Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

The Frequency of Symptoms in Patients With a Diagnosis of Degenerative Cervical Myelopathy: Results of a Scoping Review.

STUDY DESIGN: Delayed diagnosis of degenerative cervical myelopathy (DCM) is associated with reduced quality of life and greater disability. Developing diagnostic criteria for DCM has been identified as a top research priority. OBJECTIVES: This scoping review aims to address the following questions: What is the diagnostic accuracy and frequency of clinical symptoms in patients with DCM? METHODS: A scoping review was conducted using a database of all primary DCM studies published between 2005 and 2020. Studies were included if they (i) assessed the diagnostic accuracy of a symptom using an appropriate control group or (ii) reported the frequency of a symptom in a cohort of DCM patients. RESULTS: This review identified three studies that discussed the diagnostic accuracy of various symptoms and included a control group. An additional 58 reported on the frequency of symptoms in a cohort of patients with DCM. The most frequent and sensitive symptoms in DCM include unspecified paresthesias (86%), hand numbness (82%) and hand paresthesias (79%). Neck and/or shoulder pain was present in 51% of patients with DCM, whereas a minority had back (19%) or lower extremity pain (10%). Bladder dysfunction was uncommon (38%) although more frequent than bowel (23%) and sexual impairment (4%). Gait impairment is also commonly seen in patients with DCM (72%). CONCLUSION: Patients with DCM present with many different symptoms, most commonly sensorimotor impairment of the upper extremities, pain, bladder dysfunction and gait disturbance. If patients present with a combination of these symptoms, further neuroimaging is indicated to confirm the diagnosis of DCM.

The value of Clinical signs in the diagnosis of Degenerative Cervical Myelopathy - A Systematic review and Meta-analysis.

STUDY DESIGN: Delayed diagnosis of degenerative cervical myelopathy (DCM) is likely due to a combination of its subtle symptoms, incomplete neurological assessments by clinicians and a lack of public and professional awareness. Diagnostic criteria for DCM will likely facilitate earlier referral for definitive management. OBJECTIVES: This systematic review aims to determine (i) the diagnostic accuracy of various clinical signs and (ii) the association between clinical signs and disease severity in DCM? METHODS: A search was performed to identify studies on adult patients that evaluated the diagnostic accuracy of a clinical sign used for diagnosing DCM. Studies were also included if they assessed the association between the presence of a clinical sign and disease severity. The QUADAS-2 tool was used to evaluate the risk of bias of individual studies. RESULTS: This review identified eleven studies that used a control group to evaluate the diagnostic accuracy of various signs. An additional 61 articles reported on the frequency of clinical signs in a cohort of DCM patients. The most sensitive clinical tests for diagnosing DCM were the Tromner and hyperreflexia, whereas the most specific tests were the Babinski, Tromner, clonus and inverted supinator sign. Five studies evaluated the association between the presence of various clinical signs and disease severity. There was no definite association between Hoffmann sign, Babinski sign or hyperreflexia and disease severity. CONCLUSION: The presence of clinical signs suggesting spinal cord compression should encourage health care professionals to pursue further investigation, such as neuroimaging to either confirm or refute a diagnosis of DCM.

Adverse effects of frailty on the outcomes of surgery for degenerative cervical myelopathy: results from a prospective multicenter international data set of 757 patients.

