Effect of oxytocin use during colostrum harvest and the association of cow characteristics with colostrum yield and immunoglobulin G concentration in Holstein dairy cows.

Our objectives were to determine the effect of oxytocin use during colostrum harvest on colostrum yield and IgG concentration in Holstein dairy cows on a commercial dairy in New York and to describe associations of cow characteristics with these outcomes. Animals were enrolled between July and October 2023 using a randomized block design, with day of enrollment as the unit of randomization. A median (range) of 10 (3-19) cows were enrolled per day. Treatments were (1) 40 IU oxytocin (OXY40), (2) 20 IU oxytocin (OXY20), and (3) an untreated control group (CNTR). Oxytocin was administered i.m. ∼45 s before unit attachment in a rotary parlor. Colostrum weight was measured using the colostrum bucket-embedded scale or a platform scale when the yield was less than the smallest bucket scale. The concentration of IgG ([IgG]) in colostrum was determined using radial immunodiffusion and used to calculate total IgG, and DM (%) was determined by oven drying. Individual cow characteristics such as parity, calf sex, weight, dystocia score, stillbirth, and milk production in wk 4 of lactation; additionally, for multiparous cows, dry period length and previous lactation dry-off linear SCS were collected. Data were analyzed separately for primiparous and multiparous cows using backward stepwise elimination. To produce final mixed effects ANOVA models, primiparous cows (n = 201) were randomized to 35.8% (n = 72) OXY40, 32.8% (n = 66) OXY20, and 31.3% (n = 63) CNTR. Multiparous groups (n = 435) were randomized to 34.7% (n = 151) OXY40, 29.7% (n = 129) OXY20, and 35.6% (n = 155) CNTR. The median (range) colostrum yield was 6.0 (0-20.6) kg and [IgG] was 98.5 (0.1-293.6) g/L in the study population. In primiparous cows, OXY40 had a higher colostrum yield (LSM [95% CI]) of 5.4 (4.9-5.9) kg compared with both OXY20 (4.1 [3.5-4.7] kg) and CNTR (3.8 [3.3-4.3] kg). In multiparous cows, OXY40, OXY20, and CNTR did not differ in colostrum yield (5.9 [5.3-6.5], 5.7 [5.1-6.3], and 5.4 [4.8-6.0] kg, respectively), but colostrum yield was greater in parity 2 compared with all other parities, cows giving birth to male calves, cows with the highest milk production at wk 4 of lactation, and cows with a dry period of >65 d. Oxytocin use did not affect [IgG] in either primiparous or multiparous cows, but [IgG] was highest in cows in parity ≥4 and lowest in cows dry >65 d. In summary, oxytocin use at 40 IU i.m. was associated with a higher colostrum yield in primiparous cows only and no change in [IgG]. Oxytocin use likely addressed disturbed milk ejection and therefore increased colostrum yield in heifers milked for the first time in a rotary parlor. This study confirms cow characteristics associated with colostrum production within a single herd.

Comparison of Sensor-Based and Audible Detection of Milking Liner Slips during Machine Milking of Dairy Cows.

On-farm milk flow meter technology facilitates real-time assessment of individual cow milking observations and could be used to detect milking liner slips during machine milking of dairy cows. Here, we compared the accuracy of on-farm milk flow meters for detecting milking liner slips with that of audible detection and that of a portable vacuum recording system. Compared to audible detection methods, the on-farm milk flow meter facilitated the detection of milking liner slips with moderate accuracy. Using the vacuum recording system as the gold standard, the milk flow meter system failed to detect most of the liner slips, leading to poor agreement between the two devices. We conclude that the on-farm milk flow meter system tested here compared well with audible detection; however, when vacuum recordings were considered, we found significant levels of under-detection. Taken together, dairy operators may use the on-farm milk flow meter system to inform adjustments of the milking machine settings and monitor milking routine performance. However, the system is not suitable for monitoring short-duration vacuum fluctuations. Future research is warranted to optimize the sensor-based detection of milking liner slips.

