Biomechanics and morphological comparisons of the caudal region of titanosaurs from the Cretaceous of Brazil: Paleobiology and paleoecology inferences.

Biomechanical studies in sauropod dinosaurs are mainly focused on neck posture and feeding strategy. Few works investigate other aspects such as tail movement and function, especially in the clade Titanosauria, the most diverse within Neosauropoda. This study applied biomechanical concepts of neutral pose (cartilaginous neutral pose) and range of motion to verify the shape and direction of the caudal region of the advanced titanosaurs Adamantisaurus mezzalirai and Baurutitan britoi, in addition to comparing it with other titanosaurs (e.g., Arrudatitan maximus, Lirainosaurus astibiae, and Trigonosaurus pricei). As a result, the tails analyzed have a sigmoidal-convex shape, probably close to the ground (but not touching it). The sigmoidal-convex shape could increase the moment arm for the M. caudofemoralis longus, making it possible to use the tail as a fifth stabilizing member. This work expands our knowledge about sauropod dinosaurs by exposing a diversity of shapes for the tails of titanosaur sauropods and brings new possibilities for how these dinosaurs could use their tails.

Elucidating the Significance of Zonulin in the Pathogenesis of Chronic Inflammatory Disorders: Emphasis on Intestinal Barrier Function and Tight Junction Regulation.

The intestinal barrier, a critical component of the body's defense system, plays a vital role in maintaining homeostasis by preventing the translocation of harmful substances from the gut lumen into the bloodstream. Disruptions in this barrier, often characterized by increased intestinal permeability, are increasingly recognized as contributors to the development and progression of various Chronic Inflammatory Disorders (CIDs). Zonulin, a key regulator of intestinal Tight Junctions (TJs), has emerged as a pivotal player in this process. Dysregulation of zonulin, leading to increased intestinal permeability, has been implicated in the pathogenesis of a wide range of CIDs, including Inflammatory Bowel Disease (IBD), celiac disease, and Multiple Sclerosis (MS). This review examines the intricate relationship between zonulin and intestinal permeability, emphasizing its role in regulating TJ integrity and its association with various CIDs. Recent research has demonstrated the therapeutic potential of targeting zonulin, specifically through the use of larazotide acetate, a zonulin antagonist. Preclinical and clinical studies have shown promising results in improving gut barrier integrity and reducing inflammation in patients with CIDs. These findings underscore the significance of zonulin as a potential biomarker for intestinal barrier function and a promising therapeutic target for managing CIDs. Further research is needed to elucidate the precise mechanisms of action of zonulin antagonists and evaluate their efficacy and safety in clinical trials. A deeper understanding of the complex interplay among zonulin, intestinal permeability, and CIDs is crucial, paving the way for novel therapeutic strategies and personalized approaches to patient care.

Early Growth and Physiological Acclimation to Shade and Water Restriction of Seven Sclerophyllous Species of the Mediterranean Forests of Central Chile.

The success of using active restoration in Mediterranean-type climate zones mostly depends on an appropriate matching of plant species and specific management prescriptions upon establishment. In this study, we assessed the early growth and short-term physiological acclimation of seven common species found in the sclerophyllous forests in central Chile to water restriction and shading. We established a nursery experiment that included three treatments (T0: sun-exposed and water-restricted, T1: sun-exposed and fully irrigated, and T2: shaded and fully irrigated) and seven tree species differing in their shade and drought tolerance (Quillaja saponaria Molina, Aristotelia chilensis (Mol.) Stuntz, Peumus boldus Molina, Lithraea caustica (Mol.) Hook. and Arn, Luma apiculata (DC.) Burret, Colliguaja odorifera Molina, and Escallonia pulverulenta (Ruiz and Prav.) Pers). We measured the increment in seedling height and different leaf morpho-physiological traits during two months in the dry season. Based on the measured traits, none of the species took advantage of the higher water availability in T1 relative to T0, but most of the species responded to the shade in T2, regardless of their shade or drought tolerance. Height increments due to shade varied from 0% in P. boldus to 203% in L. apiculata. Overall, all the species responded similarly to the treatments in specific leaf area, chlorophyll content index, photosynthetic rate, stomatal conductance, and intrinsic water use efficiency. This suggests that the species exhibited similar acclimation patterns of these parameters to shade and drought, even regarding the variation in midday xylem water potential found in the water-restricted treatment T0 (from -1.5 MPa in P. boldus to -3.1 MPa in E. pulverulenta). In this study, shading had a higher positive effect on the seedling performance of sclerophyllous species than watering, which at operational level highlights the need for investing in tree shelters when using these species in restoration programs.

