Area-based conservation in the twenty-first century.

Humanity will soon define a new era for nature-one that seeks to transform decades of underwhelming responses to the global biodiversity crisis. Area-based conservation efforts, which include both protected areas and other effective area-based conservation measures, are likely to extend and diversify. However, persistent shortfalls in ecological representation and management effectiveness diminish the potential role of area-based conservation in stemming biodiversity loss. Here we show how the expansion of protected areas by national governments since 2010 has had limited success in increasing the coverage across different elements of biodiversity (ecoregions, 12,056 threatened species, 'Key Biodiversity Areas' and wilderness areas) and ecosystem services (productive fisheries, and carbon services on land and sea). To be more successful after 2020, area-based conservation must contribute more effectively to meeting global biodiversity goals-ranging from preventing extinctions to retaining the most-intact ecosystems-and must better collaborate with the many Indigenous peoples, community groups and private initiatives that are central to the successful conservation of biodiversity. The long-term success of area-based conservation requires parties to the Convention on Biological Diversity to secure adequate financing, plan for climate change and make biodiversity conservation a far stronger part of land, water and sea management policies.

Author Correction: Area-based conservation in the twenty-first century.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Retaining natural vegetation to safeguard biodiversity and humanity.

Global efforts to deliver internationally agreed goals to reduce carbon emissions, halt biodiversity loss, and retain essential ecosystem services have been poorly integrated. These goals rely in part on preserving natural (e.g., native, largely unmodified) and seminatural (e.g., low intensity or sustainable human use) forests, woodlands, and grasslands. To show how to unify these goals, we empirically derived spatially explicit, quantitative, area-based targets for the retention of natural and seminatural (e.g., native) terrestrial vegetation worldwide. We used a 250-m-resolution map of natural and seminatural vegetation cover and, from this, selected areas identified under different international agreements as being important for achieving global biodiversity, carbon, soil, and water targets. At least 67 million km2 of Earth's terrestrial vegetation (∼79% of the area of vegetation remaining) required retention to contribute to biodiversity, climate, soil, and freshwater conservation objectives under 4 United Nations' resolutions. This equates to retaining natural and seminatural vegetation across at least 50% of the total terrestrial (excluding Antarctica) surface of Earth. Retention efforts could contribute to multiple goals simultaneously, especially where natural and seminatural vegetation can be managed to achieve cobenefits for biodiversity, carbon storage, and ecosystem service provision. Such management can and should co-occur and be driven by people who live in and rely on places where natural and sustainably managed vegetation remains in situ and must be complemented by restoration and appropriate management of more human-modified environments if global goals are to be realized.

Retención de la vegetación natural para salvaguardar la biodiversidad y la humanidad Resumen Hoy en día hay muy poca integración de los esfuerzos mundiales para alcanzar los objetivos internacionales de reducción de las emisiones de carbono, impedimento de la pérdida de biodiversidad y conservación de los servicios ambientales esenciales. Estos objetivos dependen parcialmente de la conservación de los bosques, selvas y praderas naturales (por ejemplo, nativos y en su mayoría sin alteraciones) y seminaturales (por ejemplo, de uso humano sostenible o de baja intensidad). Obtuvimos de manera empírica objetivos espacialmente explícitos, cuantitativos y basados en áreas para la conservación de la vegetación terrestre natural y seminatural (por ejemplo, nativa) en todo el mundo para mostrar cómo unificar los objetivos internacionales. Usamos un mapa de 250 m de resolución de la cubierta vegetal natural y seminatural y, a partir de él, seleccionamos las áreas identificadas como importantes en diferentes acuerdos internacionales para alcanzar los objetivos globales de biodiversidad, carbono, suelo y agua. Al menos 67 millones de km2 de la vegetación terrestre de la Tierra (∼79% de la superficie de vegetación restante) requieren ser conservados para contribuir a los objetivos de conservación de la biodiversidad, el clima, el suelo y el agua dulce en virtud de cuatro de las resoluciones de las Naciones Unidas. Esto equivale a conservar la vegetación natural y seminatural en al menos el 50% de la superficie terrestre total de la Tierra (sin contar a la Antártida). Los esfuerzos de retención podrían contribuir a alcanzar múltiples objetivos simultáneamente, especialmente en donde la vegetación natural y seminatural puede gestionarse para lograr beneficios colaterales para la biodiversidad, el almacenamiento de carbono y la provisión de servicios ambientales. Esta gestión puede y debe ser impulsada y llevada a cabo por las personas que viven en y dependen de los lugares donde la vegetación natural y gestionada de forma sostenible permanece in situ y debe complementarse con la restauración y la gestión adecuada de entornos modificados por el hombre si se quieren alcanzar los objetivos globales.

