bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering
Novosphingobium aromaticivorans
to produce
cis,cis
-muconic acid from biomass aromatics
Authors: Vilbert Avery C. , Kontur Wayne S. , Gille Derek , Noguera Daniel R. , Donohue Timothy J. 
Published: December 2023

ABSTRACT

The platform chemical
cis,cis-
muconic acid (
cc
MA) provides facile access to a number of monomers used in the synthesis of commercial plastics. It is also a metabolic intermediate in the β-ketoadipic acid pathway of many bacteria and, therefore, a current target for microbial production from abundant renewable resources via metabolic engineering. This study investigates
Novosphingobium aromaticivorans
DSM12444 as a chassis for the production of
cc
MA from biomass aromatics. The
N. aromaticivorans
genome predicts that it encodes a previously uncharacterized protocatechuic acid (PCA) decarboxylase and a catechol 1,2-dioxygenase, which would be necessary for the conversion of aromatic metabolic intermediates to
cc
MA. This study confirmed the activity of these two enzymes
in vitro
and compared their activity to ones that have been previously characterized and used in
cc
MA production. From these results, we generated one strain that is completely derived from native genes and a second that contains genes previously used in microbial engineering synthesis of this compound. Both of these strains exhibited stoichiometric production of
cc
MA from PCA and produced greater than 100% yield of
cc
MA from the aromatic monomers that were identified in liquor derived from alkaline pretreated biomass. Our results show that a strain completely derived from native genes and one containing homologs from other hosts are both capable of stoichiometric production of
cc
MA from biomass aromatics. Overall, this work combines previously unknown aspects of aromatic metabolism in
N. aromaticivorans
and the genetic tractability of this organism to generate strains that produce
cc
MA from deconstructed biomass.

IMPORTANCE

The production of commodity chemicals from renewable resources is an important goal toward increasing the environmental and economic sustainability of industrial processes. The aromatics in plant biomass are an underutilized and abundant renewable resource for the production of valuable chemicals. However, due to the chemical composition of plant biomass, many deconstruction methods generate a heterogeneous mixture of aromatics, thus making it difficult to extract valuable chemicals using current methods. Therefore, recent efforts have focused on harnessing the pathways of microorganisms to convert a diverse set of aromatics into a single product.
Novosphingobium aromaticivorans
DSM12444 has the native ability to metabolize a wide range of aromatics and, thus, is a potential chassis for conversion of these abundant compounds to commodity chemicals. This study reports on new features of
N. aromaticivorans
that can be used to produce the commodity chemical
cis,cis
-muconic acid from renewable and abundant biomass aromatics.
A neutralizing single-domain antibody that targets the trimer interface of the human metapneumovirus fusion protein
Authors: Ballegeer Marlies , van Scherpenzeel Revina C. , Delgado Teresa , Iglesias-Caballero Maria , García Barreno Blanca , Pandey Shubham , Rush Scott A. , Kolkman Joost A. , Mas Vicente , McLellan Jason S. , Saelens Xavier 
Published: December 2023

ABSTRACT

Human metapneumovirus (hMPV) is a leading cause of viral lower respiratory tract disease in children and adults. The hMPV fusion protein F is a trimeric class I fusion protein that is initially synthesized as a precursor (F
0
) and requires proteolytic activation by a host cell protease to generate the metastable, fusion-competent prefusion conformation of F. hMPV F is considered the main target of the neutralizing antibody response against hMPV infection. We isolated single-domain antibodies (sdAbs) directed against hMPV F that potently neutralize hMPV A and B strains. One of these sdAbs, sdHMPV16, specifically bound to cleaved and uncleaved prefusion F. Co-crystal structure analysis revealed that sdHMPV16 binds to a site located at the trimer interface of prefusion F. Moreover, prophylactic treatment with a sdHMPV16-Fc fusion protein reduced viral titers in the lungs of hMPV-infected cotton rats. In summary, sdHMPV16 broadly neutralizes hMPV, can be turned into a candidate biologic that restricts hMPV replication in an
in vivo
model, and, unexpectedly, binds to an unconventional epitope at the prefusion F trimer interface.

