Negative Sentiments Toward Anterior Cruciate Ligament Injury Prevention Outweigh Positive Awareness Discussions on Social Media.

OBJECTIVES: The aim of this study is to understand the current public discussion surrounding anterior cruciate ligament (ACL) injury prevention on social media and determine factors that influence levels of public engagement. METHODS: We performed a qualitative and quantitative cross-sectional analysis of ACL injury prevention techniques discussed on social media via the Twitter application programming interface (API). The Twitter API was queried from inception to May 2023 using keywords related to ACL injury and prevention. We conducted a thematic analysis of the posts and performed a sentiment analysis using natural language processing. A multivariable regression model was used to identify metadata that predicted higher engagement (media, links, tagging, hashtags). RESULTS: A subset of 1823 unique posts were analyzed from 1701 unique accounts. Most posts were raising awareness about ACL injury prevention (n=733, 40.2%), followed by opinions on the topic (n=390, 21.4%), specific prevention techniques (n=289, 15.9%), personal experiences (n=272, 14.9%), and research (n=139, 7.6%). The majority consisted of posts from patients or caregivers (n=948, 55.7%), whereas healthcare providers accounted for 14.7% of posts. Posts containing media increased Tweet engagement count by an average of 6.1 (95% CI 2.8 to 9.4, p=0.00033) and posts discussing personal opinions increased engagement by 6.7 (95% CI 3.5 to 9.8, p=0.00004). On sentiment analysis of all included Tweets, 822 (45.1%) posts were positive, 309 (17.0%) were negative, and 692 (38.0%) were neutral. Sentiments expressed in posts related to ACL prevention were 2.8 times more negative compared to those discussing raising awareness. CONCLUSIONS: There is active discussion about ACL injury prevention on Twitter. The use of visual media increased public engagement. We identified a potential knowledge gap between the available prevention techniques and the perspectives of athletes, highlighting the need for healthcare professionals to enhance their engagement with ACL injury prevention on social media. LEVEL OF EVIDENCE: III.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

ERBB2 amplification in gastric cancer: a genomic insight into ethnic disparities.

Overall, gastric adenocarcinoma (GC) incidence rates have declined in recent years, but racial/ethnic disparities persist. Individuals who identify as Hispanic/Spanish/Latino are diagnosed with GC at younger ages and have poorer outcomes than non-Hispanic individuals. However, our understanding of GC biology across racial/ethnic groups remains limited. We assessed tumor genomic patterns by race/ethnicity among 1019 patients with primary GC in the AACR Project GENIE Consortium. Hispanic individuals presented with significantly higher rates of ERBB2/HER2 amplification vs other racial/ethnic groups (Hispanic: 13.9% vs 9.8% non-Hispanic White, 8.1% non-Hispanic Asian, and 11.0% non-Hispanic Black; p < .001, FDR adjusted q < 0.001). Hispanic patients also had higher odds of an ERBB2 amplification vs non-Hispanic whites in adjusted models (OR = 2.52, 95%CI = 1.20-5.33, p = .015). These findings underscore the important role of genomic factors in GC disparities. Ensuring equitable access to genomic profiling and targeted therapies, such as trastuzumab for HER2-overexpressing GC, is a promising avenue to mitigate GC disparities and improve outcomes.

Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines.

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo, antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\.

Defluorination of Organofluorine Compounds Using Dehalogenase Enzymes from Delftia acidovorans (D4B).

Organofluorine compounds have been widely used as pharmaceuticals, agricultural pesticides, and water-resistant coatings for decades; however, these compounds are recognized as environmental pollutants. The capability of microorganisms and enzymes to defluorinate organofluorine compounds is both rare and highly desirable to facilitate environmental remediation efforts. Recently, a strain of Delftia acidovorans (D4B) was identified with potential biodegradation activity toward perfluoroalkyl substances (PFAS) and other organofluorine compounds. Genomic analysis found haloacid and fluoroacetate dehalogenases as enzymes associated with Delftia acidovorans. Here, defluorination activity of these enzymes toward different fluorinated substrates was investigated after their recombinant expression and purification from E. coli. Using an electrochemical fluoride probe, 19F NMR, and mass spectrometry to monitor defluorination, we identified two dehalogenases, DeHa2 (a haloacid dehalogenase) and DeHa4 (a fluoroacetate dehalogenase), with activity toward mono- and difluoroacetate. Of the two dehalogenases, DeHa4 demonstrated a low pH optimum compared to DeHa2, which lost catalytic activity under acidic conditions. DeHa2 and DeHa4 are relatively small proteins, operate under aerobic conditions, and remain active for days in the presence of substrates. Significantly, while there have been many reports on dehalogenation of monofluoroacetate by dehalogenases, this study adds to the relatively small list of enzymes reported to carry out enzymatic defluorination of the more recalcitrant disubstituted carbon in an organofluorine compound. Thus, DeHa2 and DeHa4 represent organofluorine dehalogenases that may be used in the future to design and engineer robust defluorination agents for environmental remediation efforts.

