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Hardware performance monitoring units (PMUs) are a standard feature in modern microprocessors, providing a rich set of microarchitectural event samplers. Recently, numerous profile-guided optimization (PGO) frameworks have exploited them to feature much lower profiling overhead compared to conventional instrumentation-based frameworks. However, existing PGO frameworks mainly focus on optimizing the layout of binaries; they overlook rich information provided by the PMU about data access behaviors over the memory hierarchy. Thus, we propose MaPHeA, a lightweight M emory hierarchy- a ware P rofile-guided He ap A llocation framework applicable to both HPC and embedded systems. MaPHeA guides and applies the optimized allocation of dynamically allocated heap objects with very low profiling overhead and without additional user intervention to improve application performance. To demonstrate the effectiveness of MaPHeA, we apply it to optimizing heap object allocation in an emerging DRAM-NVM heterogeneous memory system (HMS), selective huge-page utilization, and controlling the cacheability of the objects with the low temporal locality. In an HMS, by identifying and placing frequently accessed heap objects to the fast DRAM region, MaPHeA improves the performance of memory-intensive graph-processing and Redis workloads by 56.0% on average over the default configuration that uses DRAM as a hardware-managed cache of slow NVM. By identifying large heap objects that cause frequent TLB misses and allocating them to huge pages, MaPHeA increases the performance of the read and update operations of Redis by 10.6% over the transparent huge-page implementation of Linux. Also, by distinguishing the objects that cause cache pollution due to their low temporal locality and applying write-combining to them, MaPHeA improves the performance of STREAM and RADIX workloads by 20.0% on average over the system without cacheability control.

Human polyomavirus 7 (HPyV7) is associated with pruritic dermatoses that primarily affect immunocompromised patients. We identified extensive host–virus DNA hybrids in HPyV7-associated rash, highlighting the need for additional studies on long-term consequences of HPyV7 infection, including its oncogenic potential.

Gating strategy for mouse PBMCs

IL-6Ralpha expression in murine PDAC tumors

IL-6Ralpha expression on murine PDAC cell lines

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.

Cleaved caspase 3 (CC3) expression in tumors treated with or without IL-6Ralpha antibodies and gemcitabine chemotherapy

IL-6Ralpha expression on human PBMCs

IL-6 activation of STAT3/SOCS3 in human monocytes

Anti-IL-6Ralpha antibodies can be detected in stromal tissue surrounding malignant PDAC cells

A long battery life is a first-class design objective for mobile devices, and main memory accounts for a major portion of total energy consumption. Moreover, the energy consumption from memory is expected to increase further with ever-growing demands for bandwidth and capacity. A hybrid memory system with both DRAM and PCM can be an attractive solution to provide additional capacity and reduce standby energy. Although providing much greater density than DRAM, PCM has longer access latency and limited write endurance to make it challenging to architect it for main memory. To address this challenge, this article introduces CAMP, a novel DRAM c ache a rchitecture for m obile platforms with P CM-based main memory. A DRAM cache in this environment is required to filter most of the writes to PCM to increase its lifetime, and deliver highest efficiency even for a relatively small-sized DRAM cache that mobile platforms can afford. To address this CAMP divides DRAM space into two regions: a page cache for exploiting spatial locality in a bandwidth-efficient manner and a dirty block buffer for maximally filtering writes. CAMP improves the performance and energy-delay-product by 29.2% and 45.2%, respectively, over the baseline PCM-oblivious DRAM cache, while increasing PCM lifetime by 2.7×. And CAMP also improves the performance and energy-delay-product by 29.3% and 41.5%, respectively, over the state-of-the-art design with dirty block buffer, while increasing PCM lifetime by 2.5×.

Supplemental Figure 3: Ablative RT augments CCL2 in tumors; Supplemental Figure 4: PDAC cell lines induce migration of inflammatory monocytes

Supplemental Figure 1: Flow cytometry gating strategy; Supplemental Figure 2: T cell infiltration is not altered by ablative RT

Supplemental Figure 7: Neutralization of CCL2 delays tumor growth in vivo; Supplemental Figure 8: CCR2 is expressed by a subset of CD45+ leukocytes in tumors

Purpose: Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC.Experimental Design: PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression.Results: Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy.Conclusions: PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2–CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC. Clin Cancer Res; 23(1); 137–48. ©2016 AACR.