IMPORTANCE
Human metapneumovirus (hMPV) is an important respiratory pathogen for which no licensed antivirals or vaccines exist. Single-domain antibodies represent promising antiviral biologics that can be easily produced and formatted. We describe the isolation and detailed characterization of two hMPV-neutralizing single-domain antibodies that are directed against the fusion protein F. One of these single-domain antibodies broadly neutralizes hMPV A and B strains, can prevent proteolytic maturation of F, and binds to an epitope in the F trimer interface. This suggests that hMPV pre-F undergoes trimer opening or “breathing” on infectious virions, exposing a vulnerable site for neutralizing antibodies. Finally, we show that this single-domain antibody, fused to a human IgG1 Fc, can protect cotton rats against hMPV replication, an important finding for potential future clinical applications.
Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis
Authors: Chen Luping , Ding Ling , Wang Xian , Huang Yufei , Gao Shou-Jiang 
Published: December 2023

ABSTRACT
Hyperinflammation is the hallmark of Kaposi’s sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone, which functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of the NF-κB pathway and IL-1α expression. These results reveal an important role of the IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.

IMPORTANCE
Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.
Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation
Authors: Raymonda Matthew H. , Rodríguez-Sánchez Irene , Schafer Xenia L. , Smorodintsev-Schiller Leonid , Harris Isaac S. , Munger Joshua 
Published: December 2023

ABSTRACT

Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV U
L
38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the U
L
38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of U
L
38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through U
L
38’s inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Furthermore, expression of U
L
38 or the inactivation of TSC2 results in anabolic rigidity, in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.

IMPORTANCE

Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral U
L
38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as U
L
38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that U
L
38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of U
L
38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.
Permian–Triassic magmatism above a slab window in the Eastern Tianshan: Implications for the evolution of the southern Altaids
Authors: Muhtar M.N. , Xiao Wenjiao , Brzozowski Matthew J. , Mao Qigui , Yang He , Wu Changzhi 
Published: December 2023

Abstract
Permian–Triassic metaluminous–peraluminous granitoids, mafic–ultramafic plutons, and Ni-Cu and Au deposits are prominent features in the Eastern Tianshan of the southern Altaids. However, the genetic relationship between coeval granitoids and mafic–ultramafic intrusions, and the geodynamics of magmatism and related mineralization, remain ambiguous. To address these ambiguities, we present petrological, geochemical, and bulk-rock Sr-Nd-Fe and zircon U-Pb-Hf isotope analyses of granitoids from the Shuangchagou Complex and gabbros from the Huangshandong Complex in the Eastern Tianshan. Zircon U-Pb ages demonstrate that the Huangshandong gabbro was emplaced at ca. 277.8 ± 1.4 Ma. In contrast, U-Pb ages determined from zircons in the granitic rocks of the Shuangchagou Complex suggest that the complex crystallized from three stages of magmatism: (1) strongly peraluminous S-type granitic magma represented by early-stage gneiss and granitic veins (ca. 289 Ma), (2) metaluminous to weakly peraluminous I-type granitic magmas represented by the intermediate-stage granitoids (ca. 283–261 Ma), and (3) late-stage granitoids (ca. 250–241 Ma). The intermediate- and late-stage granitoids (ca. 283–241 Ma) show clear enrichments in the light rare earth elements and large ion lithophile elements (e.g., Rb, Th, and U), and depletions in high field strength elements (e.g., Nb, Ta, and Ti), similar to arc magmas, which indicates that the North Tianshan oceanic plate was still subducting during the Middle Triassic. Considering the diversity of magmatic rocks (e.g., mid-oceanic-ridge–type mafic rocks, and I-, S- and A-type igneous rocks), mineralization styles (e.g., Alaskan-type Ni-Cu sulfide deposits and orogenic gold deposits), and the dextral strike-slip faults (e.g., Kanggur Fault) that occurred concurrently in the Eastern Tianshan during the Early Permian to Middle Triassic, we suggest that splitting of the subducted portion of the North Tianshan oceanic plate created a slab window that allowed the upwelling and partial melting of asthenospheric mantle to form the mafic–ultramafic intrusions and related Ni-Cu sulfide deposits. Sustained migration of magma provided the heat necessary to induce partial melting, devolatilization, and desulfurization of crustal materials, producing the Permian–Triassic, high-K to calc-alkaline I- and S-type granitoids, and associated orogenic gold deposits. By integrating the results of this study with published work regarding the Kanggur Accretionary Complex, we suggest that the subduction of the North Tianshan Ocean may have lasted until the Late Triassic.
Evolution of an earthquake-induced landslide complex in the South Island of New Zealand: How fault damage zones and seismicity contribute to slope failures
Authors: Singeisen Corinne , Massey Chris , Wolter Andrea , Stahl Tim , Kellett Richard , Bruce Zane , Bloom Colin , Mason Dougal 
Published: December 2023