Wilderness forms and their implications for global environmental policy and conservation.

With the intention of securing industry-free land and seascapes, protecting wilderness entered international policy as a formal target for the first time in the zero draft of the Post-2020 Global Biodiversity Framework under the Convention on Biological Diversity. Given this increased prominence in international policy, it is timely to consider the extent to which the construct of wilderness supports global conservation objectives. We evaluated the construct by overlaying recently updated cumulative human pressure maps that offer a global-scale delineation of industry-free land as wilderness with maps of carbon stock, species richness, and ground travel time from urban centers. Wilderness areas took variable forms in relation to carbon stock, species richness, and proximity to urban centers, where 10% of wilderness areas represented high carbon and species richness, 20% low carbon and species richness, and 3% high levels of remoteness (>48 h), carbon, and species richness. Approximately 35% of all remaining wilderness in 2013 was accessible in <24 h of travel time from urban centers. Although the construct of wilderness can be used to secure benefits in specific contexts, its application in conservation must account for contextual and social implications. The diverse characterization of wilderness under a global environmental conservation lens shows that a nuanced framing and application of the construct is needed to improve understanding, communication, and retention of its variable forms as industry-free places.

Formas de las Áreas Silvestres y sus Implicaciones para las Políticas y la Conservación Mundial Resumen Con la intención de asegurar paisajes terrestres y marinos libres de la industria, la protección de las áreas silvestres entró a la política internacional por primera vez como un objetivo formal en el primer borrador del Marco de Trabajo para la Biodiversidad Mundial Post-2020 bajo el Convenio sobre la Diversidad Biológica. Con este incremento en la presencia dentro de la política internacional, es oportuno considerar el grado al que el concepto de área silvestre ayuda a los objetivos de conservación mundial. Evaluamos este concepto mediante la superposición de mapas de la presión humana acumulada recientemente actualizados que brindan una definición a escala mundial de las tierras libres de industria con mapas del stock de carbono, riqueza de especies y el tiempo de traslado terrestre desde los centros urbanos. Las áreas silvestres mostraron formas variables con respecto al stock de carbono, la riqueza de especies y la cercanía a los centros urbanos, de las cuales el 10% representó una elevada riqueza de especies y presencia de carbono, el 20% una baja riqueza de especies y presencia de carbono y el 3% una elevada lejanía (>48 horas), presencia de carbono y riqueza de especies. Aproximadamente el 35% de todas las áreas silvestres en 2013 era accesible en <24 horas de traslado desde los centros urbanos. Aunque el concepto de áreas silvestres puede usarse para garantizar beneficios en contextos específicos, su aplicación en la conservación debe considerar las implicaciones contextuales y sociales. La caracterización diversa de las áreas silvestres bajo el lente de la conservación ambiental mundial muestra que un encuadre matizado y la aplicación de este concepto son necesarios para aumentar el conocimiento, la comunicación y la retención de sus formas variables como lugares libres de industria.

Difficulty in Advancing Flexible Epidural Catheters When Establishing Labor Analgesia: An Observational Open-Label Randomized Trial.