Current teachers' perceptions and students' perspectives regarding activities modalities, instructional settings during primary school physical education classes in China: a cross-sectional observational study.

Introduction: This study set out to understand the association between teaching practices, teacher confidence, competence, self-efficacy, and the resulting student outcomes. Methods: Data regarding teaching behaviours were collected via video recording and then evaluated using the MASTER Observation Tool. The information about demographics, self-reported teaching confidence, competence, self-efficacy, and student outcomes was collected using questionnaires. The association between teacher characteristics, and teacher and/or student outcome variables were tested using a one-way analysis of variance (ANOVA). Results: A total of ten primary schools were involved, including 597 children (age range: 10-12 years, grade 4-6) and 16 grade 4-6 PE teachers (with 16 PE classes). Most of the Physical Education (PE) lesson time was spent in training-form activities (60.2% ± 9.1), followed by instructional time (33.1% ± 8.6%), reflection (3.4% ± 2.3%), and warm-up (2.9% ± 2.0 %). It was observed that teaching behaviours and student outcomes were significantly better in urban than rural areas. Smaller class sizes (21-30 children) were found to have more positive feedback than larger ones (41-50 children). PE teachers with more than 10 years of teaching experience reported more teaching competence and self-efficacy than teachers with less than 10 years of experience. PE teachers with class sizes of 21-30 children enjoyed significantly better scores in self-efficacy than classes with 41-50 children. They also scored more highly in confidence and competence than classes with 41-50 and 51-60 pupils. Conclusion: The current study confirmed that teachers dedicated a large proportion of lesson time to PE delivering training-form activities, followed by instructional time. Teaching behaviour and student outcomes were associated with location and class size, but not gender. The study contributes to our understanding of PE instruction in Chinese primary schools and offers preliminary evidence to improve future PE teaching strategies in the country.

Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

Immunoglobulin A Nephropathy in a Patient With Bilateral Metal-on-Metal Hip Arthroplasty.

Immunoglobulin A (IgA) nephropathy in the presence of a metal-on-metal (MoM) hip arthroplasty is a rare condition that requires close monitoring. A 61-year-old male with bilateral hip osteoarthritis underwent resurfacing hip arthroplasty with MoM articulating surfaces. Prior to his four-year postoperative visit, the patient was diagnosed with IgA nephropathy. During this visit, the patient reported clicking in the left resurfacing hip arthroplasty, and serum metal ions were significantly elevated. Consequently, the patient underwent conversion to bilateral ceramic-on-cross-linked polyethylene total hip arthroplasty, which resulted in the restoration of metal ion levels to normal. This case highlights that IgA nephropathy played a critical role in impeding the clearance of metal ions. Routine metal ion counts are warranted in patients with MoM articulating interfaces and a newly diagnosed nephropathy.

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

DYNamic Assessment of Multi-Organ level dysfunction in patients recovering from COVID-19: DYNAMO COVID-19.

We evaluated the impacts of COVID-19 on multi-organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5-7 months post-discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole-body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual-energy X-ray absorptiometry, short physical performance battery (SPPB), intra-muscular electromyography, quadriceps strength and fatigability, and daily step-count. There was a greater insulin response (incremental area under the curve, median (inter-quartile range)) during the OGTT in patients [18,289 (12,497-27,448) mIU/min/L] versus controls [8655 (7948-11,040) mIU/min/L], P < 0.001. Blood glucose response and fasting and post-prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole-body/regional adiposity, but step-count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force-loss, motor unit properties and post-exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross-sectional study, individuals without known previous morbidity who survived severe COVID-19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery.

Corneal Manifestations in Patients with Hidradenitis Suppurativa.

PURPOSE: To report two cases of bilateral blepharokeratoconjunctivitis associated with hidradenitis suppurativa (HS). METHODS: Case report and literature review. The clinical courses of two patients with HS, including ocular presentation and medical management, are described. RESULTS: Two female patients aged 18 and 23-years-old with severe HS presented with bilateral blepharokeratoconjunctivitis. Shared slit lamp findings included bilateral corneal neovascularization and inferior corneal thinning. Systemic immunosuppression was needed in the first case, which resulted in improvement in the patient's ophthalmic and dermatological findings. CONCLUSION: We report two cases of bilateral blepharokeratoconjunctivitis in two patients with severe HS. To our knowledge, this association has not previously been described in the literature. Clinicians should be aware of this association given its potentially visually devastating manifestations and the need for early therapeutic interventions.

Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

Differential Gene Expression in the Upper Respiratory Tract following Acute COVID-19 Infection in Ambulatory Patients That Develop Long COVID.