A longitudinal prospective cohort study investigating the association of premilking stimulation and teat-end shape on milking characteristics and teat tissue condition in dairy cows.

BACKGROUND: Premilking udder preparation is essential for harvesting high-quality milk as gently, completely, and quickly as possible. The associations between characteristics such as teat-end shape and premilking stimulation on milking characteristics and machine milking-induced changes to the teat tissue condition have not been rigorously investigated. The primary objective was to investigate the interactive effects of manual premilking stimulation (i.e., preparation lag time) and teat-end shape on total milk yield, two-minute milk yield, milking unit-on time, and time in low milk flow rate. Our secondary objective was to study the association of manual premilking stimulation and changes to the teat tissue condition after machine milking (i.e., short-term changes). In a longitudinal prospective cohort study, 384 milking observations from 129 cows were analysed. Holstein cows were housed in sand-bedded free-stall pens, fed a total mixed ration, and milked 3 times a day. Cows were classified by teat-end shape into 1 of 3 categories: pointed, flat, or round. Individual cow milking characteristics were recorded with electronic on-farm milk meters. The duration of manual stimulation, preparation lag time, and presence of short-term changes were documented for each milking observation. General linear mixed models were used to study the interactive effects of preparation lag time and teat-end shape on milking characteristics. RESULTS: There was an interaction between preparation lag time and teat-end shape for two-minute milk yield and time in low milk flow rate. The preparation lag time effect was modified by teat-end shape, while no interaction was observed for total milk yield or milking unit-on time. A generalized linear mixed model revealed that preparation lag time was associated with short-term changes in teat tissue condition, where the odds of short-term changes decreased as preparation lag time increased. CONCLUSIONS: In summary, cows with different teat-end shapes may require different premilking stimulation regimens. Increasing preparation lag time benefits teat tissue condition during machine milking. Further research is warranted to optimize individual premilking stimulation in dairy cows.

Alopecia in Belgian Blue crossbred calves: a case series.

BACKGROUND: Alopecia is defined as the partial or complete absence of hair from areas of the body where it normally grows. Alopecia secondary to an infectious disease or parasitic infestation is commonly seen in cattle. It can also have metabolic causes, for example in newborn calves after a disease event such as diarrhoea. In the article, the investigation of a herd problem of acquired alopecia in Belgian Blue (BB) crossbred calves is described. CASE PRESENTATION: Several BB crossbred calves had presented with moderate to severe non-pruritic alopecia in a single small herd located in Southern Germany. The referring veterinarian had ruled out infectious causes, including parasitic infection and had supplemented calves with vitamins (vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, and K3) orally. Results of the diagnostic workup at the Clinic for Ruminants are presented for three affected calves and findings from a farm visit are discussed. Because of these investigations, an additional four calves were brought to the referral clinic within the first week of life, and before onset of alopecia, in order to study the course of the condition; however, these calves never developed any signs of alopecia during their clinic stay. CONCLUSIONS: Because all other plausible differential diagnoses were ruled out during our investigation, we concluded that the documented alopecia was due to malabsorption of dietary fat and consecutive disruption of lipid metabolism leading to telogen or anagen effluvium. In this particular case, this was caused by a mixing error of milk replacer in conjunction with insufficiently tempered water. We conclude that nutritional, management or environmental factors alone can lead to moderate to severe alopecia in calves in the absence of a prior or concurrent disease event or infectious cause.

Endosialin Promotes Atherosclerosis Through Phenotypic Remodeling of Vascular Smooth Muscle Cells.

