C-Peptide Prevents Hippocampal Apoptosis in Type 1 Diabetes

To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)- positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide

The Insulin-Like Growth Factor System and Neurological Complications in Diabetes

The IGF system plays vital roles in neuronal development, metabolism, regeneration and survival. It consists of IGF-I, IGF-II, insulin, IGF-I-receptor, and those of IGF-II and insulin as well as IGF-binding proteins. In the last decades it has become clear that perturbations of the IGF system play important roles in the pathogenesis of diabetic neurological complications. In the peripheral nervous system IGF-I, insulin, and C-peptide particularly in type 1 diabetes participate in the development of axonal degenerative changes and contributes to impaired regenerative capacities. These abnormalities of the IGF system appear to be less pronounced in type 2 diabetes, which may in part account for the relatively milder neurological complications in this type of diabetes. The members of the IGF system also provide anti-apoptotic effects on both peripheral and central nervous system neurons. Furthermore, both insulin and C-peptide and probably IGF-I possess gene regulatory capacities on myelin constituents and axonal cytoskeletal proteins. Therefore, replenishment of various members of the IGF system provides a reasonable rational for prevention and treatment of diabetic neurological complications

The Effects of C-peptide on Type 1 Diabetic Polyneuropathies and Encephalopathy in the BB/Wor-rat

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes

C-peptide and Retinal Microangiopathy in Diabetes

Increased extracellular matrix (ECM) protein deposition and capillary basement membrane (BM) thickening are characteristic features of diabetic retinal microangiopathy. Recent observations in the authors' laboratories suggest that high glucose in endothelial cells as well as diabetes causes up-regulation of total fibronectin (FN), as well as extradomain-B (EDB) containing the spliced variant of FN, oncofetal FN, in the retina. This splice variant is normally absent in mature adult tissues and is believed to be involved in angiogenesis. In this study, the authors have investigated the role of C-peptide in the production of ECM proteins and capillary BM thickening in the retina of diabetic rats. They investigated retinas from poorly controlled diabetic BB/Wor rats with or without C-peptide treatment as well as those from age-matched nondiabetic control rats after 8 months of diabetes. In addition, the authors investigated retinas from BBDRZ/Wor rats, a model of type 2 diabetes. Following a treatment period of 8 months, retinal tissues were harvested for gene expression and histological analyses. In the retinas of diabetic BB/Wor rats, a significant increase of oncofetal FN was demonstrated compared to control rats. C-peptide treatment of BB/Wor rats completely prevented such increase. Furthermore, retinas from BBDRZ/Wor rats, did not exhibit any such alteration in oncofetal FN expression. The authors further examined retinal capillary BM thickening using ultrastructural morphometry. C-peptide treatment was ineffective in preventing the diabetes-induced increase in capillary BM thickness. The authors' previous studies of cultured endothelial cells demonstrated that oncofetal FN synthesis is, at least in part, mediated via transforming growth factor-β (TGF-β) and endothelin-1 (ET-1). Hence, they examined these two transcripts in the retina of these animals. Diabetes caused significant increase in mRNA expression of ET-1 and TGF-β, which was not prevented by C-peptide treatment. Hence it appears that C-peptide is effective in preventing diabetes-induced oncofetal FN expression and that these effects are not mediated via ET-1 or TGF-β. In conclusion, these data suggest that C-peptide is involved in regulating ECM protein composition. Furthermore, normalization of diabetes-induced oncofetal FN up-regulation may suggest importance of C-peptide in advanced alterations in diabetic retinopathy such as angiogenesis

ViT-Lens: Towards Omni-modal Representations

Though the success of CLIP-based training recipes in vision-language models, their scalability to more modalities (e.g., 3D, audio, etc.) is limited to large-scale data, which is expensive or even inapplicable for rare modalities. In this paper, we present ViT-Lens that facilitates efficient omni-modal representation learning by perceiving novel modalities with a pretrained ViT and aligning to a pre-defined space. Specifically, the modality-specific lens is tuned to project multimodal signals to the shared embedding space, which are then processed by a strong ViT that carries pre-trained image knowledge. The encoded multimodal representations are optimized toward aligning with the modal-independent space, pre-defined by off-the-shelf foundation models. A well-trained lens with a ViT backbone has the potential to serve as one of these foundation models, supervising the learning of subsequent modalities. ViT-Lens provides a unified solution for representation learning of increasing modalities with two appealing benefits: (i) Exploiting the pretrained ViT across tasks and domains effectively with efficient data regime; (ii) Emergent downstream capabilities of novel modalities are demonstrated due to the modality alignment space. We evaluate ViT-Lens in the context of 3D as an initial verification. In zero-shot 3D classification, ViT-Lens achieves substantial improvements over previous state-of-the-art, showing 52.0% accuracy on Objaverse-LVIS, 87.4% on ModelNet40, and 60.6% on ScanObjectNN. Furthermore, we enable zero-shot 3D question-answering by simply integrating the trained 3D lens into the InstructBLIP model without any adaptation. We will release the results of ViT-Lens on more modalities in the near future.Comment: 19 pages, 4 figures and 9 table