OBJECTIVE: The goal of this study was to determine the effect of the degree of frailty on long-term neurological and functional outcomes after surgery for degenerative cervical myelopathy (DCM). METHODS: A combined database of patients enrolled in the Cervical Spondylotic Myelopathy-North America and Cervical Spondylotic Myelopathy-International prospective international multicenter observational studies who underwent surgery for DCM was used as the source data. All patients underwent baseline and follow-up assessment at 2 years after surgery for functional, disability, and quality of life measurements (modified Japanese Orthopaedic Association [mJOA] scale, Neck Disability Index, SF-36 physical and mental component summary scores). Patients were separated into 4 groups according to their baseline modified frailty index 5-point scale score: not frail, pre-frail, frail, and severely frail. Differences among groups were analyzed at baseline and at 2 years after surgery, including change in scores (delta values) and the odds ratio of achieving the minimum clinically important difference (MCID) through univariate and multivariable logistic regression adjusting for age, approach, number of levels treated, and sex. RESULTS: A total of 757 patients (63% male) with a mean age of 56 (95% CI 55.5-57.2) years were included: 470 patients underwent an anterior approach, 310 had a posterior approach, and 23 had a combined anterior/posterior approach. A total of 50% (n = 378) of patients were classified as not frail, with 33% (n = 250) pre-frail, 13% (n = 101) frail, and 4% (n = 28) severely frail. The baseline mJOA score was significantly lower with increasing frailty (14.00 [95% CI 13.75-14.19] for not frail vs 9.71 [95% CI 9.01-10.42] for severely frail patients; p < 0.05), but the change at 2 years was not significantly different among all groups (2.43 [95% CI 2.16-2.71] for not frail vs 2.56 [95% CI 1.10-4.02] for severely frail). The SF-36 delta values were also not different among groups, but significantly worse at baseline with increasing frailty. The odds ratio of achieving MCID for mJOA was significantly higher in the not frail group (1.89 [95% CI 1.36-2.61]; p < 0.05) compared to the other frailty cohorts, which remained after adjusting for age, approach, levels treated, and sex. The odds ratio of achieving MCID for the SF-36 domains was similar among all frailty groups. CONCLUSIONS: Increasing frailty is associated with worse baseline functional and quality of life measures in patients undergoing surgery for DCM. Frailty does not affect the magnitude of improvement in outcome measures after surgery, but reduces the chance of achieving the MCID for functional impairment significantly. Preoperative frailty assessment can therefore help guide clinicians in managing expectations after surgery for DCM. Potentially modifiable factors should be optimized in frail patients preoperatively to enhance functional outcomes.

What the geological past can tell us about the future of the ocean's twilight zone.

Paleontological reconstructions of plankton community structure during warm periods of the Cenozoic (last 66 million years) reveal that deep-dwelling 'twilight zone' (200-1000 m) plankton were less abundant and diverse, and lived much closer to the surface, than in colder, more recent climates. We suggest that this is a consequence of temperature's role in controlling the rate that sinking organic matter is broken down and metabolized by bacteria, a process that occurs faster at warmer temperatures. In a warmer ocean, a smaller fraction of organic matter reaches the ocean interior, affecting food supply and dissolved oxygen availability at depth. Using an Earth system model that has been evaluated against paleo observations, we illustrate how anthropogenic warming may impact future carbon cycling and twilight zone ecology. Our findings suggest that significant changes are already underway, and without strong emissions mitigation, widespread ecological disruption in the twilight zone is likely by 2100, with effects spanning millennia thereafter.

Methylprednisolone in acute traumatic spinal cord injury: case-matched outcomes from the NASCIS2 and Sygen historical spinal cord injury studies with contemporary statistical analysis.

OBJECTIVE: Methylprednisolone (MP) to treat acute traumatic spinal cord injury (ATSCI) remains controversial since the release of the second National Acute Spinal Cord Injury Study (NASCIS2) in 1990. As two historical studies, NASCIS2 and Sygen in ATSCI, used identical MP dosages, it was possible to construct a new case-level pooled ATSCI data set satisfying contemporary criteria and able to clarify the effect of MP. METHODS: The new pooled data set was first modernized by excluding patients with injury levels caudal to T10, lower-extremity American Spinal Injury Association (ASIA) motor scores (LEMSs) ≥ 46, Glasgow Coma Scale scores ≤ 11, and age < 15 or > 75 years, and then standardized to the ASIA grading and scoring format. A new updated NASCIS2 data set from this pooled data set contained 31.6% fewer patients than the 1990 NASCIS2 data set. RESULTS: In the new pooled data set, recovery of LEMSs from baseline to 26 weeks, the primary outcome variable, was separated statistically into five different injury severity cohorts (p < 0.0001). The severity cohorts contained groups with severe floor (62.9%) and ceiling (10.7%) effects, which do not contribute to drug effects. The new NASCIS2 data set duplicated the p value for MP versus placebo in the sub-subgroup analysis of MP initiated ≤ 8 hours (the subgroup) and recovery of motor function on only the right side of the body (a further subgroup within the ≤ 8-hour subgroup), presented as the positive MP effect in the original NASCIS2 reporting. However, current statistical interpretation considers results seen only in post hoc sub-subgroups, without multi-test corrections, to be random effects without clinical significance. The combined case-level pooled data set from the NASCIS2 and Sygen studies increased the MP group from 106 to 431 patients, creating a new MP combined group. This new data set served as a surrogate for a contemporary MP study and found that administration of MP did not enhance ASIA motor score improvement in the lower extremities at 26 weeks. Secondary analysis of descending ASIA motor and sensory cervical neurological levels in cervical ATSCI patients at 26 weeks also found no MP drug effect. CONCLUSIONS: Analysis of both the new updated NASCIS2 data set and the new case-matched pooled data set from two historical ATSCI studies revealed that administration of MP after spinal cord injury did not demonstrate any enhancement in neurological recovery at 26 weeks. The results of this analysis warrant review by clinical guideline groups.