Supplemental Figure 5: Ablative RT induces recruitment of inflammatory monocytes in an orthotopic model of PDAC; Supplemental Figure 6: Impact of ablative RT on inflammatory monocyte/macrophage gene expression

Supplemental Figure 9: CCL2 neutralization, with or without ablative RT, does not induce T cell infiltration into PDAC tumors

Autoimmune central nervous system (CNS) demyelinating diseases are a major public health burden and poorly controlled by current immunosuppressants. More precise immunotherapies with higher efficacy and fewer side effects are sought. We investigated the effectiveness and mechanism of an injectable myelin-based antigenic polyprotein MMPt (myelin oligodendrocyte glycoprotein, myelin basic protein and proteolipid protein, truncated). We find that it suppresses mouse experimental autoimmune encephalomyelitis without major side effects. MMPt induces rapid apoptosis of the encephalitogenic T cells and suppresses inflammation in the affected CNS. Intravital microscopy shows that MMPt is taken up by perivascular F4/80 + cells but not conventional antigen-presenting dendritic cells, B cells, or microglia. MMPt-stimulated F4/80 + cells induce reactive T cell immobilization and apoptosis in situ, resulting in reduced infiltration of inflammatory cells and chemokine production. Our study reveals alternative mechanisms that explain how cognate antigen suppresses CNS inflammation and may be applicable for effectively and safely treating demyelinating diseases.

Recently, Graph Neural Networks (GNNs) have been receiving a spotlight as a powerful tool that can effectively serve various inference tasks on graph structured data. As the size of real-world graphs continues to scale, the GNN training system faces a scalability challenge. Distributed training is a popular approach to address this challenge by scaling out CPU nodes. However, not much attention has been paid to disk-based GNN training, which can scale up the single-node system in a more cost-effective manner by leveraging high-performance storage devices like NVMe SSDs. We observe that the data movement between the main memory and the disk is the primary bottleneck in the SSD-based training system, and that the conventional GNN training pipeline is sub-optimal without taking this overhead into account. Thus, we propose Ginex, the first SSD-based GNN training system that can process billion-scale graph datasets on a single machine. Inspired by the inspector-executor execution model in compiler optimization, Ginex restructures the GNN training pipeline by separating sample and gather stages. This separation enables Ginex to realize a provably optimal replacement algorithm, known as Belady's algorithm, for caching feature vectors in memory, which account for the dominant portion of I/O accesses. According to our evaluation with four billion-scale graph datasets, Ginex achieves 2.11x higher training throughput on average (up to 2.67x at maximum) than the SSD-extended PyTorch Geometric., Published in 2022 International Conference on Very Large Databases (VLDB)

Individuals with motor incomplete spinal cord injuries (iSCI) often have impaired abilities to maintain upright balance. For able-bodied (AB) individuals, the ankle and hip joint accelerations are in antiphase to minimize the postural sway during quiet standing. Here we investigated how interjoint coordination between the ankle and hip joints was affected in individuals with iSCI, leading to their larger postural sway during quiet standing. Data from 16 individuals with iSCI, 14 age- and sex-matched AB individuals, and 13 young AB individuals were analyzed. The participants performed quiet standing during which kinematic and kinetic data were recorded. Postural sway was quantified using center-of-pressure velocity and center-of-mass acceleration. Individual ankle and hip joint kinematics were quantified, and the interjoint coordination was assessed using the cancellation index (CI), goal-equivalent variance (GEV), nongoal-equivalent variance (NGEV), and uncontrolled manifold (UCM) ratio. Individuals with iSCI displayed greater postural sway compared with AB individuals. The contribution of ankle angular acceleration toward one's sway was significantly greater for those with iSCI compared with AB groups. CI and the UCM ratios were not statistically different between the groups, while GEV and NGEV were significantly greater for the iSCI group compared with the AB groups. We demonstrated that individuals with iSCI show larger postural sway compared with the AB individuals during quiet standing, primarily due to larger ankle joint acceleration. We also demonstrated that the interjoint coordination between ankle and hip joint is not affected in individuals with iSCI, which is not successfully able to reduce the large COM acceleration.