BACKGROUND: While flexible epidural catheters reduce the risk of paresthesia and intravascular cannulation, they may be more challenging to advance beyond the tip of a Tuohy needle. This may increase placement time, number of attempts, and possibly complications when establishing labor analgesia. This study investigated the ability to advance flexible epidural catheters through different epidural needles from 2 commonly used, commercially available, epidural kits. METHODS: We hypothesized that the multiorifice wire-reinforced polyamide nylon blend epidural catheters will have a higher rate of successful first attempt insertion than the single-end hole wire-reinforced polyurethane catheters for the establishment of labor analgesia. The primary outcome was a difference in proportions of failure to advance the epidural catheter between the 2 epidural kits and was tested by a χ2 test. Two-hundred forty epidural kits were collected (n = 120/group) for 240 laboring patients requesting epidural analgesia in this open-label clinical trial from November 2018 to September 2019. Two-week time intervals were randomized for the exclusive use of 1 of the 2 kits in this study, where all patients received labor analgesia through either the flexible epidural catheter "A" or the flexible epidural catheter "B." Engineering properties of the equipment used were then determined. RESULTS: Flexible epidural catheter "A," the single-end hole wire-reinforced polyurethane catheter, did not advance at the first attempt in 15% (n = 18 of 120) of the parturients compared to 0.8% (n = 1 of 120) of the catheter "B," the multiorifice wire-reinforced polyamide nylon blend epidural catheter (P < .0001). Twenty-five additional epidural needle manipulations were recorded in the laboring patients who received catheter "A," while 1 epidural needle manipulation was recorded in the parturients who received catheter "B" (P < .0001). Bending stiffness of the epidural catheters used from kit "B" was twice the bending stiffness of the catheters used from kit "A" (bending stiffness catheters "A" 0.64 ± 0.04 N·mm2 versus bending stiffness catheters "B" 1.28 ± 0.20 N·mm2, P = .0038), and the angle formed by the needle and the epidural catheter from kit "A" was less acute than the angle formed from kit "B" (kit "A" 14.17 ± 1.72° versus kit "B" 21.83 ± 1.33°, P = .0036), with a mean difference of 7.66° between the 2 kits' angles. CONCLUSIONS: The incidence of an inability to advance single-end hole wire-reinforced polyurethane catheter was higher compared to the use of multiorifice wire-reinforced polyamide nylon blend epidural catheter. Variation of morphological features of epidural needles and catheters may play a critical role in determining the successful establishment of labor epidural analgesia.

CoPhosK: A method for comprehensive kinase substrate annotation using co-phosphorylation analysis.

We present CoPhosK to predict kinase-substrate associations for phosphopeptide substrates detected by mass spectrometry (MS). The tool utilizes a Naïve Bayes framework with priors of known kinase-substrate associations (KSAs) to generate its predictions. Through the mining of MS data for the collective dynamic signatures of the kinases' substrates revealed by correlation analysis of phosphopeptide intensity data, the tool infers KSAs in the data for the considerable body of substrates lacking such annotations. We benchmarked the tool against existing approaches for predicting KSAs that rely on static information (e.g. sequences, structures and interactions) using publically available MS data, including breast, colon, and ovarian cancer models. The benchmarking reveals that co-phosphorylation analysis can significantly improve prediction performance when static information is available (about 35% of sites) while providing reliable predictions for the remainder, thus tripling the KSAs available from the experimental MS data providing to a comprehensive and reliable characterization of the landscape of kinase-substrate interactions well beyond current limitations.

Integrated microRNA and mRNA network analysis of the human myometrial transcriptome in the transition from quiescence to labor.

We conducted integrated transcriptomics network analyses of miRNA and mRNA interactions in human myometrium to identify novel molecular candidates potentially involved in human parturition. Myometrial biopsies were collected from women undergoing primary Cesarean deliveries in well-characterized clinical scenarios: (1) spontaneous term labor (TL, n = 5); (2) term nonlabor (TNL, n = 5); (3) spontaneous preterm birth (PTB) with histologic chorioamnionitis (PTB-HCA, n = 5); and (4) indicated PTB nonlabor (PTB-NL, n = 5). RNAs were profiled using RNA sequencing, and miRNA-target interaction networks were mined for key discriminatory subnetworks. Forty miRNAs differed between TL and TNL myometrium, while seven miRNAs differed between PTB-HCA vs. PTB-NL specimens; six of these were cross-validated using quantitative PCR. Based on the combined sequencing data, unsupervised clustering revealed two nonoverlapping cohorts that differed primarily by absence or presence of uterine quiescence, rather than gestational age or original clinical cohort. The intersection of differentially expressed miRNAs and their targets predicted 22 subnetworks with enriched representation of miR-146b-5p, miR-223-3p, and miR-150-5p among miRNAs, and of myocyte enhancer factor-2C (MEF2C) among mRNAs. Of four known MEF2 transcription factors, decreased MEF2A and MEF2C expression in women with uterine nonquiescence was observed in the sequencing data, and validated in a second cohort by quantitative PCR. Immunohistochemistry localized MEF2A and MEF2C to myometrial smooth muscle cells and confirmed decreased abundance with labor. Collectively, these results suggest altered MEF2 expression may represent a previously unrecognized process through which miRNAs contribute to the phenotypic switch from quiescence to labor in human myometrium.