Effects of cultural dynamics on everyday acoustic environmentsa).

Differences in acoustic environments have previously been linked to socioeconomic status (SES). However, it is crucial to acknowledge that cultural values can also play a significant role in shaping acoustic environments. The goal of this study was to investigate if social behaviors related to cultural heritage and SES could help us understand how Latinx and European college students in the U.S. have different acoustic environments. College students were given digital recorders to record their daily acoustic environments for two days. These recordings were used to (1) evaluate nearfield noise levels in their natural surroundings and (2) quantify the percentage of time participants spent on behavioral collectivistic activities such as socializing and interacting with others. Behavioral collectivism was examined as a mediator between cultural heritage, SES, and nearfield noise levels. Findings revealed that both SES and cultural heritage were associated with nearfield noise levels. However, behavioral collectivism mediated the relationship between culture and nearfield noise levels. These findings show that collectivist cultural norms significantly relate to Latinx' daily noise levels. The implications of these findings for public health and health inequities included promoting equitable auditory well-being and better knowledge of socio-cultural settings.

Full-length structure and heme binding in the transcriptional regulator HcpR.

HcpR is a CRP-family transcriptional regulator found in many Gram-negative anaerobic bacteria. In the perio-pathogen Porphyromonas gingivalis, HcpR is crucial for the response to reactive nitrogen species such as nitric oxide (NO). Binding of NO to the heme group of HcpR leads to transcription of the redox enzyme Hcp. However, the molecular mechanisms of heme binding to HcpR remain unknown. In this study we present the 2.3 Å structure of the P. gingivalis HcpR. Interdomain interactions present in the structure help to form a hydrophobic pocket in the N-terminal sensing domain. A comparison analysis with other CRP-family members reveals that the molecular mechanisms of HcpR-mediated regulation may be distinct from other family members. Using docking studies, we identify a putative heme binding site in the sensing domain. In vitro complementation and mutagenesis studies verify Met68 as an important residue in activation of HcpR. Finally, heme binding studies with purified forms of recombinant HcpR support Met68 and His149 residues as important for proper heme coordination in HcpR.

Pelage variation and morphometrics of closely related Callithrix marmoset species and their hybrids.

BACKGROUND: Hybrids are expected to show greater phenotypic variation than their parental species, yet how hybrid phenotype expression varies with genetic distances in closely-related parental species remains surprisingly understudied. Here, we investigate pelage and morphometric trait variation in anthropogenic hybrids between four species of Brazilian Callithrix marmosets, a relatively recent primate radiation. Marmoset species are distinguishable by pelage phenotype and morphological specializations for eating tree exudates. In this work, we (1) describe qualitative phenotypic pelage differences between parental species and hybrids; (2) test whether significant quantitative differences exist between parental and hybrid morphometric phenotypes; and (3) determine which hybrid morphometic traits show heterosis, dysgenesis, trangression, or intermediacy relative to the parental trait. We investigated cranial and post-cranial morphometric traits, as most hybrid morphological studies focus on the former instead of the latter. Finally, we estimate mitogenomic distances between marmoset species from previously published data. RESULTS: Marmoset hybrid facial and overall body pelage variation reflected novel combinations of coloration and patterns present in parental species. In morphometric traits, C. jacchus and C. penicillata were the most similar, while C. aurita was the most distinct, and C. geoffroyi trait measures fell between these species. Only three traits in C. jacchus x C. penicillata hybrids showed heterosis. We observed heterosis and dysgenesis in several traits of C. penicillata x C. geoffroyi hybrids. Transgressive segregation was observed in hybrids of C. aurita and the other species. These hybrids were also C. aurita-like for a number of traits, including body length. Genetic distance was closest between C. jacchus and C. penicillata and farthest between C. aurita and the other species. CONCLUSION: We attributed significant morphometric differences between marmoset species to variable levels of morphological specialization for exudivory in these species. Our results suggest that intermediate or parental species-like hybrid traits relative to the parental trait values are more likely in crosses between species with relatively lesser genetic distance. More extreme phenotypic variation is more likely in parental species with greater genetic distance, with transgressive traits appearing in hybrids of the most genetically distant parental species. We further suggest that fewer developmental disturbances can be expected in hybrids of more recently diverged parental species, and that future studies of hybrid phenotypic variation should investigate selective pressures on Callithrix cranial and post-cranial morphological traits.

