genes and gene co-expression networks. Our findings highlight the advantages of stability-driven machine learning for plausible biological discovery from dense spatial gene expression data that are infeasible by conventional manual approaches.
Proformer: a hybrid macaron transformer model predicts expression values from promoter sequences
Authors: Kwak Il-Youp , Kim Byeong-Chan , Lee Juhyun , Garry Daniel J. , Zhang Jianyi , Gong Wuming
Published: March 2023

The breakthrough high-throughput measurement of the cis-regulatory activity of millions of randomly generated promoters provides an unprecedented opportunity to systematically decode the cis-regulatory logic that determines the expression values. We developed an end-to-end transformer encoder architecture named Proformer to predict the expression values from DNA sequences. Proformer used a Macaron-like Transformer encoder architecture, where two half-step feed forward (FFN) layers were placed at the beginning and the end of each encoder block, and a separable 1D convolution layer was inserted after the first FFN layer and in front of the multi-head attention layer. The slidingk-mers from one-hot encoded sequences were mapped onto a continuous embedding, combined with the learned positional embedding and strand embedding (forward strand vs. reverse complemented strand) as the sequence input. Moreover, Proformer introduced multiple expression heads with mask filling to prevent the transformer models from collapsing when training on relatively small amount of data. We empirically determined that this design had significantly better performance than the conventional design such as using the global pooling layer as the output layer for the regression task. These analyses support the notion that Proformer provides a novel method of learning and enhances our understanding of how cis-regulatory sequences determine the expression values.
The Role of Terminal Uridyl Transferases in the Circadian Rhythm
Authors: Song Wei , Wang Juan , Piao Weilan , Yang Yuening , Son Ahyeon , Chang Hyeshik , Wen Xianghui , Zhang Honglei , Li Chong , Na Daxiang , Lu Yanming , Menet Jerome , Kim V. Narry , Jin Hua
Published: March 2023

The 3’ terminal oligo-uridylation, a post-transcriptional mRNA modification, is conserved among eukaryotes and drives mRNA degradation, thereby affecting several key biological processes such as animal development and viral infection. Our TAIL-seq experiment of mouse liver mRNA collected from six zeitgeber times reveals transcripts with rhythmic poly(A) tail lengths and demonstrates that overall 3’ terminal uridylation frequencies at mRNA poly(A) tail very-ends undergo rhythmic change. Consistently, major terminal uridylyl transferases, TUT4 and TUT7, have cycling protein expression in mouse liver corresponding to 3’ terminal uridylation rhythms, indicating that the cycling expression of TUTases correlates with the rhythmic pattern of uridylation. Furthermore, the double knockdown of TUT4 and TUT7 in U2OS cells lengthens the circadian period and decreases the rhythmic amplitude of clock gene expression. Our work thoroughly profiles the dynamic changes in poly(A) tail lengths and terminal modifications and uncovers uridylation as a post-transcriptional modulator in the mammalian circadian clock.
The Colibactin-ProducingEscherichia colialters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance
Authors: de Oliveira Alves Brito Nilmara , Dalmasso Guillaume , Nikitina Darja , Vaysse Amaury , Ruez Richard , Ledoux Lea , Pedron Thierry , Bergsten Emma , Boulard Olivier , Autier Lora , Allam Sofian , Motreff Laurence , Sauvanet Pierre , Letourneur Diane , Tang Gabriel , Gagnière Johan , Pezet Denis , Godfraind Catherine , Salzet Michel , Lemichez Emmanuel , Bonnet Mathilde , Najjar Imène , Malabat Christophe , Monot Marc , Mestivier Denis , Barnich Nicolas , Fournier Isabelle , Kennedy Sean P. , Mettouchi Amel , Bonnet Richard , Sobhani Iradj , Chamaillard Mathias
Published: March 2023