This article presents a framework, Genesis (genome analysis), to efficiently and flexibly accelerate generic data manipulation operations that have become performance bottlenecks in the genomic data processing pipeline utilizing FPGAs-as-a-service. Genesis conceptualizes genomic data as a very large relational database and uses extended SQL as a domain-specific language to construct data manipulation queries. To accelerate the queries, we designed a Genesis hardware library of efficient coarse-grained primitives that can be composed into a specialized dataflow architecture. This approach explores a systematic and scalable methodology to expedite domain-specific end-to-end accelerated system development and deployment.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease for which the 5-year survival rate is about 10%. Rare long-term survivors after surgical resection have been characterized as having high quality immune responses to primary tumors. However, the mechanisms that regulate immune surveillance in PDAC remain ill-defined. METHODS: Here, we used patient data and genetic mouse models to study potential determinants of T cell surveillance in PDAC. SUMMARY: Long-term survivors (>3 years) compared to short-term survivors (>3 months and CONCLUSIONS: Our findings define a pivotal role for hepatocytes in regulating productive T cell surveillance in cancer. Specifically, our data show that IL-6 can activate STAT3 in hepatocytes to release SAA which then suppress productive T cell surveillance. Taken together, these data suggest that activation of hepatocytes and their release of SAA are novel therapeutic targets for improving the productivity of cancer immunity and patient outcomes after surgery. Citation Format: Meredith L. Stone, Jesse Lee, Jae W. Lee, Heather Coho, Max M. Wattenberg, Hana Choi, Veronica M. Hererra, Yuqing Xue, Shaanti Choi-Bose, Vinod Balachandran, Gregory L. Beatty. Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2888.

Previous findings indicate that co-contractions of plantarflexors and dorsiflexors during quiet standing increase the ankle mechanical joint stiffness, resulting in increased postural sway. Balance impairments in individuals with incomplete spinal cord injury (iSCI) may be due to co-contractions like in other individuals with reduced balance ability. Here we investigated the effect of co-contraction between plantar- and dorsiflexors on postural balance in individuals with iSCI (iSCI-group) and able-bodied individuals (AB-group). Thirteen able-bodied individuals and 13 individuals with iSCI were asked to perform quiet standing with their eyes open (EO) and eyes closed (EC). Kinetics and electromyograms from the tibialis anterior (TA), soleus and medial gastrocnemius were collected bilaterally. The iSCI-group exhibited more co-contractions than the AB-group (EO: 0.208% vs. 75.163%, p = 0.004; EC: 1.767% vs. 92.373%, p = 0.016). Furthermore, postural sway was larger during co-contractions than during no co-contraction in the iSCI-group (EO: 1.405 cm/s

Background Individuals with incomplete spinal cord injury (iSCI) demonstrate greater postural sway and increased dependency on vision to maintain balance compared to able-bodied individuals. Research on standing balance after iSCI has focused on the joint contribution of the lower limbs; however, inter-limb synchrony in quiet standing is a sensitive measure of individual limb contributions to standing balance control in other neurological populations. It is unknown if and how reduced inter-limb synchrony contributes to the poor standing balance of individuals with iSCI. Research question How does an iSCI affect inter-limb synchrony and weight-bearing symmetry in standing? Methods Eighteen individuals with non-progressive motor iSCI and 15 age- and sex-matched able-bodied individuals (M-AB) were included in the study. Participants stood in a standardized position on two adjacent force plates in eyes open and closed conditions for 70 s per condition. Net centre-of-pressure (COP) root mean square (RMS), net COP velocity, COP inter-limb synchrony (i.e. cross-correlation between left and right COP), and weight-bearing asymmetry (i.e. vertical force from each limb over total vertical force) were calculated. Muscle strength of the lower limbs was assessed with manual muscle testing. Results Individuals with iSCI demonstrated reduced inter-limb synchrony when standing with eyes open and eyes closed, but did not differ to M-AB with respect to weight-bearing asymmetry. They also produced greater net COP RMS and velocity when compared to M-AB. Muscle strength of the two lower limbs demonstrated an overall asymmetry in individuals with iSCI. Significance Individuals with iSCI demonstrated impaired balance control as evidenced by reduced inter-limb synchrony and greater COP RMS and velocity compared to M-AB individuals. This increased understanding of how balance control is impaired following iSCI may inform balance assessment and intervention for this population. Future work examining the association between inter-limb synchrony and the occurrence of falls in iSCI is warranted.

An 8-bit switched-capacitor multiply-and-accumulator (MAC) in 65nm CMOS is presented. Based on a cascaded low-power ring-amplifier-based switched-capacitor DACs, the MAC circuit features a programmable accumulation length in MAC computation. Fabricated in 65nm CMOS, the prototype MAC circuit achieves a precision-scaled energy efficiency of 1.32fJ per MAC operation, which is comparable to other state-of-the-art MAC circuits, along with best-in-class linearity. The noise performance has been verified using four real-world convolutional neural networks (CNNs) and 10,000-image data sets with up to 1,000 classes with an accuracy drop of less than 2% compared to the baseline 32-bit floating-point MAC.