Real-World Effectiveness of Nirsevimab Against Respiratory Syncytial Virus: A Test-Negative Case-Control Study.

IMPORTANCE: Nirsevimab, a long-acting monoclonal antibody, has demonstrated efficacy against RSV-related lower respiratory tract infections (LRTIs) in clinical trials. Post-licensure monitoring is essential to confirm these benefits in real-world settings. OBJECTIVE: To evaluate the real-world effectiveness of nirsevimab against medically attended RSV infections in infants and to assess how effectiveness varies by disease severity, dosage, and time since immunization. DESIGN SETTING AND PARTICIPANTS: This test-negative case-control study used inpatient, outpatient, and emergency room data from the Yale New Haven Health System. Nirsevimab-eligible infants who were tested for RSV using polymerase chain reaction between October 1, 2023 and May 9, 2024 were included. Cases were infants with confirmed RSV infections; controls were those who tested negative. EXPOSURE: Nirsevimab immunization, verified through state immunization registries. MAIN OUTCOMES AND MEASURES: Effectiveness was estimated using multivariable logistic regression, adjusting for age, calendar month, and individual risk factors. Separate models examined effectiveness by clinical setting, disease severity, dose, and time since immunization. Broader outcomes, including all-cause LRTI and LRTI-related hospitalization, were also analyzed, with stratification by early and late respiratory seasons. RESULTS: The analytic sample included 3,090 infants (median age 6.7 months, IQR 3.6-9.7), with 680 (22.0%) RSV-positive and 2,410 (78.0%) RSV-negative. 21 (3.1%) RSV-positive and 309 (12.8%) RSV-negative infants received nirsevimab. Effectiveness against RSV infection was 68.4% (95% CI, 50.3%-80.8%). Effectiveness was 61.6% (95% CI, 35.6%-78.6%) for outpatient visits and 80.5% (95% CI, 52.0%-93.5%) for hospitalizations. The highest effectiveness, 84.6% (95% CI, 58.7%-95.6%), was observed against severe RSV outcomes requiring ICU admission or high-flow oxygen. Although effectiveness against RSV infections declined over time, it remained significant at 55% (95% credible interval, 16%-75%) at 14 weeks post-immunization. Protective effectiveness was also observed against all-cause LRTI and LRTI-related hospitalizations during peak RSV season (49.4% [95% CI, 10.7%-72.9%] and 79.1% [95% CI, 27.6%-94.9%], respectively). However, from February to May, when RSV positivity was low, effectiveness against these broader outcomes was negligible. CONCLUSIONS AND RELEVANCE: Nirsevimab provided substantial protection against RSV-related outcomes for at least three months. These findings support the continued use of nirsevimab and provide evidence that may help build public confidence in the immunization program. Key Points: Question: What is the effectiveness of nirsevimab against medically attended respiratory syncytial virus (RSV) infections in infants?Findings: 680 RSV test-positive cases and 2,410 RSV test-negative controls were included in this test-negative case-control study. Nirsevimab's effectiveness was 69% against RSV infections, 81% against RSV-associated hospitalization, and 85% against severe RSV disease. Effectiveness against RSV infection declined from 79% at 2 weeks post-immunization to 55% at 14 weeks post-immunization.Meaning: Nirsevimab provides strong protection against a wide range of RSV outcomes, but its effectiveness diminishes over time. These data can be utilized to optimize nirsevimab's implementation and sustain its uptake.

