Parallel convolutional processing using an integrated photonic tensor core.

With the proliferation of ultrahigh-speed mobile networks and internet-connected devices, along with the rise of artificial intelligence (AI)1, the world is generating exponentially increasing amounts of data that need to be processed in a fast and efficient way. Highly parallelized, fast and scalable hardware is therefore becoming progressively more important2. Here we demonstrate a computationally specific integrated photonic hardware accelerator (tensor core) that is capable of operating at speeds of trillions of multiply-accumulate operations per second (1012 MAC operations per second or tera-MACs per second). The tensor core can be considered as the optical analogue of an application-specific integrated circuit (ASIC). It achieves parallelized photonic in-memory computing using phase-change-material memory arrays and photonic chip-based optical frequency combs (soliton microcombs3). The computation is reduced to measuring the optical transmission of reconfigurable and non-resonant passive components and can operate at a bandwidth exceeding 14 gigahertz, limited only by the speed of the modulators and photodetectors. Given recent advances in hybrid integration of soliton microcombs at microwave line rates3-5, ultralow-loss silicon nitride waveguides6,7, and high-speed on-chip detectors and modulators, our approach provides a path towards full complementary metal-oxide-semiconductor (CMOS) wafer-scale integration of the photonic tensor core. Although we focus on convolutional processing, more generally our results indicate the potential of integrated photonics for parallel, fast, and efficient computational hardware in data-heavy AI applications such as autonomous driving, live video processing, and next-generation cloud computing services.

Quantitative Time-Course Analysis of Osmotic and Salt Stress in Arabidopsis thaliana Using Short Gradient Multi-CV FAIMSpro BoxCar DIA.

A major limitation when undertaking quantitative proteomic time-course experimentation is the tradeoff between depth-of-analysis and speed-of-analysis. In high complexity and high dynamic range sample types, such as plant extracts, balance between resolution and time is especially apparent. To address this, we evaluate multiple compensation voltage (CV) high field asymmetric waveform ion mobility spectrometry (FAIMSpro) settings using the latest label-free single-shot Orbitrap-based DIA acquisition workflows for their ability to deeply quantify the Arabidopsis thaliana seedling proteome. Using a BoxCarDIA acquisition workflow with a -30 -50 -70 CV FAIMSpro setting, we were able to consistently quantify >5000 Arabidopsis seedling proteins over a 21-min gradient, facilitating the analysis of ∼42 samples per day. Utilizing this acquisition approach, we then quantified proteome-level changes occurring in Arabidopsis seedling shoots and roots over 24 h of salt and osmotic stress, to identify early and late stress response proteins and reveal stress response overlaps. Here, we successfully quantify >6400 shoot and >8500 root protein groups, respectively, quantifying nearly ∼9700 unique protein groups in total across the study. Collectively, we pioneer a short gradient, multi-CV FAIMSpro BoxCarDIA acquisition workflow that represents an exciting new analysis approach for undertaking quantitative proteomic time-course experimentation in plants.

Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

Genome-scale analysis of Arabidopsis splicing-related protein kinase families reveals roles in abiotic stress adaptation.

Nearly 60 - 80 % of intron-containing plant genes undergo alternative splicing in response to either stress or plant developmental cues. RNA splicing is performed by a large ribonucleoprotein complex called the spliceosome in conjunction with associated subunits such as serine arginine (SR) proteins, all of which undergo extensive phosphorylation. In plants, there are three main protein kinase families suggested to phosphorylate core spliceosome subunits and related splicing factors based on orthology to human splicing-related kinases: the SERINE/ARGININE PROTEIN KINASES (SRPK), ARABIDOPSIS FUS3 COMPLEMENT (AFC), and Pre-mRNA PROCESSING FACTOR 4 (PRP4K) protein kinases. To better define the conservation and role(s) of these kinases in plants, we performed a genome-scale analysis of the three families across photosynthetic eukaryotes, followed by extensive transcriptomic and bioinformatic analysis of all Arabidopsis thaliana SRPK, AFC, and PRP4K protein kinases to elucidate their biological functions. Unexpectedly, this revealed the existence of SRPK and AFC phylogenetic groups with distinct promoter elements and patterns of transcriptional response to abiotic stress, while PRP4Ks possess no phylogenetic sub-divisions, suggestive of functional redundancy. We also reveal splicing-related kinase families are both diel and photoperiod regulated, implicating different orthologs as discrete time-of-day RNA splicing regulators. This foundational work establishes a number of new hypotheses regarding how reversible spliceosome phosphorylation contributes to both diel plant cell regulation and abiotic stress adaptation in plants.

Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

Single-marker and haplotype-based genome-wide association studies for the number of teats in two heavy pig breeds.