Spinal arachnoid cysts: A case series & systematic review of the literature.

Introduction: Spinal arachnoid cysts (SACs) are rare lesions with challenging and controversial management. Research question: We analyzed our experiences from a case series and provide a systematic review to determine 1) Demographic and clinical features of SACs, 2) Optimal imaging for diagnosis and operative planning, 3) Optimal management of SACs, and 4) Clinical outcomes following surgery. Materials and methods: A single-institution, ambispective analysis of patients with symptomatic SACs surgically managed between May 2005 and May 2019 was performed. Data were collected as per local ethics committee stipulations. A systematic review of SACs in adults was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and a preapproved protocol. Results: Our series consisted of 11 patients, M:F 8:3, mean age 47.8 years (range 18-73 years). Mean follow-up was 19 months (range 5-36 months). SACs were excised or marsupialised (7), fenestrated (3) or partially excised (1). Eight patients had expansile duroplasty, 3 primary dural closure. One patient had a cystoperitoneal shunt. All patients were AIS D preoperatively; 4 remained unchanged and 7 improved to AIS E at follow-up. Our systematic search retrieved 725 citations. Fourteen case series met the inclusion criteria. There was no evidence to support superiority of one surgical strategy over another. Surgery for symptomatic patients resulted in positive clinical outcomes. Discussion and conclusions: Symptomatic SACs require surgical intervention. Limited evidence suggests that decompressing the cord, breakdown of arachnoid adhesions, and establishing CSF flow by consideration of expansile duroplasty are important for positive outcomes.

The biological carbon pump in CMIP6 models: 21st century trends and uncertainties.

The biological carbon pump (BCP) stores ∼1,700 Pg C from the atmosphere in the ocean interior, but the magnitude and direction of future changes in carbon sequestration by the BCP are uncertain. We quantify global trends in export production, sinking organic carbon fluxes, and sequestered carbon in the latest Coupled Model Intercomparison Project Phase 6 (CMIP6) future projections, finding a consistent 19 to 48 Pg C increase in carbon sequestration over the 21st century for the SSP3-7.0 scenario, equivalent to 5 to 17% of the total increase of carbon in the ocean by 2100. This is in contrast to a global decrease in export production of -0.15 to -1.44 Pg C y-1. However, there is significant uncertainty in the modeled future fluxes of organic carbon to the deep ocean associated with a range of different processes resolved across models. We demonstrate that organic carbon fluxes at 1,000 m are a good predictor of long-term carbon sequestration and suggest this is an important metric of the BCP that should be prioritized in future model studies.

Engaging Native American High School Students in Public Health Career Preparation Through the Indigenous Summer Enhancement Program.

Native American populations are systematically marginalized in the healthcare and public health workforce. One effective approach to reduce health disparities and improve health care delivery among Indigenous populations is to train more Native American health professionals who integrate academic and cultural knowledge to understand and influence health behaviors and perspectives. Diné College partnered with Northern Arizona University to develop the Navajo Native American Research Center for Health (NARCH) Partnership, funded by the National Institutes of Health. The high school component of the Navajo NARCH Partnership created the Indigenous Summer Enhancement Program (ISEP), a 1-week summer training program providing exposure to health careers and mentorship in pursuing public health careers for Native American high school students. ISEP utilizes the Diné Educational Philosophy (DEP), a Navajo conceptual framework to serve as the foundation of the program. In 2020-2021, due to COVID-19 restrictions, the DEP model had to be incorporated in the Navajo NARCH high school virtual program activities. ISEP used 2018 and 2019 past program evaluation data to inform the virtual programming. Students' perception of the program was collected using an online Qualtrics evaluation questionnaire. Students stated appreciation for program staff, fellow students, peer mentors and culturally relevant learning experiences in both virtual and in-person environments. Recommendations included: expanding the length of ISEP and continuing the hands-on activities and Public Health Leadership series.

Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice.

Rho kinase (ROCK) is implicated in the development of pulmonary arterial hypertension (PAH) in which abnormal pulmonary vascular smooth muscle (VSM) contractility and remodeling lead to right heart failure. Pharmacologic ROCK inhibitors block experimental pulmonary hypertension (PH) development in rodents but can have off-target effects and do not distinguish between the two ROCK forms, ROCK1 and ROCK2, encoded by separate genes. An earlier study using gene knock out (KO) in mice indicated that VSM ROCK2 is required for experimental PH development, but the role of ROCK1 is not well understood. Here we investigated the in vivo role of ROCK1 in PH development by generating a VSM-targeted homozygous ROCK1 gene KO mouse strain. Adult control mice exposed to Sugen5416 (Su)/hypoxia treatment to induce PH had significantly increased right ventricular systolic pressures (RVSP) and RV hypertrophy versus normoxic controls. In contrast, Su/hypoxia-exposed VSM ROCK1 KO mice did not exhibit significant RVSP elevation, and RV hypertrophy was blunted. Su/hypoxia-induced pulmonary small vessel muscularization was similarly elevated in both control and VSM ROCK1 KO animals. siRNA-mediated ROCK1 knock-down (KD) in human PAH pulmonary arterial SM cells (PASMC) did not affect cell growth. However, ROCK1 KD led to reduced AKT and MYPT1 signaling in serotonin-treated PAH PASMC. The findings suggest that like VSM ROCK2, VSM ROCK1 actively contributes to PH development, but in distinction acts via nonproliferative pathways to promote hypoxemia, and thus may be a distinct therapeutic target in PH.

Development of an American Indian Diabetes Education Cultural Supplement: A Qualitative Approach.

OBJECTIVE: The purpose of this study was to culturally enhance a diabetes education program for Diné (Navajo) community members with Type 2 diabetes. Though the recommendation to culturally adapt health education curricula was meant to improve health education for American Indians and Alaskan Natives (AIANs), it has inadvertently created a "one size fits all" approach. This approach does not properly address the need for tribe-specific cultural health messaging, defined as incorporating cultural elements deemed relevant to the population. Tribe-specific health information and programming, such as integrating Diné worldviews and Indigenous knowledge among Diné people as described here, are essential to creating a culturally relevant and effective and meaningful approach to disease self-management. METHODS: A conversation guide, based on the Hózhó Resilience Model-a Diné framework on healthy living, was used to engage key cultural experts in interviews about traditional stories and teachings regarding health and wellness. Three specific self-care behaviors relevant to Type 2 diabetes self-management were discussed: (1) healthy eating, (2) physical activity, and (3) healthy coping. Interviews were audio-recorded, transcribed and analyzed using a qualitative thematic analysis method. RESULTS: Diné healers and cultural experts informed the development of an educational tool called Diné Health. Key themes that emerged from the data included the importance of discipline, positivity and mindfulness in the context of Hózhó. CONCLUSION: Culturally safe and meaningful engagement with cultural leaders and the use of qualitative research methods can inform deep-level cultural adaptations essential to developing tribe-specific diabetes education programs. The approaches used here can guide the development, implementation, and testing of culturally-informed health education for AIAN populations.

Reducing local synthesis of estrogen in the tubular striatum promotes attraction to same-sex odors in female mice.

Brain-derived 17ß-estradiol (E2) confers rapid effects on neural activity. The tubular striatum (TuS, also called the olfactory tubercle) is both capable of local E2 synthesis due to its abundant expression of aromatase and is a critical locus for odor-guided motivated behavior and odor hedonics. TuS neurons also contain mRNA for estrogen receptors α, ß, and the G protein-coupled estrogen receptor. We demonstrate here that mRNA for estrogen receptors appears to be expressed upon TuS dopamine 1 receptor-expressing neurons, suggesting that E2 may play a neuromodulatory role in circuits which are important for motivated behavior. Therefore, we reasoned that E2 in the TuS may influence attraction to urinary odors which are highly attractive. Using whole-body plethysmography, we examined odor-evoked high-frequency sniffing as a measure of odor attaction. Bilateral infusion of the aromatase inhibitor letrozole into the TuS of gonadectomized female adult mice induced a resistance to habituation over successive trials in their investigatory sniffing for female mouse urinary odors, indicative of an enhanced attraction. All males displayed resistance to habituation for female urinary odors, indicative of enhanced attraction that is independent from E2 manipulation. Letrozole's effects were not due to group differences in basal respiration, nor changes in the ability to detect or discriminate between odors (both monomolecular odorants and urinary odors). Therefore, de novo E2 synthesis in the TuS impacts females' but not males' attraction to female urinary odors, suggesting a sex-specific influence of E2 in odor hedonics.