Intratumoral bacteria locally contribute to cellular and molecular tumor heterogeneity that support cancer stemness through poorly understood mechanisms. This study aims to explore how Colibactin-producingEscherichia coli(CoPEC) flexibly alters the tumor microenvironment in right-sided colorectal cancer (CRC). Metabolomic and transcriptomic spatial profiling uncovered that CoPEC colonization establishes a high-glycerophospholipid microenvironment within the tumor that is conducive to exhaustion of infiltrated CD8+T cell and has a lowered prognostic value in right-sided CRC. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress and supply with sufficient energy for sustaining cell survival and lowering tumor immunogenicity. Specifically, a heightened phosphatidylcholine remodeling of CoPEC-infected cancer cells by the enzyme of the Land’s cycle coincided with a lowered accumulation of proapoptotic ceramide and lysophosphatidylcholine. Consequently, a reduced infiltration of CD8+T lymphocytes that produce the cytotoxic cytokines IFN-γ was found where invading bacteria have been geolocated. By contrast, such an immunosuppressive dysmetabolic process was not observed when human colon cancer cells were infected with the mutant strain that did not produce colibactin (11G5δClbQ). This work revealed an unexpected property of CoPEC on lipid overload within tumors that could locally provide an inflammatory environment leading to immunosuppressive mechanisms and tumor expansion. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
PathogenicLeptospiraare widespread in the urban wildlife of southern California
Authors: Helman Sarah K. , Tokuyama Amanda F.N. , Mummah Riley O. , Gamble Mason W. , Snedden Celine E. , Borremans Benny , Gomez Ana C.R. , Cox Caitlin , Nussbaum Julianne , Tweedt Isobel , Haake David A. , Galloway Renee L. , Monzón Javier , Riley Seth P.D. , Sikich Jeff A. , Brown Justin , Friscia Anthony , Lynch Jessica W. , Prager Katherine C. , Lloyd-Smith James O.
Published: March 2023

Leptospirosis is the most widespread zoonotic disease in the world, yet it is broadly understudied in multi-host wildlife systems. Knowledge gaps regardingLeptospiracirculation in wildlife, particularly in densely populated areas, contribute to frequent misdiagnoses in humans and domestic animals. We assessedLeptospiraprevalence levels and risk factors in five target wildlife species across the greater Los Angeles region: striped skunks (Mephitis mephitis), Northern raccoons (Procyon lotor), coyotes (Canis latrans), Virginia opossums (Didelphis virginiana), and fox squirrels (Sciurus niger). We sampled more than 960 individual animals, including over 700 from target species in the greater Los Angeles region, and an additional 260 sampled opportunistically from other regions and species. In the five target species, seroprevalences ranged from 5-60% and active infection prevalences ranged from 0.8-15.2% in all except fox squirrels (0%). Patterns of serologic reactivity suggest that mainland terrestrial wildlife, particularly mesocarnivores, could be the source of repeated observed introductions ofLeptospirainto local marine and island ecosystems. Overall, we found evidence of widespreadLeptospiraexposure in wildlife across Los Angeles and surrounding regions. This indicates exposure risk for humans and domestic animals and highlights that this pathogen can circulate endemically in many wildlife species even in densely populated urban areas.
Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation
Authors: Kim Yuna , Jung Kwan-Young , Kim Yun Hak , Xu Pan , Jo Yunju , Kang Baeki E. , Pandit Navin , Kwon Jeongho , Gariani Karim , Gariani Joanna , Lee Junguee , Verbeek Jef , Nam Seungyoon , Bae Sung-Jin , Ha Ki-Tae , Yi Hyon-Seung , Shong Minho , Kim Kyun-Hwan , Kim Doyoun , Lee Chang-Woo , Jung Hee Jung , Kim Kwang Rok , Schoonjans Kristina , Ryu Dongryeol , Auwerx Johan
Published: March 2023

The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling.

Highlights

Sorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation.

Suppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib.

SIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation.
Molecular signature of domestication in the arboviral vectorAedes aegypti
Authors: Lozada-Chávez A.N. , Lozada-Chávez I. , Alfano N. , Palatini U. , Sogliani D. , Elfekih S. , Degefa T. , Sharakhova M.V. , Badolo A. , Patchara S. , Casas-Martinez M. , Carlos B.C , Carballar-Lejarazú R. , Lambrechts L. , Souza-Neto J.A. , Bonizzoni M.
Published: March 2023

Background

Domestication is a complex, multi-stage and species-specific process that results in organisms living close to humans. In the arboviral vectorAedes aegyptiadaptation to living in proximity with anthropogenic environments has been recognized as a major evolutionary shift, separating a generalist form,Aedes aegypti formosus(Aaf), from the domestic formAedes aegypti aegypti(Aaa), which tends to deposit eggs artificial containers and bite humans for a blood meal. These behaviors enhance the mosquito vectorial capacity. The extent to which domestication has impacted theAe. aegyptigenome has not been thoroughly investigated yet.