OBJECTIVE: Vascular smooth muscle cells (VSMC) play a key role in the pathogenesis of atherosclerosis, the globally leading cause of death. The transmembrane orphan receptor endosialin (CD248) has been characterized as an activation marker of cells of the mesenchymal lineage including tumor-associated pericytes, stromal myofibroblasts, and activated VSMC. We, therefore, hypothesized that VSMC-expressed endosialin may display functional involvement in the pathogenesis of atherosclerosis. APPROACH AND RESULTS: Expression of endosialin was upregulated during atherosclerosis in apolipoprotein E (ApoE)-null mice and human atherosclerotic samples analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry. Atherosclerosis, assessed by Oil Red O staining of the descending aorta, was significantly reduced in ApoE/endosialin-deficient mice on Western-type diet. Marker analysis of VSMC in lesions induced by shear stress-modifying cast implantation around the right carotid artery identified a more pronounced contractile VSMC phenotype in the absence of endosialin. Moreover, in addition to contributing to neointima formation, endosialin also potentially regulated the proinflammatory phenotype of VSMC as evidenced in surrogate cornea pocket assay experiments in vivo and corresponding flow cytometry and ELISA analyses in vitro. CONCLUSIONS: The experiments identify endosialin as a potential regulator of phenotypic remodeling of VSMC contributing to atherosclerosis. The association of endosialin with atherosclerosis and its absent expression in nonatherosclerotic samples warrant further consideration of endosialin as a therapeutic target and biomarker.

BMP-9 interferes with liver regeneration and promotes liver fibrosis.

OBJECTIVE: Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-ß family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN: Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. RESULTS: Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. CONCLUSIONS: Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study.

OBJECTIVES: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings. METHODS: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers. RESULTS: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock. CONCLUSION: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.

The Association of Delayed Milk Ejection with Milking Performance in Holstein Cows in a Large Dairy Herd with Suboptimal Premilking Teat Stimulation.

The primary objective was to investigate the association between delayed milk ejection (DME) and the average milk flow rate, milking unit-on time, and duration in a low milk flow rate in Holstein dairy cows in a large dairy herd with suboptimal premilking teat stimulation. Our second objective was to study the association between peak lactation milk yield and the occurrence of DME. This longitudinal field study was conducted at a 4300-cow dairy farm with a thrice-daily milking schedule over a 1-week period. We analyzed data from 61,677 cow milking observations from 2937 cows. Delayed milk ejection was defined as present if the 30-60 s milk flow rate was ≤3.1 kg/min. The mean average milk flow rate (MAMF, kg/min), mean milking unit-on time (MMUT, s), and mean duration of a low milk flow rate (MLMF, s) were calculated as the mean values from the 21 milking observations. General linear multivariable models revealed associations of DME with MAMF, MMUT, and MLMF. A multivariable ordinal logistic regression model revealed an association between peak lactation milk yield and DME. Cows with lower peak lactation milk yield had greater odds of exhibiting a higher frequency level of DME. The observed associations between DME and milking performance indices suggest that DME can negatively affect milking and parlor efficiency. Peak lactation milk yield may serve as a proxy to estimate cows' risk of recurrent DME. Future research is warranted to test if alleviating DME through, for example, a modified milking routine influences the milking performance indices described herein.

[Outbreak of Staphylococcus aureus mastitis in a dairy herd: A case report]. / Gehäuftes Auftreten von Staphylococcus-aureus-Mastitiden in einer Milchviehherde: Ein Fallbericht.

The report describes an outbreak of Staphylococcus aureus mastitis in a dairy herd. The risk assessment included the analysis of data from milk recordings, bacteriological milk cultures, clinical mastitis records and influence of infected status on the culling risk of affected animals, as well as an evaluation of the milking routine. The milking routine and the treatment protocol of animals with Staphylococcus aureus infection were identified as possible risk factors. The implemented measures included changes to the milking routine, a different treatment protocol for infected animals, and culling and segregation of infected animals to reduce overall prevalence.

Teat open lesions can lead to challenges at milking time on dairies in the Northeast United States.