Background: Post-acute sequelae of COVID-19, or long COVID, is a condition characterized by persistent COVID-19 symptoms. As long COVID is defined by clinical criteria after an elapsed period, an opportunity for early intervention may aid in future prophylactic approaches; however, at present, the pathobiological mechanisms are multifactorial. By analyzing early virally infected upper respiratory tract tissue prior to eventual clinical diagnosis, it may be possible to identify biomarkers of altered immune response to facilitate future studies and interventions. Methods: This is a sub-group analysis of samples collected from those with confirmed COVID-19. RNA extraction from nasopharyngeal/mid-turbinate samples, sequencing, and bioinformatic analysis were performed to analyze long COVID and non-long COVID cohorts at day 14 post infection. Differences in mean viral load at various timepoints were analyzed as well as serological data. Results: We identified 26 upregulated genes in patients experiencing long COVID. Dysregulated pathways including complement and fibrinolysis pathways and IL-7 upregulation. Additionally, genes involved in neurotransmission were dysregulated, and the long COVID group had a significantly higher viral load and slower viral clearance. Conclusions: Uncovering early gene pathway abnormalities associated with eventual long COVID diagnosis may aid in early identification. We show that, post acute infection, in situ pathogenic deviations in viral response are associated with patients destined to meet consensus long COVID diagnosis that is entirely dependent on clinical factors. These results identify an important biological temporal window in the natural history of COVID-19 infection and long COVID pathogenesis amenable to testing from standard-of-care upper respiratory tract specimens.

A second space age spanning omics, platforms and medicine across orbits.

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons.

Cardiopulmonary deconditioning and plasma volume loss are not sufficient to provoke orthostatic hypertension.

Orthostatic hypertension, defined by an increase of systolic blood pressure (SBP) of ≥20 mmHg upon standing, harbors an increased cardiovascular risk. We pooled data from two rigorously conducted head-down tilt bedrest studies to test the hypothesis that cardiopulmonary deconditioning and hypovolemia predispose to orthostatic hypertension. With bedrest, peak VO2 decreased by 6 ± 4 mlO2/min/kg (p < 0.0001) and plasma volume by 367 ± 348 ml (p < 0.0001). Supine SBP increased from 127 ± 9 mmHg before to 133 ± 10 mmHg after bedrest (p < 0.0001). In participants with stable hemodynamics following head-up tilt, the incidence of orthostatic hypertension was 2 out of 67 participants before bedrest and 2 out of 57 after bedrest. We conclude that in most healthy persons, cardiovascular deconditioning and volume loss associated with long-term bedrest are not sufficient to cause orthostatic hypertension.

The prevalence of rumination syndrome and rumination disorder: A systematic review and meta-analysis.

BACKGROUND: Rumination is characterized by the repeated regurgitation of food. Rumination syndrome is a disorder of gut-brain interaction diagnosed by Rome criteria, whereas rumination disorder is a feeding and eating disorder diagnosed by DSM-5 criteria. We aimed to determine the global prevalence of rumination according to these criteria across all age groups. METHODS: We performed a systematic review and meta-analysis of studies reporting the prevalence of rumination syndrome according to Rome III and Rome IV and rumination disorder according to the following validated DSM-5 assessments: PARDI, EDA-5, EDY-Q, STEP, and STEP-CHILD. We searched MEDLINE, EMBASE, and PsychINFO (from January 1, 2006, to June 1, 2023) to identify studies reporting the prevalence of rumination in community settings in participants of any age. We did a meta-analysis to estimate the pooled prevalence and odds ratio (OR) of rumination according to diagnostic criteria, country, and characteristics such as age and sex. KEY RESULTS: The search strategy generated 1243 studies, of which 147 studies appeared to be relevant. Thirty studies were included, with a total of 114,228 participants, of whom 61,534 of these were adults and 52,694 were children. The pooled prevalence of rumination syndrome in children of all ages according to Rome III criteria was 1.0% (95% CI 0.3-1.6; I2 91.1%), but no data were available for adults. According to Rome IV criteria, the pooled prevalence of rumination syndrome in children of all ages was 0.4% (95% CI 0.2-0.6; I2 56.4%) and 3.7% in adults (95% CI 2.3-5.1; I2 91.4%). The pooled prevalence of rumination disorder in children of all ages according to EDY-Q was 2.1% (95% CI 0.9-3.4; I2 = 78.1%), but only one study utilizing EDY-Q in adults was included (0.7% [95% CI 0.4-1.0]). No data were available for children or adults using any other validated DSM-5 assessments for rumination disorder. Irrespective of diagnostic criteria, the pooled prevalence of rumination was higher in adults compared to children and adolescents (3.0% [95% CI 1.4-4.7; I2 = 98.1%] vs. 0.8% [95% CI 0.4-1.3; I2 = 90.8%]), but higher in adolescents than in children (1.1% [95% CI 0.3-2.0; I2 = 92.8%] vs. 0.1% [95% CI 0.0-0.2; I2 = 24.5%]). In adults, factors independently associated with rumination were female gender (OR 1.4 [95% CI 1.0-2.0]), anxiety (OR 2.3 [95% CI 2.1-2.6]), and depression (OR 1.8 [95% CI 1.2-2.9]). No association between gender and rumination was seen in children. CONCLUSIONS AND INFERENCES: The prevalence of rumination is more common in adults than in children. In adults, rumination is associated with female gender, anxiety, and depression. Future population studies should aim to better understand why this behavior is more common in adults and also compare validated DSM-5 assessments for rumination disorder with Rome criteria for rumination syndrome as prevalence may differ.

The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.