Results

Taking advantage of two forms’ distinct and historically documented geographic distributions, we analyzed the genomes of 634 worldwideAe. aegyptimosquitoes. Using more than 300 million high-confidence SNPs, we found a unique origin for all out-of-AfricaAe. aegyptimosquitoes, with no evidence of admixture events in Africa, apart from Kenya. A group of genes were under positive selection only in out-of-Africa mosquitoes and 236 genes had nonsynonymous mutations, occurring at statistically different frequencies in Aaa and Aaf mosquitoes.

Conclusion

We identified a clear signal of genetic differentiation between Aaa and Aaf, circumscribed to a catalogue of candidate genes. These “Aaa molecular signature” genes extend beyond chemosensory genes to genes linked to neuronal and hormonal functions. This suggests that the behavioral shift to domestication may rely on the fine regulation of metabolic and neuronal functions, more than the role of a few significant genes. Our results also provide the foundation to investigate new targets for the control ofAe. aegyptipopulations.
Mechanisms of octopus arm search behavior without visual feedback
Authors: Sivitilli Dominic M. , Strong Terrell , Weertman Willem , Ullmann Joseph , Smith Joshua R. , Gire David H.
Published: March 2023

The octopus coordinates multiple, highly flexible arms with the support of a complex distributed nervous system. The octopus’s suckers, staggered along each arm, are employed in a wide range of behaviors. Many of these behaviors, such as foraging in visually occluded spaces, are executed under conditions of limited or absent visual feedback. In coordinating unseen limbs with seemingly infinite degrees of freedom across a variety of adaptive behaviors, the octopus appears to have solved a significant control problem facing the field of soft-bodied robotics. To study the strategies that the octopus uses to find and capture prey within unseen spaces, we designed and 3D printed visually occluded foraging tasks and tracked arm motion as the octopus attempted to find and retrieve a food reward. By varying the location of the food reward within these tasks, we can characterize how the arms and suckers adapt to their environment to find and capture prey. We compared these results to simulated experimental conditions performed by a model octopus arm to isolate the primary mechanisms driving our experimental observations. We found that the octopus relies on a contact-based search strategy that emerges from local sucker coordination to simplify the control of its soft, highly flexible limbs.
GITR and TIGIT immunotherapy provokes divergent multi-cellular responses in the tumor microenvironment of gastrointestinal cancers
Authors: Sathe Anuja , Ayala Carlos , Bai Xiangqi , Grimes Susan M. , Lee Byrne , Kin Cindy , Shelton Andrew , Poultsides George , Ji Hanlee P.
Published: March 2023

Understanding the cellular mechanisms of novel immunotherapy agents in the human tumor microenvironment (TME) is critical to their clinical success. We examined GITR and TIGIT immunotherapy in gastric and colon cancer patients usingex vivoslice tumor slice cultures derived from cancer surgical resections. This primary culture system maintains the original TME in a near-native state. We applied paired single-cell RNA and TCR sequencing to identify cell type specific transcriptional reprogramming. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. The TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells, including clonotypes indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. Overall, we identified cellular mechanisms of action of these two immunotherapy targets in the patients’ TME.
Foxtrot migration and dynamic over-wintering range of an arctic raptor
Authors: Pokrovsky Ivan , Curk Teja , Dietz Andreas , Fufachev Ivan , Kulikova Olga , Rößler Sebastian , Wikelski Martin
Published: March 2023