During evaluations of teat skin by the authors using National Mastitis Council procedures, teat open lesions (TOL) have been more commonly identified in dairies in the Northeast United States over the last 10 years. The TOL described here are found in all stages of lactation and in any age lactating cow, which is unique from TOL that present mainly in first lactation animals just after calving. Cows with these TOL exhibit more abnormal cow behaviors during the milking event. Based on the authors' subjective field evaluations, dry teat skin condition appears to be a significant risk factor. Although there is a paucity of published literature, the other risk factors that the authors have observed are exposure to wind and significant temperature fluctuations, wet bedding, certain bedding additives, and occasionally mechanical, chemical, or thermal trauma. Teat open lesions have been observed in herds with all the common types of bedding. Treatment and preventative measures have focused on supporting skin conditions through higher emollients in the postmilking teat disinfection (PMTD) and controlling the environmental conditions to which the teat is exposed. This includes an evaluation of cow positioning in the stall as well as bedding levels, which influence bedding contamination. The accuracy of PMTD application can also have an influence. The objective of this narrative review was to search the current literature describing TOL, identify knowledge gaps, describe the authors' field experience with TOL on dairy operations in the Northeast United States, and identify opportunities for future research.

Self-folding soft-robotic chains with reconfigurable shapes and functionalities.

Magnetic continuum soft robots can actively steer their tip under an external magnetic field, enabling them to effectively navigate in complex in vivo environments and perform minimally invasive interventions. However, the geometries and functionalities of these robotic tools are limited by the inner diameter of the supporting catheter as well as the natural orifices and access ports of the human body. Here, we present a class of magnetic soft-robotic chains (MaSoChains) that can self-fold into large assemblies with stable configurations using a combination of elastic and magnetic energies. By pushing and pulling the MaSoChain relative to its catheter sheath, repeated assembly and disassembly with programmable shapes and functions are achieved. MaSoChains are compatible with state-of-the-art magnetic navigation technologies and provide many desirable features and functions that are difficult to realize through existing surgical tools. This strategy can be further customized and implemented for a wide spectrum of tools for minimally invasive interventions.

Separable Confident Transductive Learning for Dairy Cows Teat-End Condition Classification.

Teat-end health assessments are crucial to maintain milk quality and dairy cow health. One approach to automate teat-end health assessments is by using a convolutional neural network to classify the magnitude of teat-end alterations based on digital images. This approach has been demonstrated as feasible with GoogLeNet but there remains a number of challenges, such as low performance and comparing performance with different ImageNet models. In this paper, we present a separable confident transductive learning (SCTL) model to improve the performance of teat-end image classification. First, we propose a separation loss to ameliorate the inter-class dispersion. Second, we generate high confident pseudo labels to optimize the network. We further employ transductive learning to narrow the gap between training and test datasets with categorical maximum mean discrepancy loss. Experimental results demonstrate that the proposed SCTL model consistently achieves higher accuracy across all seventeen different ImageNet models when compared with retraining of original approaches.

Risk Factors of Forced Take-Off in Dairy Cows Milked Three Times per Day in A Rotary Milking Parlor: A Case Control Study.

The aims of the research were to: (1) describe a protocol for the identification of cows that are subjected repeatedly to a forced retraction event at the end of milking; (2) study risk factors of repeated forced take-off (RFTO); and (3) assess the average milk flow rate at which the forced retraction event occurred. In a retrospective study, we collected milk flow data over a 1-week period from a 4300-cow dairy with a rotary milking parlor and a thrice-daily milking schedule. We identified 109 cases of RFTO and 2467 controls. A multivariable logistic regression model revealed associations of parity, stage of lactation, average daily milk production, and milking speed with RFTO. Cows in parity 3 or greater, animals ≤100 days in milk, high-producing animals, and cows with low milking speed had higher odds of RFTO. The average (least squares means (95% CI)) milk flow rates at the time of removal of the milking unit were 2.1 (2.0-2.1) kg/min in milking observations that were terminated with the forced retract and 1.5 (1.4-1.5) kg/min when milking units were removed with the automatic cluster remover. Future research to better understand the effect of RFTO on milk production, udder health, and animal well-being is warranted.