Linearity of network proximity measures: implications for set-based queries and significance testing.

Motivation: In recent years, various network proximity measures have been proposed to facilitate the use of biomolecular interaction data in a broad range of applications. These applications include functional annotation, disease gene prioritization, comparative analysis of biological systems and prediction of new interactions. In such applications, a major task is the scoring or ranking of the nodes in the network in terms of their proximity to a given set of 'seed' nodes (e.g. a group of proteins that are identified to be associated with a disease, or are deferentially expressed in a certain condition). Many different network proximity measures are utilized for this purpose, and these measures are quite diverse in terms of the benefits they offer. Results: We propose a unifying framework for characterizing network proximity measures for set-based queries. We observe that many existing measures are linear, in that the proximity of a node to a set of nodes can be represented as an aggregation of its proximity to the individual nodes in the set. Based on this observation, we propose methods for processing of set-based proximity queries that take advantage of sparse local proximity information. In addition, we provide an analytical framework for characterizing the distribution of proximity scores based on reference models that accurately capture the characteristics of the seed set (e.g. degree distribution and biological function). The resulting framework facilitates computation of exact figures for the statistical significance of network proximity scores, enabling assessment of the accuracy of Monte Carlo simulation based estimation methods. Availability and Implementation: Implementations of the methods in this paper are available at https://bioengine.case.edu/crosstalker which includes a robust visualization for results viewing. Contact: stm@case.edu or mxk331@case.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Phosphoproteomics Profiling of Nonsmall Cell Lung Cancer Cells Treated with a Novel Phosphatase Activator.

Activation of protein phosphatase 2A (PP2A) is a promising anticancer therapeutic strategy, as this tumor suppressor has the ability to coordinately downregulate multiple pathways involved in the regulation of cellular growth and proliferation. In order to understand the systems-level perturbations mediated by PP2A activation, we carried out mass spectrometry-based phosphoproteomic analysis of two KRAS mutated non-small cell lung cancer (NSCLC) cell lines (A549 and H358) treated with a novel small molecule activator of PP2A (SMAP). Overall, this permitted quantification of differential signaling across over 1600 phosphoproteins and 3000 phosphosites. Kinase activity assessment and pathway enrichment implicate collective downregulation of RAS and cell cycle kinases in the case of both cell lines upon PP2A activation. However, the effects on RAS-related signaling are attenuated for A549 compared to H358, while the effects on cell cycle-related kinases are noticeably more prominent in A549. Network-based analyses and validation experiments confirm these detailed differences in signaling. These studies reveal the power of phosphoproteomics studies, coupled to computational systems biology, to elucidate global patterns of phosphatase activation and understand the variations in response to PP2A activation across genetically similar NSCLC cell lines.

Proteomics and Network Analyses Reveal Inhibition of Akt-mTOR Signaling in CD4+ T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan.

Mycobacterium tuberculosis (Mtb) cell wall glycolipid mannose-capped lipoarabinomannan (ManLAM) inhibits CD4+ T-cell activation by inhibiting proximal T-cell receptor (TCR) signaling when activated by anti-CD3. To understand the impact of ManLAM on CD4+ T-cell function when both the TCR-CD3 complex and major costimulator CD28 are engaged, we performed label-free quantitative MS and network analysis. Mixed-effect model analysis of peptide intensity identified 149 unique peptides representing 131 proteins that were differentially regulated by ManLAM in anti-CD3- and anti-CD28-activated CD4+ T cells. Crosstalker, a novel network analysis tool identified dysregulated translation, TCA cycle, and RNA metabolism network modules. PCNA, Akt, mTOR, and UBC were found to be bridge node proteins connecting these modules of dysregulated proteins. Altered PCNA expression and cell cycle analysis showed arrest at the G2M phase. Western blot confirmed that ManLAM inhibited Akt and mTOR phosphorylation, and decreased expression of deubiquitinating enzymes Usp9x and Otub1. Decreased NF-κB phosphorylation suggested interference with CD28 signaling through inhibition of the Usp9x-Akt-mTOR pathway. Thus, ManLAM induced global changes in the CD4+ T-cell proteome by affecting Akt-mTOR signaling, resulting in broad functional impairment of CD4+ T-cell activation beyond inhibition of proximal TCR-CD3 signaling.