Advances in tracking technologies have revealed the diverse migration patterns of birds, which are critical for range mapping and population estimation. Population trends are usually estimated in breeding ranges where birds remain stationary, but for species that breed in remote areas like the Arctic, these trends are often assessed in over-wintering ranges. Evaluating population trends during the wintering season is challenging due to the extensive movements of birds in these ranges, which require a deep understanding of the movement dynamics. However, these movements remain understudied, particularly in the mid-latitudes, where many Arctic breeders overwinter, increasing uncertainty in their ranges and numbers. Here, we show that the Arctic breeding raptor Rough-legged buzzard, which overwinters in the mid-latitudes, has a specific wintering strategy. After migrating ca 1,500 km from the Arctic to mid-latitudes, the birds continue to move throughout the entire over-wintering period, covering an additional 1,000 km southwestward and then back northeastward as the snowline advances. This ongoing movement makes their wintering range dynamic over the course of the season. In essence, this movement represents an extension of the quick migration process, albeit at a slower pace, and we have termed this migration pattern ‘foxtrot migration,’ drawing an analogy to the alternating fast and slow movements of the foxtrot dance. These results highlight the potential errors in range mapping from single mid-winter surveys and emphasize the importance of this migration pattern in assessing the conservation status of bird species. Understanding this migration pattern could help to correctly estimate bird populations in over-wintering ranges, which is especially important for species that nest in hard-to-reach regions such as the Arctic.
Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis
Authors: Su Xin , Brassard Ariane , Bartolomucci Alexandra , Dhoparee-Doomah Iqraa , Qiu Qian , Tsering Thupten , Rohanizadeh Ramin , Koufos Olivia , Giannias Betty , Bourdeau France , Feng Lixuan , Leo Sabrina , Sangwan Veena , Tankel James , Quail Daniela , Spicer Jonathan , Burnier Julia V , Bailey Swneke Donovan , Ferri Lorenzo , Cools-Lartigue Jonathan
Published: March 2023

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities.

Graphic Abstract

Illustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden.
Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage
Authors: Park Chung , Hwang Il-Young , Yan Serena Li-Sue , Vimonpatranon Sinmanus , Wei Danlan , Ryk Don Van , Girard Alexandre , Cicala Claudia , Arthos James , Kehrl John H.
Published: March 2023

The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike proteinin vivoand its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF-α and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
Aversive experience drives offline ensemble reactivation to link memories across days
Authors: Zaki Yosif , Pennington Zachary T. , Morales-Rodriguez Denisse , Francisco Taylor R. , LaBanca Alexa R. , Dong Zhe , Lamsifer Sophia , Segura Simón Carrillo , Chen Hung-Tu , Christenson Wick Zoé , Silva Alcino J. , van der Meer Matthijs , Shuman Tristan , Fenton André , Rajan Kanaka , Cai Denise J.
Published: March 2023

Memories are encoded in neural ensembles during learning and stabilized by post-learning reactivation. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unknown. Here we show that in mice, a strong aversive experience drives the offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed two days prior, linking the fear from the recent aversive memory to the previous neutral memory. We find that fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with prior studies, we find reactivation of the recent aversive memory ensemble during the offline period following learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Taken together, these results demonstrate that strong aversive experience can drive retrospective memory-linking through the offline co-reactivation of recent memory ensembles with memory ensembles formed days prior, providing a neural mechanism by which memories can be integrated across days.
Quantifying peripheral modulation of olfaction by trigeminal agonists
Authors: Federica Genovese , Jiang Xu , Marco Tizzano , Johannes Reisert
Published: March 2023

In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants in fact are able to activate the trigeminal system, and vice versa, most trigeminal agonists activate the olfactory system as well. Although these two systems constitute two separate sensory modalities, trigeminal activation modulates the neural representation of an odor. The mechanisms behind the modulation of olfactory response by trigeminal activation are still poorly understood. In this study, we addressed this question by looking at the olfactory epithelium, where olfactory sensory neurons and trigeminal sensory fibers co-localize and where the olfactory signal is generated. We characterize the trigeminal activation in response to five different odorants by measuring intracellular Ca2+changes from primary cultures of trigeminal neurons (TGNs). We also measured responses from mice lacking TRPA1 and TRPV1 channels known to mediate some trigeminal responses. Next, we tested how trigeminal activation affects the olfactory response in the olfactory epithelium using electro-olfactogram (EOG) recordings from WT and TRPA1/V1-KO mice. The trigeminal modulation of the olfactory response was determined by measuring responses to the odorant, 2-phenylethanol (PEA), an odorant with little trigeminal potency after stimulation with a trigeminal agonist. Trigeminal agonists induced a decrease in the EOG response to PEA, which depended on the level of TRPA1 and TRPV1 activation induced by the trigeminal agonist. This suggests that trigeminal activation can alter odorant responses even at the earliest stage of the olfactory sensory transduction.