Vacuum Dynamics as an Alternative Method for Detection of Bimodal Milk Ejection in Dairy Cows.

The primary objective of our study was to assess the ability of a vacuum recorder to detect the presence of bimodal milk flow curves in dairy cows compared with a portable milk flow meter. In a cross-sectional study, 241 individual cow milking observations were analyzed. We simultaneously collected (1) individual cow vacuum events during milking using portable vacuum recorders, and (2) individual cow milk flow curves by attaching a portable milk flow meter to the same milking unit. Presence of bimodality was assessed with the vacuum recorder visually (BIMVA) and with the gold standard method of a milk flow meter through automatic detection (BIMLA). Kappa statistics revealed moderate agreement between BIMVA and BIMLA [κ, 95% confidence intervals (95% CI) = 0.59 (0.46-0.71)]. Diagnostic test statistics for BIMVA for detection of bimodality indicated moderate performance for sensitivity [0.65 (0.52-0.76)] and positive predictive value [0.71 (0.58-0.82)] and high values for specificity [0.92 (0.87-0.95)] and negative predictive value [0.93 (0.84-0.93)]. We conclude that milking vacuum dynamics are a suitable measure to assess bimodal milk flow curves in dairy cows.

From Understanding Mechanical Behavior to Curvature Prediction of Humidity-Triggered Bilayer Actuators.

Nature will always be an endless source of bioinspiration for man-made smart materials and multifunctional devices. Impressively, even cutoff leaves from resurrection plants can autonomously and reproducibly change their shape upon humidity changes, which goes along with total recovery of their mechanical properties after being completely dried. In this work, simple bilayers are presented as autonomously moving, humidity-triggered bending actuators. The bilayers-showing reproducible bending behavior with reversible kinematics and multiway behavior-are studied in terms of their mechanical behavior upon humidity changes. The active layer consists of a highly conducting polymer film based on poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) with poly(dimethylsiloxane) (PDMS) as passive layer. The response to humidity is explored with dynamic mechanical thermal analysis and quartz crystal microbalance measurements. Introduction of a composite beam model allows to predict the curvature of the actuators with input from the rheological measurements. It is clearly demonstrated that volumetric strain and Young's modulus, both heavily influenced by the water uptake, dominate the bending behavior and therefore the curvature of the actuators. This loop of rheological characterization coupled with an analytical model allows to predict curvatures of in principle any complex geometry and material combination for moving parts in soft robotics.

Humidity-Controlled Water Uptake and Conductivities in Ion and Electron Mixed Conducting Polythiophene Films.

Mixed conducting polymer films are of great interest in applications where an interface between electronic and ionic charge transport is needed, e.g., in bioelectronics, electrochemical energy applications, and photovoltaic device interfaces. The role of water on charge transport is of high relevance not only for aqueous environments but also for devices that are manufactured at ambient conditions with varying relative humidities. In this contribution, we present our results on the influence of controlled humidity changes on the mixed conductivity and correlation to the concomitant water uptake in the films. Two sulfonate-bearing polythiophene systems are studied: a self-made conjugated polyelectrolyte, poly(6-(thiophen-3-yl)hexane-1-sulfonate)-sodium (PTS-Na), and poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT/PSS) with different ratios of PEDOT and the polyelectrolyte PSS. Our data give clear evidence of the similarities between the aforementioned polythiophene systems and pure ionic membranes such as Nafion used in fuel cells. As such, a phase separation between the hydrophobic electronically conducting polythiophene phase and the hydrophilic water-swellable ion-conducting phase is proposed. Changing the humidity from dry conditions up to ∼90% relative humidity results in extremely high water uptakes of more than 90 wt %, which corresponds to ∼13 water molecules per sulfonate unit at maximum water uptake. Conversely, the electronic conductivity is less sensitive to increasing humidity, which is due to percolation pathways. The ionic conductivity strongly increases from 10-10 S/cm at dry conditions to 10-3 S/cm at around 30 wt % water content and then levels off at maximum conductivities of 10-3-10-2 S/cm up to water contents of 90 wt %.