The number of teats is a reproductive-related trait of great economic relevance as it affects the mothering ability of the sows and thus the number of properly weaned piglets. Moreover, genetic improvement of this trait is fundamental to parallelly help the selection for increased litter size. We present the results of single-marker and haplotypes-based genome-wide association studies for the number of teats in two large cohorts of heavy pig breeds (Italian Large White and Italian Landrace) including 3990 animals genotyped with the 70K GGP Porcine BeadChip and other 1927 animals genotyped with the Illumina PorcineSNP60 BeadChip. In the Italian Large White population, genome scans identified three genome regions (SSC7, SSC10, and SSC12) that confirmed the involvement of the VRTN gene (as we previously reported) and highlighted additional loci known to affect teat counts, including the FRMD4A and HOXB1 gene regions. A different picture emerged in the Italian Landrace population, with a total of 12 genome regions in eight chromosomes (SSC3, SSC6, SSC8, SSC11, SSC13, SSC14, SSC15, and SSC16) mainly detected via the haplotype-based genome scan. The most relevant QTL was close to the ARL4C gene on SSC15. Markers in the VRTN gene region were not significant in the Italian Landrace breed. The use of both single-marker and haplotype-based genome-wide association analyses can be helpful to exploit and dissect the genome of the pigs of different populations. Overall, the obtained results supported the polygenic nature of the investigated trait and better elucidated its genetic architecture in Italian heavy pigs.

Runs of homozygosity provide a genome landscape picture of inbreeding and genetic history of European autochthonous and commercial pig breeds.

ROHs are long stretches of DNA homozygous at each polymorphic position. The proportion of genome covered by ROHs and their length are indicators of the level and origin of inbreeding. Frequent common ROHs within the same population define ROH islands and indicate hotspots of selection. In this work, we investigated ROHs in a total of 1131 pigs from 20 European local pig breeds and in three cosmopolitan breeds, genotyped with the GGP Porcine HD Genomic Profiler. plink software was used to identify ROHs. Size classes and genomic inbreeding parameters were evaluated. ROH islands were defined by evaluating different thresholds of homozygous SNP frequency. A functional overview of breed-specific ROH islands was obtained via over-representation analyses of GO biological processes. Mora Romagnola and Turopolje breeds had the largest proportions of genome covered with ROH (~1003 and ~955 Mb respectively), whereas Nero Siciliano and Sarda breeds had the lowest proportions (~207 and 247 Mb respectively). The highest proportion of long ROH (>16 Mb) was in Apulo-Calabrese, Mora Romagnola and Casertana. The largest number of ROH islands was identified in the Italian Landrace (n = 32), Cinta Senese (n = 26) and Lithuanian White Old Type (n = 22) breeds. Several ROH islands were in regions encompassing genes known to affect morphological traits. Comparative ROH structure analysis among breeds indicated the similar genetic structure of local breeds across Europe. This study contributed to understanding of the genetic history of the investigated pig breeds and provided information to manage these pig genetic resources.

The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4-year-old boy with lethal Epstein-Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL-2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription-1 (STAT-5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Haplotype-based genome-wide association studies reveal new loci for haematological and clinical-biochemical parameters in Large White pigs.

We report haplotype-based GWASs for 33 blood parameters measured in 843 Italian Large White pigs. In the single-trait analysis, a total of 30 QTL for number of basophils, six erythrocyte traits (haemoglobin, haematocrit, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, mean corpuscular volume and red blood cell count) and two clinical-biochemical traits (alkaline phosphatase and Ca2+ contents) were identified. In the multiple-trait analysis, a total of five QTL affected three different clusters of traits. Only four of these QTL were already reported in the single-marker and multi-marker GWASs we previously carried out on the same pig population. QTL on SSC11 and SSC17 showed effects on multiple traits. These results further dissected the genetic architecture of parameters that could be used as proxies in breeding programmes for more complex traits. In addition, these results might help to better define the pig as an animal model for several blood-related biological functions.

Genome-wide association studies for the number of teats and teat asymmetry patterns in Large White pigs.

The number of teats is a morphological trait that influences the mothering ability of the sows and thus their reproduction performances. In this study, we carried out GWASs for the total number of teats and other 12 related parameters in 821 Italian Large White heavy pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip array. For four investigated parameters (total number of teats, the number of teats of the left line, the number of teats of the right line and the maximum number of teats comparing the two sides), significant markers were identified on SSC7, in the region of the vertnin (VRTN) gene. Significant markers for the numbers of posterior teats and the absolute difference between anterior and posterior teat numbers were consistently identified on SSC6. The most significant SNP for these parameters was an intron variant in the TOX high mobility group box family member 3 (TOX3) gene. For the other four parameters (absolute difference between the two sides; anterior teats; the ratio between the posterior and the anterior number of teats; and the absence or the presence of extra teats) only suggestively significant markers were identified on several other chromosomes. This study further supported the role of the VRTN gene region in affecting the recorded variability of the number of teats in the Italian Large White pig population and identified a genomic region potentially affecting the biological mechanisms controlling the developmental programme of morphological features in pigs.