Significance Statement

Most odorants reaching the olfactory epithelium can simultaneously activate olfactory and trigeminal systems. Although these two systems constitute two separate sensory modalities, trigeminal activation can alter odor perception. Here, we analyzed the trigeminal activity induced by different odorants proposing an objective quantification of their trigeminal potency independent from human perception. We show that trigeminal activation by odorants reduces the olfactory response in the olfactory epithelium and that such modulation correlates with the trigeminal potency of the trigeminal agonist. These results show that the trigeminal system impacts the olfactory response from its earliest stage.
Post COVID-19 conditions in Children and Adolescents at 3 months following a Delta outbreak in Australia: a cohort study
Authors: Britton Philip N , Burrell Rebecca , Chapman Emily , Boyle Julia , Alexander Shirley , Belessis Yvonne , Dalby-Payne Jacqueline , Knight Katherine , Lau Christine , McMullan Brendan , Milne Bronwyn , Paull Marilyn , Nguyen Jonathan , Selvadurai Hiran , Dale Russell , Baillie Andrew
Published: March 2023

Background

Long COVID remains incompletely understood in children and adolescents with scant Australian data available. We aimed to assess the impacts of the 2021 Delta variant of SARS-CoV-2 outbreak on symptoms and functioning 12 weeks post-acute infection in a cohort of children and adolescents.

Methods

The parents (or next of kin) of 11864 children and adolescents from a population catchment who had mandatory contact with Sydney Children’s Hospital Network facilities during acute SARS-CoV-2 infection (confirmed by PCR) were contacted by email or text message.

Findings

1731 (17.7%) responded to an online survey assessing symptoms, functional impairment. 203 of the responders (11.7%) gave answers that were consistent with continued symptoms and/or functional impairment and were flagged for clinical review. Of the 169 subsequently clinically reviewed, many had already recovered (n=63, 37.3%) or had a pre-existing condition exacerbated by COVID-19 (18, 10.7%); 64 (37.9%) were diagnosed with a Post COVID Condition (PCC). Of these, a minority we considered to have features compatible with the United Kingdom consensus cases definition for Long COVID (n=21).

Interpretation

During an outbreak of the Delta variant of SARS-CoV-2 an online questionnaire with clinical review follow-up provided evidence that a majority of children with COVID-19 had complete recovery at 12 weeks post infection, but those with persisting symptoms demonstrated a wide spectrum of severity and phenotype that comprises a likely significant burden that warrants attention for individuals and at a population level.

Funding

New South Wales Health COVID-19 Emergency Response Priority Research Funding.
Identifying interaction interface betweenPseudomonasmajor biofilm forming functional amyloid FapC and disordered chaperone FapA during fibrillation deceleration
Authors: Byeon Chang-Hyeock , Saricayir Hakan , Hansen Kasper Holst , Jeffrey Jasper , Andreasen Maria , Akbey Ümit
Published: March 2023

Functional bacterial amyloids (FuBA) play a crucial role in the formation of biofilms, which are mediating chronic infections and contribute to antimicrobial resistance. This study focuses on the FapC protein fromPseudomonas, a major contributor to biofilm formation. We investigate the initial steps of FapC amyloid formation and the impact of the chaperone-like protein FapA on this process. Using solution NMR spectroscopy, we show that both FapC and FapA, which are part of the same biofilm-forming protein operon, are intrinsically disordered proteins (IDPs) in their soluble monomeric state. These SSPs were determined and compared to the Alphafold models. We further demonstrate that the IDP chaperone FapA interacts with FapC and significantly slows down the formation of FapC fibrils, while maintaining the fibril morphology unchanged. Our NMR titration experiments reveal that ∼18% of the resonances show FapA induced chemical shift perturbations (CPSs) which has not been previously observed, the largest being for A82, N201, C237, C240, A241 and G245 residues. These sites may suggest a specific interaction site and/or hotspots of fibrillation inhibition/control interface at the R1/L2 and L2/R3 transition areas and at the C-terminus of FapC. Remarkably, ∼90% of FapA NMR signals exhibit substantial CSPs upon titration with FapC. A temperature dependent effect of FapA was observed on FapC by ThT and NMR experiments. This study provides a detailed understanding of the interaction between the chaperone/chaperone-like FapA and the functional amyloid protein FapC, shedding light on the regulation and slowing down of amyloid formation. Our findings have important implications for the development of therapeutic strategies targeting biofilms and associated infections, leveraging these structural and mechanistic insights.