Too Large; Data Reduction for Vision-Language Pre-Training

This paper examines the problems of severe image-text misalignment and high redundancy in the widely-used large-scale Vision-Language Pre-Training (VLP) datasets. To address these issues, we propose an efficient and straightforward Vision-Language learning algorithm called TL;DR, which aims to compress the existing large VLP data into a small, high-quality set. Our approach consists of two major steps. First, a codebook-based encoder-decoder captioner is developed to select representative samples. Second, a new caption is generated to complement the original captions for selected samples, mitigating the text-image misalignment problem while maintaining uniqueness. As the result, TL;DR enables us to reduce the large dataset into a small set of high-quality data, which can serve as an alternative pre-training dataset. This algorithm significantly speeds up the time-consuming pretraining process. Specifically, TL;DR can compress the mainstream VLP datasets at a high ratio, e.g., reduce well-cleaned CC3M dataset from 2.82M to 0.67M ($\sim$24\%) and noisy YFCC15M from 15M to 2.5M ($\sim$16.7\%). Extensive experiments with three popular VLP models over seven downstream tasks show that VLP model trained on the compressed dataset provided by TL;DR can perform similar or even better results compared with training on the full-scale dataset. The code will be made available at \url{https://github.com/showlab/data-centric.vlp}.Comment: Work in progress. Code: https://github.com/showlab/data-centric.vl

C-peptide reverses nociceptive neuropathy in type 1 diabetes

Autorzy zbadali działanie terapeutyczne peptydu C w ustalonej neuropatii nocyceptywnej u szczurów BB/Wor z cukrzycą typu 1. Oceniono nocyceptywną funkcję nerwów, morfometrię niezmielinizowanych włókien nerwu łydkowego i zwoju korzenia grzbietowego (DRG), zawartość peptydu nocyceptywnego oraz ekspresję czynników neurotroficznych i ich receptorów. Peptyd C podawano w dawce substytucyjnej drogą pompy osmotycznej w ciągłym wlewie lub raz dziennie w iniekcji podskórnej. Szczury z cukrzycą leczono od 4.-7. miesiąca trwania cukrzycy i porównywano z nieleczonymi szczurami z grupy kontrolnej w tym samym okresie choroby. Peptyd C podawany przez pompę osmotyczną, lecz nie w iniekcjach podskórnych, zmniejszył hiperalgezję i cukrzycozależną redukcję liczby włókien niezmielinizowanych (p < 0,01) oraz średnią wielkość aksonów (p < 0,05) w nerwie łydkowym. Ekspresja receptora czynnika wzrostu nerwu (NGF) o dużym podobieństwie (NGFR-TrkA) w DRG zmniejszyła się znamiennie w 4. miesiącu (p < 0,01). Ekspresja receptorów insulinowego oraz IGF-1 w DGR i NFG w nerwie kulszowym zmniejszyła się znamiennie w 7. miesiącu u szczurów z cukrzycą (odpowiednio: p < 0,01, p < 0,05 i p < 0,005). Podawanie przez pompę osmotyczną zapobiegło spadkowi ekspresji NGFR-TrkA, receptora insulinowego (p < 0,05) i IGF-IR (p < 0,005) w DRG oraz zwiększyło zawartość NGF (p < 0,05) w nerwie kulszowym. Natomiast peptyd C podawany drogą podskórną wpłynął jedynie w niewielkim stopniu na morfometryczne i molekularne zmiany u szczurów z cukrzycą. Stwierdzono, że peptyd C korzystnie wpływa na cukrzycową neuropatię nocyceptywną; aby uzyskać efekt optymalny, należy utrzymywać fizjologiczne stężenie peptydu C w ciągu dnia.We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Worrats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetesinduced reduction of unmyelinated fiber number (p < 0.01) and mean axonal size (p < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (p < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (p < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (p < 0.05), and IGF-IR (p < 0.005) expressions in DRGs and improved NGF content (p < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day