Establishing Diagnostic Criteria for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 3].

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss the importance of establishing diagnostic criteria in Degenerative Cervical Myelopathy (DCM), including factors that must be taken into account and challenges that must be overcome in this process. METHODS: Literature review summarising current evidence of establishing diagnostic criteria for DCM. RESULTS: Degenerative Cervical Myelopathy (DCM) is characterised by a degenerative process of the cervical spine resulting in chronic spinal cord dysfunction and subsequent neurological disability. Diagnostic delays lead to progressive neurological decline with associated reduction in quality of life for patients. Surgical decompression may halt neurologic worsening and, in many cases, improves function. Therefore, making a prompt diagnosis of DCM in order to facilitate early surgical intervention is a clinical priority in DCM. CONCLUSION: There are often extensive delays in the diagnosis of DCM. Presently, no single set of diagnostic criteria exists for DCM, making it challenging for clinicians to make the diagnosis. Earlier diagnosis and subsequent specialist referral could lead to improved patient outcomes using existing treatment modalities.

Improving Awareness Could Transform Outcomes in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 1].

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To introduce the number one research priority for Degenerative Cervical Myelopathy (DCM): Raising Awareness. METHODS: Raising awareness has been recognized by AO Spine RECODE-DCM as the number one research priority. This article reviews the evidence that awareness is low, the potential drivers, and why this must be addressed. Case studies of success from other diseases are also reviewed, drawing potential parallels and opportunities for DCM. RESULTS: DCM may affect as many as 1 in 50 adults, yet few will receive a diagnosis and those that do will wait many years for it. This leads to poorer outcomes from surgery and greater disability. DCM is rarely featured in healthcare professional training programs and has received relatively little research funding (<2% of Amyotrophic Lateral Sclerosis or Multiple Sclerosis over the last 25 years). The transformation of stroke and acute coronary syndrome services, from a position of best supportive care with occasional surgery over 50 years ago, to avoidable disability today, represents transferable examples of success and potential opportunities for DCM. Central to this is raising awareness. CONCLUSION: Despite the devastating burden on the patient, recognition across research, clinical practice, and healthcare policy are limited. DCM represents a significant unmet need that must become an international public health priority.

Frailty is an important predictor of 30-day morbidity in patients treated for lumbar spondylolisthesis using a posterior surgical approach.

BACKGROUND CONTEXT: Traditionally, a nonoperative approach has been favored for elderly patients with lumbar spondylolisthesis due to a perceived higher risk of morbidity with surgery. However, most studies have used an arbitrary age cut-off to define "elderly" and this research has yielded conflicting results. PURPOSE: The purpose of this study was to investigate the impact of frailty on morbidity after surgery for degenerative lumbar spondylolisthesis treated with a posterior approach. STUDY DESIGN: A retrospective cohort study was performed. PATIENT SAMPLE: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, with years 2010 to 2018 included in this study. Patients who received posterior lumbar spine decompression with or without single level posterior instrumented fusion for degenerative lumbar spondylolisthesis were included. Patients who received anterior and/or lateral approaches were excluded. OUTCOME MEASURES: The primary outcome was Clavien-Dindo grade IV complication. Secondary outcomes were readmission, reoperation, and discharge to location other than home. METHODS: Patient demographics and comorbidities were extracted. Logistic regression analysis was performed to investigate the association between outcomes and the Modified Frailty Index-5, adjusting for age, gender, body mass index, smoking status, and surgical procedure performed. A sub-analysis was done to assess the effect of frailty in three different age groups (18-45 years, 46-65 years, and >65 years) for the two surgical cohorts. RESULTS: There were 15,658 patients in this study. The mean age was 62.5 years. Approximately 70% of the patients received decompression with fusion. Frailty was significantly associated with an increased risk of major complication, unplanned readmission, reoperation, and non-home discharge. The risk increased with increasing frailty. For patients who received decompression, frailty was associated with a higher risk of readmission and non-home discharge in patients >65 years. For patients who received decompression and fusion, frailty was associated with a higher risk of complications, readmission, and non-home discharge in patients >65 years. CONCLUSIONS: Frailty is independently associated with a higher risk of morbidity after posterior surgery in patients with lumbar spondylolisthesis, especially in patients older than 65. These data are of significance to clinicians in planning treatment for these patients.