The terminally redundant, nonpermuted genome of Listeria bacteriophage A511: a model for the SPO1-like myoviruses of gram-positive bacteria.

Only little information on a particular class of myoviruses, the SPO1-like bacteriophages infecting low-G+C-content, gram-positive host bacteria (Firmicutes), is available. We present the genome analysis and molecular characterization of the large, virulent, broad-host-range Listeria phage A511. A511 contains a unit (informational) genome of 134,494 bp, encompassing 190 putative open reading frames (ORFs) and 16 tRNA genes, organized in a modular fashion common among the Caudovirales. Electron microscopy, enzymatic fragmentation analyses, and sequencing revealed that the A511 DNA molecule contains linear terminal repeats of a total of 3,125 bp, encompassing nine small putative ORFs. This particular genome structure explains why A511 is unable to perform general transduction. A511 features significant sequence homologies to Listeria phage P100 and other morphologically related phages infecting Firmicutes such as Staphylococcus phage K and Lactobacillus phage LP65. Equivalent but more-extensive terminal repeats also exist in phages P100 (approximately 6 kb) and K (approximately 20 kb). High-resolution electron microscopy revealed, for the first time, the presence of long tail fibers organized in a sixfold symmetry in these viruses. Mass spectrometry-based peptide fingerprinting permitted assignment of individual proteins to A511 structural components. On the basis of the data available for A511 and relatives, we propose that SPO1-like myoviruses are characterized by (i) their infection of gram-positive, low-G+C-content bacteria; (ii) a wide host range within the host bacterial genus and a strictly virulent lifestyle; (iii) similar morphology, sequence relatedness, and collinearity of the phage genome organization; and (iv) large double-stranded DNA genomes featuring nonpermuted terminal repeats of various sizes.

ChronicOnline: Implementing a mHealth solution for monitoring and early alerting in chronic obstructive pulmonary disease.

Lack of time or economic difficulties prevent chronic obstructive pulmonary disease patients from communicating regularly with their physicians, thus inducing exacerbation of their chronic condition and possible hospitalization. Enhancing Chronic patients' Health Online proposes a new, sustainable and innovative business model that provides at low cost and at significant savings to the national health system, a preventive health service for chronic obstructive pulmonary disease patients, by combining human medical expertise with state-of-the-art online service delivery based on cloud computing, service-oriented architecture, data analytics, and mobile applications. In this article, we implement the frontend applications of the Enhancing Chronic patients' Health Online system and describe their functionality and the interfaces available to the users.

Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin.

Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC-expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis. Indeed, the histological analysis of human HCC samples revealed an inverse correlation between tumor cell proliferation and stromal endosialin expression. Correspondingly, global genetic inactivation of endosialin resulted in accelerated tumor growth in an inducible mouse HCC model. A candidate-based screen of tumor lysates and differential protein arrays of cultured HSC identified several established hepatotropic cytokines, including IGF2, RBP4, DKK1, and CCL5 as being negatively regulated by endosialin. Taken together, the experiments identify endosialin-expressing HSC as a negative regulator of HCC progression.

Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage.

Liver fibrosis is a reversible wound-healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [HSC] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C-type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin-deficient (EN(KO)) mice. Correspondingly, acute-liver-damage-induced hepatocyte proliferation (partial hepatectomy) was increased in EN(KO) mice. A candidate-based screen of known regulators of hepatocyte proliferation identified insulin-like growth factor 2 (IGF2) as selectively endosialin-dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non-neoplastic settings.