Abstract
Tectonic deformation within fault damage zones can influence slope stability and landslide failure mechanisms due to rock mass strength effects and the presence of tectonic structures. Here, we used detailed site investigations to evaluate controls on deformation within the Half Moon Bay landslide complex, located ~1 km from the surface trace of the Hope fault in the South Island of New Zealand. During the 2016 Mw 7.8 Kaikōura earthquake, the slope experienced up to ~13 m of displacement and partially transitioned into a rock avalanche (with a volume of ~350,000 m3). Deep-seated deformation of the entire slope predated the 2016 earthquake. Results of geomorphological analysis, field mapping, geophysical surveys, slope displacement, and a 60-m-deep borehole in the incipient portion of the landslide indicated the presence of a subvertical tectonic fabric and intense fracturing and weathering of the rock mass, which gradually decrease with depth. Based on these results, we established a conceptual model wherein the landslide failure mechanism is a combination of flexural toppling along the subvertical structures coupled with joint-step-path sliding along preexisting, closely spaced discontinuities within the graywacke rock mass. Coseismic slope displacements revealed a large area of incipient failure behind the headscarp of the 2016 rock avalanche, which will likely result in further avalanching at the site. This case study demonstrates that inherited tectonic structures (combined with seismicity and weathering in an oversteepened coastal slope) play an important role in the evolution of hillslopes near active faults.
Encephalitis as an initial presentation of type 2 amiodarone-induced thyrotoxicosis
Authors: Cilia Kyle , Mifsud Simon , Craus Sarah , Vella Sandro , Dingli Nicola 
Published: December 2023

We report a case of a woman in her mid-20s presenting with encephalitis as the initial presentation of type 2 amiodarone-induced thyrotoxicosis (AIT). She was on amiodarone in view of a history of hypertrophic cardiomyopathy. Symptomatology included acute personality change and focal myoclonic jerks.Cerebrospinal fluid analysis showed a non-specific protein count elevation with negative microbiology, virology, autoimmune screen and onconeural antibodies. The electroencephalogram was consistent with a generalised cerebral dysrhythmia. An MRI of the head revealed symmetrical oedema within the motor cortices and a high T2 signal within the cerebellar dentate nuclei, with no restricted diffusion. Blood investigations confirmed thyrotoxicosis with negative antithyroid antibodies. She did not fulfil the criteria for a thyroid storm. Other possible causes of encephalitis were excluded.There was an excellent clinical, laboratory and radiological response to glucocorticoids, suggesting a diagnosis of steroid-responsive encephalitis secondary to type 2-AIT in the absence of a thyroid storm.
Race and socioeconomic disparities in mortality and end-of-life care following aneurysmal subarachnoid hemorrhage
Authors: Kabangu Jean-Luc K , Fry Lane , Bhargav Adip G , Heskett Cody , Eden Sonia V , Peterson Jeremy C , Camarata Paul J , Ebersole Koji 
Published: December 2023