Exploring the impact of climate change on the global distribution of non-spinose planktonic foraminifera using a trait-based ecosystem model.

Planktonic foraminifera are one of the primary calcifiers in the modern ocean, contributing 23%-56% of total global pelagic carbonate production. However, a mechanistic understanding of how physiology and environmental conditions control their abundance and distribution is lacking, hindering the projection of the impact of future climate change. This understanding is important, not only for ecosystem dynamics, but also for marine carbon cycling because of foraminifera's key role in carbonate production. Here we present and apply a global trait-based ecosystem model of non-spinose planktonic foraminifera ('ForamEcoGEnIE') to assess their ecology and global distribution under future climate change. ForamEcoGEnIE considers the traits of calcium carbonate production, shell size, and foraging. It captures the main characteristic of biogeographical patterns of non-spinose species - with maximum biomass concentrations found in mid- to high-latitude waters and upwelling areas. The model also reproduces the magnitude of global carbonate production relatively well, although the foraminifera standing stock is systematically overestimated. In response to future scenarios of rising atmospheric CO2 (RCP6 and RCP8.5), on a regional scale, the modelled foraminifera biomass and export flux increases in the subpolar regions of the North Atlantic and the Southern Ocean while it decreases everywhere else. In the absence of adaptation, the biomass decline in the low-latitude South Pacific suggests extirpation. The model projects a global average loss in non-spinose foraminifera biomass between 8% (RCP6) and 11% (RCP8.5) by 2050 and between 14% and 18% by 2100 as a response to ocean warming and associated changes in primary production and ecological dynamics. Global calcium carbonate flux associated with non-spinose foraminifera declines by 13%-18% by 2100. That decline can slow down the ocean carbonate pump and create short-term positive feedback on rising atmospheric pCO2 .

Cyanobacteria and biogeochemical cycles through Earth history.

Cyanobacteria are the only prokaryotes to have evolved oxygenic photosynthesis, transforming the biology and chemistry of our planet. Genomic and evolutionary studies have revolutionized our understanding of early oxygenic phototrophs, complementing and dramatically extending inferences from the geologic record. Molecular clock estimates point to a Paleoarchean origin (3.6-3.2 billion years ago, bya) of the core proteins of Photosystem II (PSII) involved in oxygenic photosynthesis and a Mesoarchean origin (3.2-2.8 bya) for the last common ancestor of modern cyanobacteria. Nonetheless, most extant cyanobacteria diversified after the Great Oxidation Event (GOE), an environmental watershed ca. 2.45 bya made possible by oxygenic photosynthesis. Throughout their evolutionary history, cyanobacteria have played a key role in the global carbon cycle.

Vascular cell-specific roles of mineralocorticoid receptors in pulmonary hypertension.

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.

CDC2 Is an Important Driver of Vascular Smooth Muscle Cell Proliferation via FOXM1 and PLK1 in Pulmonary Arterial Hypertension.

A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein, we identify cyclin-dependent kinase 1 (CDK1), also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7, and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.

IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes.

Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier. IEL respond to epithelial cell-derived IL-15, which is complexed to the IL-15 receptor α chain (IL-15/Rα). IL-15 is essential both for maintaining IEL homeostasis and inducing IEL responses to epithelial stress, which has been associated with Coeliac disease. Here, we apply quantitative mass spectrometry to IL-15/Rα-stimulated IEL to investigate how IL-15 directly regulates inflammatory functions of IEL. IL-15/Rα drives IEL activation through cell cycle regulation, upregulation of metabolic machinery and expression of a select repertoire of cell surface receptors. IL-15/Rα selectively upregulates the Ser/Thr kinases PIM1 and PIM2, which are essential for IEL to proliferate, grow and upregulate granzyme B in response to inflammatory IL-15. Notably, IEL from patients with Coeliac disease have high PIM expression. Together, these data indicate PIM kinases as important effectors of IEL responses to inflammatory IL-15.