Germline mutations in a G protein identify signaling cross-talk in T cells.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

Surgery and postoperative definitive radiotherapy for management of canine soft tissue sarcoma: a multi-institutional retrospective study of 272 dogs (2010-2020).

OBJECTIVE: To report local progression and survival in dogs following surgery and postoperative definitive radiotherapy (dRT) for management of soft tissue sarcoma (STS) and to evaluate risk factors for local progression and survival. METHODS: Records were retrospectively reviewed at 9 referral hospitals for dogs managed with postoperative dRT between January 1, 2010, and January 1, 2020, following surgery for STS. Data related to presentation, surgery, dRT, systemic therapy, and outcome were abstracted. Selected variables were assessed for association with local progression and overall survival. RESULTS: 272 dogs were included. Histologic grade was reported in 249 dogs: 102 were grade 1 (40.9%), 120 were grade 2 (48.2%), and 27 were grade 3 (10.8%). Local progression was suspected or confirmed in 56 dogs. Local progression rates were similar for grade 1 (24 of 89 [26.7%]), grade 2 (23 of 111 [20.7%]), and grade 3 tumors (6 of 22 [27.3%]). Previous recurrence (P = .010) and subsequent distant metastasis (P = .014) were associated with more frequent local progression; intensity-modulated radiotherapy was associated with decreased local progression (P = .025) compared to other forms of delivery. Age (P = .049), grade (P = .009), previous recurrence (P = .009), and institution type for surgery (P = .043) were associated with overall survival. CONCLUSIONS: Outcomes for most dogs were good; however, the frequency of local progression indicates an ongoing need to critically appraise local management strategies, particularly for low-grade STS. Intensity-modulated radiotherapy was associated with lower rates of local progression and may be preferred to less precise forms of delivery. CLINICAL RELEVANCE: These data may guide clinicians when making decisions regarding dRT for management of STS.

Acceptance of a third COVID-19 vaccine dose, vaccine interchangeability, and clinical trial enrolment among parents of children 12-17 years in Lima, Perú.

Objectives: To characterize factors associated with parental willingness for their children participation in a COVID-19 vaccine trial, use of different COVID-19 vaccines and acceptance of a third vaccine dose. Methods: Parents of children aged 12-17 years in Lima, Perú were asked to complete an online questionnaire via social networks, from November 9, 2021, to April 23, 2022. We calculated crude and adjusted prevalence ratios with 95% confidence intervals to compare factors with the mentioned outcomes. Results: From 523 parents responding, 374 completed the survey. 90.4% would give their children a third vaccine dose, 36.6% would allow their children participation in a COVID-19 vaccine clinical trial, and 33.2% would accept different vaccine brands between doses. Parental belief that COVID-19 vaccine studies met quality standards was associated with acceptance of a third booster dose (adjusted PR 3.25; 95% CI1.57-6.74; p = 0.002), enrolment in a COVID-19 clinical trial (adjusted PR 4.49; 95% CI1.25-16.06; p = 0.02), and acceptance of different COVID-19 vaccine brands between doses (adjusted PR 10.02; 95% CI1.40-71.95; p = 0.02). Conclusion: Most parents would accept a third vaccine booster dose, approximately a third would participate in COVID-19 vaccine trials. Believing COVID-19 vaccines studies fulfilled quality standards was associated with the study outcomes. It is necessary to inform about the rigorous processes for the development of COVID-19 vaccines to generate confidence in parents to accept these vaccine-related outcomes.

Mineralocorticoid receptor antagonism partially prevents dysfunction of T cell maturation in rats chronically treated with ethanol.