Genome-wide detection of copy number variants in European autochthonous and commercial pig breeds by whole-genome sequencing of DNA pools identified breed-characterising copy number states.

In this study, we identified copy number variants (CNVs) in 19 European autochthonous pig breeds and in two commercial breeds (Italian Large White and Italian Duroc) that represent important genetic resources for this species. The genome of 725 pigs was sequenced using a breed-specific DNA pooling approach (30-35 animals per pool) obtaining an average depth per pool of 42×. This approach maximised CNV discovery as well as the related copy number states characterising, on average, the analysed breeds. By mining more than 17.5 billion reads, we identified a total of 9592 CNVs (~683 CNVs per breed) and 3710 CNV regions (CNVRs; 1.15% of the reference pig genome), with an average of 77 CNVRs per breed that were considered as private. A few CNVRs were analysed in more detail, together with other information derived from sequencing data. For example, the CNVR encompassing the KIT gene was associated with coat colour phenotypes in the analysed breeds, confirming the role of the multiple copies in determining breed-specific coat colours. The CNVR covering the MSRB3 gene was associated with ear size in most breeds. The CNVRs affecting the ELOVL6 and ZNF622 genes were private features observed in the Lithuanian Indigenous Wattle and in the Turopolje pig breeds respectively. Overall, the genome variability unravelled here can explain part of the genetic diversity among breeds and might contribute to explain their origin, history and adaptation to a variety of production systems.

Gradual weaning does not improve performance for calves with low starter intake at the beginning of the weaning process.

The weaning process may cause intense stress for dairy calves, even when low volumes of liquid diet are fed. Management tools that increase the intake of solid feeds, such as gradual weaning, can provide better physiological and metabolic conditions through better ruminal development, leading to better adaptation to ruminant metabolism and aiding in stress mitigation. The objective of this study was to evaluate the effects of 2 weaning protocols and 2 levels of concentrate intake on the performance and physiological and behavioral variables related to stress in dairy calves. Thirty-six newborn male Holstein calves were used in a randomized block design with a 2 × 2 factorial arrangement: 2 weaning strategies, abrupt or gradual, and 2 levels of concentrate intake at 5 wk of age, high (>350 g/d) or low (≤350 g/d). Calves were equally managed until they were 5 wk of age and then grouped according to concentrate intake. Statistical analyzes were performed using the MIXED procedure of SAS software (SAS Institute Inc., Cary, NC), and no significant interaction was observed between studied factors (weaning method and starter intake level); therefore, we considered each factor separately and their interactions with age. The highest dry matter intake and concentration of ß-hydroxybutyrate were recorded for animals with a high level of starter intake independent of the weaning method. Structural growth (cm/wk) and average daily gain were superior for calves with high starter intake, but weaning method had no effect. The gradual weaning protocol increased the time eating starter, regardless of the level of concentrate intake. Even animals with low concentrate intake that were weaned abruptly showed levels of cortisol and acid-soluble glycoprotein within normal physiological levels. Apparently, other factors besides the milk supply affect the starter intake level of calves in a conventional feeding program. The adoption of gradual weaning is not effective in improving performance when a calf has low intake 3 wk before weaning is complete, but it reduced vocalization on d 2 postweaning.

Dorsal hippocampal damage disrupts the auditory context-dependent attenuation of taste neophobia in mice.

Rodents exhibit neophobia for novel tastes, demonstrated by an initial reluctance to drink novel-tasting, potentially-aversive solutions. Taste neophobia attenuates across days if the solution is not aversive, demonstrated by increased consumption as the solution becomes familiar. This attenuation of taste neophobia is context dependent, which has been demonstrated by maintained reluctance to drink the novel tasting solution if the subject has to drink it after being brought to a novel environment. This spatial context-dependent attenuation of taste neophobia has been described and likely depends on the integrity of the dorsal hippocampus because this brain area is crucial for representing space and spatial context associations, but is unnecessary for processing taste memories per se. Whether changing the non-spatial auditory context causes a similar effect on attenuation of taste neophobia and the potential role of the dorsal hippocampus in processing this decidedly non-spatial information has not been determined. Here we demonstrate that changing the non-spatial auditory context affects the attenuation of taste neophobia in mice, and investigate the consequence of hippocampal lesion. The results demonstrate that the non-spatial auditory context-dependent attenuation of taste neophobia in mice is lost following NMDA excitotoxic lesions of the CA1 region of the dorsal hippocampus. These findings demonstrate that the dorsal hippocampus is crucial for the modulation non-associative taste learning by auditory context, neither of which provide information about space.

Signatures of de-domestication in autochthonous pig breeds and of domestication in wild boar populations from MC1R and NR6A1 allele distribution.