Ovarian sex cord-stromal tumors (OSCTs) are rare ovarian tumors that can develop from sex cord, stromal cells, or both. OSCTs can be benign or malignant. Bilateral and/or unilateral ovarian fibromas, a type of OSCT of the stromal cells, have been reported in individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Calcified ovarian fibromas have been reported in 15-25% of individuals diagnosed with NBCCS while 75% of those cases occur bilaterally. The average age at diagnosis of OSCT/ovarian fibromas in patients with NBCSS is in the second to third decade compared with age 50 in the general population. Ovarian tumors are rare in pediatric populations.The patient is a 5-year-old female diagnosed with bilateral ovarian fibromas at age 4. Multigene panel for the patient and subsequent targeted molecular evaluation of parents were completed. Histological evaluations on the surgically resected ovaries were performed for microscopic characterization of fibromas.Germline testing identified de novo heterozygous novel likely pathogenic variants in PTCH1 gene, exon 12 deletion, and an SMARCA4 splicing variant c.2002-1G A. Microscopic examination of bilateral tumors was consistent with an ovarian fibroma.To our knowledge, this is the first report of bilateral benign ovarian fibroma in a child with a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) with a potential predisposition to Rhabdoid Tumor Predisposition Syndrome (RTPS).

FOXG1 syndrome (FS, aka a congenital variant of Rett syndrome) is a recently defined rare and devastating neurodevelopmental disorder characterized by various symptoms, including severe intellectual disability, autistic features, involuntary, and continuous jerky movements, feeding problems, sleep disturbances, seizures, irritability, and excessive crying. FS results from mutations in a single allele of the FOXG1 gene, leading to impaired FOXG1 function. Therefore, in establishing mouse models for FS, it is important to test if heterozygous (HET) mutation in the Foxg1 gene, mimicking genotypes of the human FS individuals, also manifests phenotypes similar to their symptoms. We analyzed HET mice with a null mutation allele in a single copy of Foxg1, and found that they show various phenotypes resembling the symptoms of the human FS individuals. These include increased anxiety in the open field as well as impairment in object recognition, motor coordination, and fear learning and contextual and cued fear memory. Our results suggest that Foxg1 HET mice recapitulate at least some symptoms of the human FS individuals.

Since its public introduction in the mid-2010s, the Row Hammer (RH) phenomenon has drawn significant attention from the research community due to its security implications. Although many RH-protection schemes have been proposed by processor vendors, DRAM manufacturers, and academia, they still have shortcomings. Solutions implemented in the memory controller (MC) incur increasingly higher costs due to their conservative design for the worst case in terms of the number of DRAM banks and RH threshold to support. Meanwhile, DRAM-side implementation either has a limited time margin for RH-protection measures or requires extensive modifications to the standard DRAM interface. Recently, a new command for RH-protection has been introduced in the DDR5/LPDDR5 standards, referred to as refresh management (RFM). RFM enables the separation of the tasks for RHprotection to both MC and DRAM by having the former generate an RFM command at a specific activation frequency and the latter take proper RH-protection measures within a given time window. Although promising, no existing study presents and analyzes RFM-based solutions for RH-protection. In this paper, we propose Mithril, the first RFM interfacecompatible, DRAM-MC cooperative RH-protection scheme providing deterministic protection guarantees. Mithril has minimal energy overheads for common use cases without adversarial memory access patterns. We also introduce Mithril+, an optional extension to provide minimal performance overheads at the expense of a tiny modification to the MC, while utilizing existing DRAM commands., Comment: 16 pages, to appear in HPCA 2022

Lung endothelial permeability is a key pathological feature of acute respiratory distress syndrome. Hyaluronic acid (HA), a major component of the glycocalyx layer on the endothelium, is generated by HA synthase (HAS) during inflammation and injury and is critical for repair. We hypothesized that administration of exogenous high molecular weight (HMW) HA would restore protein permeability across human lung microvascular endothelial cells (HLMVEC) injured by an inflammatory insult via upregulation of HAS by binding to CD44. A transwell coculture system was used to study the effects of HA on protein permeability across HLMVEC injured by cytomix, a mixture of IL-1β, TNFα, and IFNγ, with or without HMW or low molecular weight (LMW) HA. Coincubation with HMW HA, but not LMW HA, improved protein permeability following injury at 24 h. Fluorescence microscopy demonstrated that exogenous HMW HA partially prevented the increase in "actin stress fiber" formation. HMW HA also increased the synthesis of HAS2 mRNA expression and intracellular HMW HA levels in HLMVEC following injury. Pretreatment with an anti-CD44 antibody or 4-methylumbelliferone, a HAS inhibitor, blocked the therapeutic effects. In conclusion, exogenous HMW HA restored protein permeability across HLMVEC injured by an inflammatory insult in part through upregulation of HAS2.