Ethanol consumption induces thymic atrophy and affects T cell maturation in the thymus. However, the mechanisms underlying such effects still need to be fully understood. We attempted to investigate the role of mineralocorticoid receptors (MR) on ethanol-induced thymic atrophy, T cell maturation dysfunction, and the role of oxidative stress in such responses. Male Wistar Hannover rats were treated with ethanol (20%; in volume ratio) and/or potassium canrenoate, an antagonist of MR (MRA; 30 mg/kg/day, gavage) for five weeks. Blockade of MR prevented ethanol-induced increases in the number of double-positive (CD4+CD8+), CD8+ single-positive (CD4-CD8+), CD4+ single-positive (CD4+CD8-), and Foxp3+CD4+ (Treg) cells in the thymus. Ethanol increased NOX2-derived superoxide (O2•-), lipoperoxidation, and superoxide dismutase (SOD) activity in the thymus. Pretreatment with the MRA fully prevented these responses. Apocynin, an antioxidant, prevented ethanol-induced increases in the number of double-positive and CD8+ single-positive cells but failed to prevent the rise in the number of CD4+ single-positive and Treg cells induced by ethanol. Apocynin, but not the MRA, prevented thymic atrophy induced by ethanol. Our findings provided novel evidence for the participation of MR in thymic dysfunction induced by ethanol consumption. Oxidative stress mediates the increase in double-positive and CD8+ single-positive cells in response to MR activation, while positive regulation of CD4+ single-positive and Treg cells is independent of oxidative stress. Oxidative stress is a significant mechanism of thymic atrophy associated with ethanol consumption, but this response is independent of MR activation.

A concentration of visual cortex-like neurons in prefrontal cortex.

Visual recognition is largely realized through neurons in the ventral stream, though recently, studies have suggested that ventrolateral prefrontal cortex (vlPFC) is also important for visual processing. While it is hypothesized that sensory and cognitive processes are integrated in vlPFC neurons, it is not clear how this mechanism benefits vision, or even if vlPFC neurons have properties essential for computations in visual cortex implemented via recurrence. Here, we investigated if vlPFC neurons in two male monkeys had functions comparable to visual cortex, including receptive fields, image selectivity, and the capacity to synthesize highly activating stimuli using generative networks. We found a subset of vlPFC sites show all properties, suggesting subpopulations of vlPFC neurons encode statistics about the world. Further, these vlPFC sites may be anatomically clustered, consistent with fMRI-identified functional organization. Our findings suggest that stable visual encoding in vlPFC may be a necessary condition for local and brain-wide computations.

Examining Clinical Features and Severe Neurologic Disease of Parechovirus Infection in Young Infants: A Multi-State Cohort Study.

BACKGROUND: Human parechovirus (HPeV) infection can result in severe disease in infants, including sepsis, seizures, brain injury, and death. In 2022, a resurgence of HPeV was noted in young infants. Spectrum of illness and outcomes remain to be fully described. METHODS: A multi-state retrospective cohort study was conducted to evaluate hospitalizations and outcomes of infants aged ≤6 months admitted in 2022 with laboratory-confirmed HPeV infection. Infants with severe disease were defined as having clinical seizures, or abnormalities on MRI or EEG during admission. Infants with severe vs non-severe disease were compared using descriptive statistics. RESULTS: 124 U.S. infants were identified with HPeV in 11 states. Cases of HPeV peaked in May and presented at a median of 25.8 days of life (0-194 d) with fever, fussiness, and poor feeding. Bacterial and other viral co-infections were rare. 33 (27%) of infants had severe neurologic disease, were more likely to present at an earlier age (13.9 vs 30 days of life, p<0.01), have preterm gestation (12% vs. 1%, p = 0.02), and present with respiratory symptoms (26% vs. 8%, p = 0.01) or apnea (41% vs. 1%, p <0.001). Subcortical white matter cytoxic cerebral edema was common in severe cases. Two infants with HPeV died during admission with severe neurologic HPeV disease; no infant with mild HPeV disease died. CONCLUSIONS: This is the largest, geographically-diverse U.S. study to describe the 2022 HPeV outbreak among infants. Longitudinal follow up of infants is needed to define predictors and outcomes of severe HPeV disease.

Imperfect symmetry facilitated the evolution of specificity and high-order stoichiometry in vertebrate hemoglobin.