Learning to Learn: How to Continuously Teach Humans and Machines

Our education system comprises a series of curricula. For example, when we learn mathematics at school, we learn in order from addition, to multiplication, and later to integration. Delineating a curriculum for teaching either a human or a machine shares the underlying goal of maximizing the positive knowledge transfer from early to later tasks and minimizing forgetting of the early tasks. Here, we exhaustively surveyed the effect of curricula on existing continual learning algorithms in the class-incremental setting, where algorithms must learn classes one at a time from a continuous stream of data. We observed that across a breadth of possible class orders (curricula), curricula influence the retention of information and that this effect is not just a product of stochasticity. Further, as a primary effort toward automated curriculum design, we proposed a method capable of designing and ranking effective curricula based on inter-class feature similarities. We compared the predicted curricula against empirically determined effectual curricula and observed significant overlaps between the two. To support the study of a curriculum designer, we conducted a series of human psychophysics experiments and contributed a new Continual Learning benchmark in object recognition. We assessed the degree of agreement in effective curricula between humans and machines. Surprisingly, our curriculum designer successfully predicts an optimal set of curricula that is effective for human learning. There are many considerations in curriculum design, such as timely student feedback and learning with multiple modalities. Our study is the first attempt to set a standard framework for the community to tackle the problem of teaching humans and machines to learn to learn continuously

Effects of nitrate on the treatment of lead contaminated groundwater by nanoscale zerovalent iron

Nanoscale zerovalent iron (nZVI) is efficient for removing Pb(2+) and nitrate from water. However, the influence of nitrate, a common groundwater anion, on Pb(2+) removal by nZVI is not well understood. In this study, we showed that under excess Fe(0) conditions (molar ratio of Fe(0)/nitrate&gt;4), Pb(2+) ions were immobilized more quickly (&lt;5 min) than in nitrate-free systems (∼ 15 min) due to increasing pH. With nitrate in excess (molar ratio of Fe(0)/nitrate&lt;4), nitrate stimulated the formation of crystal PbxFe3-xO4 (ferrite), which provided additional Pb(2+) removal. However, ∼ 7% of immobilized Pb(2+) ions were released into aqueous phase within 2h due to ferrite deformation. Oxidation-reduction potential (ORP) values below -600 mV correlated with excess Fe(0) conditions (complete Pb(2+) immobilization), while ORP values ≥-475 mV characterized excess nitrate conditions (ferrite process and Pb(2+) release occurrence). This study indicates that ORP monitoring is important for proper management of nZVI-based remediation in the subsurface to avoid lead remobilization in the presence of nitrate

The role of upfront primary tumor resection in asymptomatic patients with unresectable stage IV colorectal cancer: A systematic review and meta-analysis

BackgroundControversy exists over the role of upfront primary tumor resection (PTR) in asymptomatic patients with unresectable stage IV colorectal cancer (CRC). The purpose of this study was to evaluate the effect of upfront PTR on survival outcomes and adverse outcomes.MethodsSearches were conducted on PubMed, EMBASE, Web of Science, and Cochrane Library from inception to August 2021. Studies comparing survival outcomes with or without adverse outcomes between PTR and non-PTR treatments were included. Review Manager 5.3 was applied for meta-analyses with a random-effects model whenever possible.ResultsOverall, 20 studies with 3,088 patients were finally included in this systematic review. Compared with non-PTR, upfront PTR was associated with better 3-year (HR: 0.69, 95% CI, 0.57–0.83, P = 0.0001) and 5-year overall survival (OS) (HR: 0.77, 95% CI, 0.62–0.95, P = 0.01), while subgroup analysis indicated that there was no significant difference between upfront PTR and upfront chemotherapy (CT) group. In addition, grade 3 or higher adverse effects due to CT were more frequent in the PTR group with marginal significance (OR: 1.74, 95% CI, 0.99–3.06, P = 0.05), and other adverse outcomes were comparable.ConclusionsPTR might be related to improved OS for asymptomatic patients with unresectable stage IV CRC, whereas receiving upfront CT is a rational alternative without detrimental influence on survival or adverse outcomes compared with upfront PTR.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=27267