BackgroundThis study explores racial and socioeconomic disparities in aneurysmal subarachnoid hemorrhage (aSAH) care, highlighting the impact on treatment and outcomes. The study aims to shed light on inequities and inform strategies for reducing disparities in healthcare delivery.MethodsIn this cohort study the National Inpatient Sample database was queried for patient admissions with ruptured aSAH from 2016 to 2020. Multivariable analyses were performed estimating the impact of socioeconomic status and race on rates of acute treatment, functional outcomes, mortality, receipt of life-sustaining interventions (mechanical ventilation, tracheostomy, gastrostomy, and blood transfusions), and end-of-life care (palliative care and do not resuscitate).ResultsA total of 181 530 patients were included. Minority patients were more likely to undergo treatment (OR 1.15, 95% CI 1.09 to 1.22, P<0.001) and were less likely to die (OR 0.89, 95% CI 0.84 to 0.95, P<0.001) than White patients. However, they were also more likely to have a tracheostomy (OR 1.47, 95% CI 1.33 to 1.62, P<0.001) and gastrostomy tube placement (OR 1.43, 95%CI 1.32 to 1.54, P<0.001), while receiving less palliative care (OR 0.75, 95% CI 0.70 to 0.80, P<0.001). This trend persisted when comparing minority patients from wealthier backgrounds with White patients from poorer backgrounds for treatment (OR 1.10, 95% CI 1.00 to 1.21, P=0.046), mortality (OR 0.82, 95% CI 0.74 to 0.89, P<0.001), tracheostomy tube (OR 1.27, 95% CI 1.07 to 1.48, P<0.001), gastrostomy tube (OR 1.34, 95% CI 1.18 to 1.52, P<0.001), and palliative care (OR 0.76, 95% CI 0.69 to 0.84, P<0.001).ConclusionsCompared with White patients, minority patients with aSAH are more likely to undergo acute treatment and have lower mortality, yet receive more life-sustaining interventions and less palliation, even in higher socioeconomic classes. Addressing these disparities is imperative to ensure equitable access to optimal care and improve outcomes for all patients regardless of race or class.
Azilsartan prevents muscle loss and fast- to slow-twitch muscle fiber shift in natural ageing sarcopenic rats
Authors: Prajapati Priyanka , Kumar Anand , Mangrulkar Shubhada , Chaple D.R. , Saraf Shubhini A. , Kushwaha Sapana 
Published: December 2023

Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4–6 months and 18–21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments.
Experimental observation of distinct amplitude-modulated bursting in Liénard system
Authors: Kingston S. Leo , Vijay S. Dinesh , Kumarasamy Suresh , Kapitaniak Tomasz 
Published: December 2023

AbstractIn this study, we explore the emergence of amplitude-modulated bursting in a multi-frequency excited Liénard system. Our investigation reveals that the system exhibits distinct patterns of amplitude-modulated bursting for a lower damping value and varying forcing frequencies of the system. Conversely, for a higher damping value with distinct system frequencies, the system exhibits intricate amplitude-modulated bursting accompanied by a variety of bursting oscillations. The discrete patterns of amplitude-modulated bursting arise as a consequence of the dynamic interplay with slowly varying multiple frequency forcing within the system. To gain a deeper understanding of these dynamics, we conduct a comprehensive stability bifurcation analysis. Furthermore, to validate our findings, we perform numerical simulations and corroborate our results through a real-time hardware circuit experiment. This interdisciplinary approach provides valuable insights into the behavior of the Liénard system under multi-frequency excitation, shedding light on its complex dynamical characteristics.
UNEXPLAINED UNILATERAL LOWER LIMB NEUROLOGICAL DEFICITS AFTER POSTERIOR SPINAL DECOMPRESSION AND FUSION FOR DEGENERATIVE LUMBAR SPONDYLOLISTHESIS
Authors: Alzakri A. 
Published: December 2023

The observational data from the Spine Patient Outcomes Research Trial (SPORT) confirm the superiority of surgical over conservative management of symptomatic degenerative spondylolisthesis. The most common reported neurologic complications after lumbar posterior decompression and fusion are implant malposition, contralateral foraminal stenosis, hematoma/seroma, arachnoiditis, and nerve root oedema or vascular underlying causes. The current study reported that the patient developed unexpected left side neurological deficit after conventional lumbar posterior spinal decompression surgery for degenerative spondylolisthesis. No intraoperative dural insult. The computer topography (CT) scan and magnetic resonance imaging (MRI) of the spine after index surgery show adequate canal and foraminal decompression. No hardware-related complications or compressive hematoma could explain the patient’s symptoms. The patient recovered completely after removing the redundant posterolateral bone graft. The theory behind that is aggressive posterolateral dissection over the transverse process and abundant application of the bone graft might compress or injure the lumbar plexus. So, we suggested a delicate dissection posterolaterally and only a reasonable amount of bone graft could be applied to prevent such a devastating neurological complication.