Primary Orbital Chondromyxoid Fibroma: A Rare Case.

A 56-year-old male with history of chronic sinusitis was found to have a 3 cm left orbital lesion on CT. Subsequent MRI demonstrated a multilobulated enhancing soft tissue lesion at the superotemporal region of the left orbit. Initial biopsy was reported as a low-grade sarcoma. On further evaluation, a consensus was made that the lesion was likely a benign mixed mesenchymal type tumor but should nonetheless be surgically removed. Left lateral orbitotomy was performed which revealed a tumor originating in the lateral orbital bone with segments eroding through the wall of the orbit. Intraoperative frozen sections revealed myoepitheliod tissue with locally aggressive features and the tumor was completely removed. The final histopathologic analysis of the tissue was consistent with a chondromyxoid fibroma. Chondomyxoid fibroma is a rare entity in the orbital bones and is more commonly seen in long bones.

Diagnostic accuracy of intraoperative frozen sections during radical cystectomy does not affect disease-free or overall survival: a study of 364 patients with urothelial carcinoma of the urinary bladder.

The utility of intraoperative frozen sections for determining ureteral and urethral margin status is controversial. In this study, we evaluated the sensitivity and specificity of frozen section diagnosis with the corresponding final tissue diagnosis in a series of 364 patients undergoing radical cystectomy for urothelial carcinoma of the urinary bladder. Multiple definitions of a positive diagnosis were analyzed. We then used clinical follow-up data to determine the effect of various frozen section diagnoses, frozen/permanent section discordance, and surgical margins on overall survival and disease-free survival. Increasing severity of dysplasia was associated with corresponding increases in positive likelihood ratio, with carcinoma displaying the highest positive likelihood ratio (211.43) for an accurate frozen section diagnosis. A diagnosis of carcinoma on frozen section did not affect overall or disease-free survival nor did a positive surgical margin. Frozen/permanent discordance did not show significant associations with overall survival or disease-free survival. The lone variable approaching statistical significance was an association between frozen/permanent discordance of ureteral samples and disease-free survival (hazard ratio, 3.23; P = .07; multivariate Cox proportional hazards model). The results of this study, the first to evaluate the use of different cutoffs for a positive diagnosis and the effects of frozen/permanent discordance, do not support the routine use of intraoperative frozen section during radical cystectomy for urothelial carcinoma. However, subgroups at high risk for positive ureteral margins may benefit from intraoperative frozen section evaluation.

Discovery of common sequences absent in the human reference genome using pooled samples from next generation sequencing.

BACKGROUND: Sequences up to several megabases in length have been found to be present in individual genomes but absent in the human reference genome. These sequences may be common in populations, and their absence in the reference genome may indicate rare variants in the genomes of individuals who served as donors for the human genome project. As the reference genome is used in probe design for microarray technology and mapping short reads in next generation sequencing (NGS), this missing sequence could be a source of bias in functional genomic studies and variant analysis. One End Anchor (OEA) and/or orphan reads from paired-end sequencing have been used to identify novel sequences that are absent in reference genome. However, there is no study to investigate the distribution, evolution and functionality of those sequences in human populations. RESULTS: To systematically identify and study the missing common sequences (micSeqs), we extended the previous method by pooling OEA reads from large number of individuals and applying strict filtering methods to remove false sequences. The pipeline was applied to data from phase 1 of the 1000 Genomes Project. We identified 309 micSeqs that are present in at least 1% of the human population, but absent in the reference genome. We confirmed 76% of these 309 micSeqs by comparison to other primate genomes, individual human genomes, and gene expression data. Furthermore, we randomly selected fifteen micSeqs and confirmed their presence using PCR validation in 38 additional individuals. Functional analysis using published RNA-seq and ChIP-seq data showed that eleven micSeqs are highly expressed in human brain and three micSeqs contain transcription factor (TF) binding regions, suggesting they are functional elements. In addition, the identified micSeqs are absent in non-primates and show dynamic acquisition during primate evolution culminating with most micSeqs being present in Africans, suggesting some micSeqs may be important sources of human diversity. CONCLUSIONS: 76% of micSeqs were confirmed by a comparative genomics approach. Fourteen micSeqs are expressed in human brain or contain TF binding regions. Some micSeqs are primate-specific, conserved and may play a role in the evolution of primates.