Autochthonous pig breeds are usually reared in extensive or semi-extensive production systems that might facilitate contact with wild boars and, thus, reciprocal genetic exchanges. In this study, we analysed variants in the melanocortin 1 receptor (MC1R) gene (which cause different coat colour phenotypes) and in the nuclear receptor subfamily 6 group A member 1 (NR6A1) gene (associated with increased vertebral number) in 712 pigs of 12 local pig breeds raised in Italy (Apulo-Calabrese, Casertana, Cinta Senese, Mora Romagnola, Nero Siciliano and Sarda) and south-eastern European countries (Krskopolje from Slovenia, Black Slavonian and Turopolje from Croatia, Mangalitsa and Moravka from Serbia and East Balkan Swine from Bulgaria) and compared the data with the genetic variability at these loci investigated in 229 wild boars from populations spread in the same macro-geographic areas. None of the autochthonous pig breeds or wild boar populations were fixed for one allele at both loci. Domestic and wild-type alleles at these two genes were present in both domestic and wild populations. Findings of the distribution of MC1R alleles might be useful for tracing back the complex genetic history of autochthonous breeds. Altogether, these results indirectly demonstrate that bidirectional introgression of wild and domestic alleles is derived and affected by the human and naturally driven evolutionary forces that are shaping the Sus scrofa genome: autochthonous breeds are experiencing a sort of 'de-domestication' process, and wild resources are challenged by a 'domestication' drift. Both need to be further investigated and managed.

Memristive effects in oxygenated amorphous carbon nanodevices.

Computing with resistive-switching (memristive) memory devices has shown much recent progress and offers an attractive route to circumvent the von-Neumann bottleneck, i.e. the separation of processing and memory, which limits the performance of conventional computer architectures. Due to their good scalability and nanosecond switching speeds, carbon-based resistive-switching memory devices could play an important role in this respect. However, devices based on elemental carbon, such as tetrahedral amorphous carbon or ta-C, typically suffer from a low cycling endurance. A material that has proven to be capable of combining the advantages of elemental carbon-based memories with simple fabrication methods and good endurance performance for binary memory applications is oxygenated amorphous carbon, or a-CO x . Here, we examine the memristive capabilities of nanoscale a-CO x devices, in particular their ability to provide the multilevel and accumulation properties that underpin computing type applications. We show the successful operation of nanoscale a-CO x memory cells for both the storage of multilevel states (here 3-level) and for the provision of an arithmetic accumulator. We implement a base-16, or hexadecimal, accumulator and show how such a device can carry out hexadecimal arithmetic and simultaneously store the computed result in the self-same a-CO x cell, all using fast (sub-10 ns) and low-energy (sub-pJ) input pulses.

Taking advantage from phenotype variability in a local animal genetic resource: identification of genomic regions associated with the hairless phenotype in Casertana pigs.

Casertana is an endangered autochthonous pig breed (raised in south-central Italy) that is considered to be the descendant of the influential Neapolitan pig population that was used to improve British breeds in the 19th century. Casertana pigs are characterized by a typical, almost complete, hairless phenotype, even though a few Casertana pigs are normal haired. In this work, using Illumina PorcineSNP60 BeadChip data, we carried out a genome-wide association study and an FST analysis with this breed by comparing animals showing the classical hairless phenotype (n = 81) versus pigs classified as haired (n = 15). Combining the results obtained with the two approaches, we identified two significant regions: one on porcine chromosome (SSC) 7 and one on SSC15. The SSC7 region contains the forkhead box N3 (FOXN3) gene, the most plausible candidate gene of this region, considering that mutations in another gene of the same family (forkhead box N1; Foxn1 or FOXN1) are responsible for the nude locus in rodents and alopecia in humans. Another potential candidate gene, rho guanine nucleotide exchange factor 10 (ARHGEF10), is located in the SSC15 region. FOXN3 and ARHGEF10 have been detected as differentially expressed in androgenetic and senescent alopecia respectively. This study on an autochthonous pig breed contributes to shed some light on novel genes potentially involved in hair development and growth and demonstrates that local animal breeds can be valuable genetic resources for disclosing genetic factors affecting unique traits, taking advantage of phenotype variability segregating in small populations.

Flavor and object recognition memory impairment induced by excitotoxic lesions of the perirhinal cortex.

Recognition memory is based on the ability to assess the familiarity of a previously encountered stimulus. It can be approached using tests for different sensorial modalities. Excitotoxic lesions of the perirhinal cortex (Prh) were performed in order to assess the relevance of its integrity for object and flavor recognition memory. Object recognition memory was impaired with a 24h retention interval. Flavor neophobia attenuation was prevented on a second encounter with the tastant. These results support a role of the perirhinal cortex in mediating the transition from novel to familiar, both in object and flavor recognition memory.