Many proteins form paralogous multimers - molecular complexes in which evolutionarily related proteins are arranged into specific quaternary structures. Little is known about the mechanisms by which they acquired their stoichiometry (the number of total subunits in the complex) and heterospecificity (the preference of subunits for their paralogs rather than other copies of the same protein). Here we use ancestral protein reconstruction and biochemical experiments to study historical increases in stoichiometry and specificity during the evolution of vertebrate hemoglobin (Hb), a α2ß2 heterotetramer that evolved from a homodimeric ancestor after a gene duplication. We show that the mechanisms for this evolutionary transition was simple. One hydrophobic substitution in subunit ß after the gene duplication was sufficient to cause the ancestral dimer to homotetramerize with high affinity across a new interface. During this same interval, a single-residue deletion in subunit α at the older interface conferred specificity for the heterotetrameric form and the trans-orientation of subunits within it. These sudden transitions in stoichiometry and specificity were possible because the interfaces in Hb are isologous - involving the same surface patch on interacting subunits, rotated 180° relative to each other - but the symmetry is slightly imperfect. This architecture amplifies the impacts of individual mutations on stoichiometry and specificity, especially in higher-order complexes, and allows single substitutions to differentially affect heteromeric vs homomeric interactions. Many multimers are isologous, and symmetry in proteins is always imperfect; our findings therefore suggest that elaborate and specific molecular complexes may often evolve via simple genetic and physical mechanisms.

Inherited phosphate and pyrophosphate disorders: New insights and novel therapies changing the oral health landscape.

BACKGROUND: Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes the following 4 mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, although manifestations are distinct from those in the skeleton. TYPES OF STUDIES REVIEWED: The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may affect oral health and dental treatments of affected patients. RESULTS: Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia and hyperphosphatemic familial tumoral calcinosis and disruptions in pyrophosphate levels in hypophosphatasia and generalized arterial calcification of infancy contribute to dental mineralization defects. Traditionally, there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected patients. PRACTICAL IMPLICATIONS: Research over the past 2 decades has exponentially expanded the understanding of mineral metabolism, and has led to novel treatments for mineralization disorders. Newly implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral health care that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams.

Ocular findings in Jansen metaphyseal chondrodysplasia.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging.

Recent cervical cancer incidence, stage at diagnosis, and mortality trends in Puerto Rico, 2001-2019.

BACKGROUND: Cervical cancer incidence is rising in Puerto Rico (PR). Whether the increase is real or reflective of increased diagnostic scrutiny remains unclear. METHODS: Using data from the PR Central Cancer Registry for 2001-2019, we estimated trends of hysterectomy-corrected cervical cancer incidence and mortality rates, overall, and by stage at diagnosis and age. RESULTS: Overall, cervical cancer incidence (per 100,000) increased 1.6%/year (95% CI, -0.5% to 3.8%) from 12.5 to 15.3, with a prominent increase in distant-stage disease (4.5%/year [95% CI, 1.6% to 8.0%]), particularly among screening age eligible (25-64-year-old) women (5.8%/year [95% CI, 2.1% to 10.6%]). Mortality rates in this age-group remained stable during the study period. CONCLUSIONS: Increased occurrence of distant-stage disease among screening-eligible women is troubling and may reflect a real increase. Future research is needed to elucidate the factors underlying these trends. Improved prevention is also an urgent priority to reverse the rising cervical cancer incidence in PR.

Climate change is associated with higher phytoplankton biomass and longer blooms in the West Antarctic Peninsula.

The Antarctic Peninsula (West Antarctica) marine ecosystem has undergone substantial changes due to climate-induced shifts in atmospheric and oceanic temperatures since the 1950s. Using 25 years of satellite data (1998-2022), this study presents evidence that phytoplankton biomass and bloom phenology in the West Antarctic Peninsula are significantly changing as a response to anthropogenic climate change. Enhanced phytoplankton biomass was observed along the West Antarctic Peninsula, particularly in the early austral autumn, resulting in longer blooms. Long-term sea ice decline was identified as the main driver enabling phytoplankton growth in early spring and autumn, in parallel with a recent intensification of the Southern Annular Mode (2010-ongoing), which was observed to influence regional variability. Our findings contribute to the understanding of the complex interplay between environmental changes and phytoplankton responses in this climatically key region of the Southern Ocean and raise important questions regarding the far-reaching consequences that these ecological changes may have on global carbon sequestration and Antarctic food webs in the future.

The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.