A bolder conservation future for Indonesia by prioritising biodiversity, carbon and unique ecosystems in Sulawesi.

As more ambitious protected area (PA) targets for the post-2020 global biodiversity framework are set beyond Aichi Target 11, renew thinking into spatial prioritisation is required to enable PA expansion that maximises environmental values. Our study focuses on the biodiverse and forest-rich Indonesian island of Sulawesi, which has a terrestrial PA network that covers 10% of the island. We used Marxan to investigate trade-offs in the design of an expanded PA network that prioritised different conservation features (biodiversity, forest cover, carbon stock, karst and valuable metal-rich areas) under varying island-wide coverage targets (17%, 30%, and 50%). Our first scenario, which required existing PAs to be selected, required larger areas to meet these coverage targets, in contrast to our second scenario, which allowed for any part of the island to be chosen, irrespective of PA status. The vast Mekongga and Bangkiriang Landscapes, and Gorontalo corridor were consistently identified as a high priority for protection under all scenarios. To meet our conservation targets through expanding current PAs, creating new PAs, and creating corridors that connect existing PAs, we used a spatially explicit three-phase approach. Our findings identified 26,508 km2 of priority areas to be included in the current PA network, potentially assisting Indonesia in meeting its post-2020 GBF target, if our approach is replicated across Indonesia as a national or sub-national analysis. We discuss various land management options through other effective area-based conservation measures (OECMs) and the costs to deliver this strategy.

Changes in global terrestrial live biomass over the 21st century.

Live woody vegetation is the largest reservoir of biomass carbon, with its restoration considered one of the most effective natural climate solutions. However, terrestrial carbon fluxes remain the largest uncertainty in the global carbon cycle. Here, we develop spatially explicit estimates of carbon stock changes of live woody biomass from 2000 to 2019 using measurements from ground, air, and space. We show that live biomass has removed 4.9 to 5.5 PgC year-1 from the atmosphere, offsetting 4.6 ± 0.1 PgC year-1 of gross emissions from disturbances and adding substantially (0.23 to 0.88 PgC year-1) to the global carbon stocks. Gross emissions and removals in the tropics were four times larger than temperate and boreal ecosystems combined. Although live biomass is responsible for more than 80% of gross terrestrial fluxes, soil, dead organic matter, and lateral transport may play important roles in terrestrial carbon sink.

Degradation and forgone removals increase the carbon impact of intact forest loss by 626.

Intact tropical forests, free from substantial anthropogenic influence, store and sequester large amounts of atmospheric carbon but are currently neglected in international climate policy. We show that between 2000 and 2013, direct clearance of intact tropical forest areas accounted for 3.2% of gross carbon emissions from all deforestation across the pantropics. However, full carbon accounting requires the consideration of forgone carbon sequestration, selective logging, edge effects, and defaunation. When these factors were considered, the net carbon impact resulting from intact tropical forest loss between 2000 and 2013 increased by a factor of 6 (626%), from 0.34 (0.37 to 0.21) to 2.12 (2.85 to 1.00) petagrams of carbon (equivalent to approximately 2 years of global land use change emissions). The climate mitigation value of conserving the 549 million ha of tropical forest that remains intact is therefore significant but will soon dwindle if their rate of loss continues to accelerate.

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease.

OBJECTIVE: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). METHODS: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aß42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. RESULTS: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aß42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. INTERPRETATION: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.