Corrigendum: Tree-shrub-grass composite woodland better facilitates emotional recovery in college students emotion better than other plant communities.

[This corrects the article DOI: 10.3389/fpsyg.2024.1285792.].

Tree-shrub-grass composite woodland better facilitates emotional recovery in college students emotion better than other plant communities.

Previous research has indicated that natural landscapes exhibit a greater capacity for ameliorating negative emotional states in individuals when compared to urban landscapes. Nevertheless, significant scientific inquiries, such as the uniformity of the rejuvenating effect across distinct categories of natural landscapes on college students and the choice of the optimal plant community for achieving the most potent restorative effect, remain unexplored. This study aimed to address these questions by selecting four plant communities (single-layer grassland, single-layer woodland, tree-grass composite woodland, tree-shrub-grass composite woodland) and using an electroencephalography method to capture the neuroelectric activity of the participants in combination with the Positive and Negative Affect Schedule score to explore the effects of plant community types on emotional recovery. The results showed that all four plant communities significantly increased positive emotions and significantly reduced negative emotions. There was no significant difference in the recovery effect of positive emotions among the four plant community types, but there was a significant difference in the recovery effect of negative emotions. The effect of tree-shrub-grass composite woodland on the negative emotion recovery effect is the best; the EEG results found that the alpha wave amplitude induced by the tree-shrub-grass composite woodland was significantly higher than that of the other three groups of plant communities, and the EEG and behavioral results were consistent. The results show that the tree-shrub-grass composite woodland has the best restoration effect and has stronger planning and design significance.

[Effect of acupotomy on expressions of cellular senescence markers p16Ink4a and p21Waf1/Cip1 in cartilage tissue of rabbits with knee osteoarthritis].

OBJECTIVE: To observe the effect of acupotomy on the expressions of p16Ink4a and p21Waf1/Cip1 in knee osteoarthritis (KOA) rabbits，so as to analyze whether acupotomy can treat KOA by inhibiting the cellular senescence of chondrocytes. METHODS: Twenty-four New Zealand male rabbits were randomly divided into normal, model, acupotomy and electroacupuncture (EA) groups, with 6 rabbits in each group. The KOA model was established by left hindlimb straightening fixation. After modeling, rabbits in the acupotomy group were treated with acupotomy loosening therapy on high stress points around the affected knee joints such as tendons attachment points of vastus medialis, vastus lateralis, rectus femoris, biceps femoris and pes anserine bursa, once a week for 3 weeks. In the EA group, "Xuehai"(SP10), "Liangqiu" (ST34),"Neixiyan" (EX-LE4) and "Waixiyan" (ST35) on the affected hindlimb were selected for EA treatment (3 mA, 2 Hz/100 Hz), 20 min each time, once every other day for 3 weeks. Before and after treatments, the knee Lequesne MG score and passive range of motion (PROM) of the affected knee joint were evaluated. After the treatments, the expressions of p16Ink4a and p21Waf1/Cip1 in the cartilage tissue of the affected knee joint were detected by immunohistochemistry and Western blot respectively. RESULTS: Before and after treatment, compared with the normal group, the Lequesne MG score was significantly increased (P<0.01), the PROM was significantly decreased (P<0.01) in the model group. After treatment, compared with the normal group, the positive expression and protein expression levels of p16Ink4a and p21Waf1/Cip1 were significantly increased (P<0.01) in the model group; compared with the model group, the Lequesne MG score was significantly decreased (P<0.01), the PROM was significantly increased (P<0.01), the positive expression and protein expression levels of p16Ink4a and p21Waf1/Cip1 were significantly decreased (P<0.01，P<0.05) in the acupo-tomy and EA groups; compared with the EA group, the Lequesne MG score was decreased (P<0.05), the PROM was increased (P<0.05), the positive expression and protein expression levels of p16Ink4a and p21Waf1/Cip1 were decreased (P<0.05，P<0.01) in the acupotomy group. CONCLUSION: Acupotomy intervention can down-regulate the expressions of cellular senescence markers p16Ink4a and p21Waf1/Cip1 in chondrocytes, indicating that acupotomy therapy may alleviate cartilage degeneration by inhibiting chondrocyte premature cellular senescence to treat KOA.

Acupotomy Contributes to Suppressing Subchondral Bone Resorption in KOA Rabbits by Regulating the OPG/RANKL Signaling Pathway.

Subchondral bone lesions, as the crucial inducement for accelerating cartilage degeneration, have been considered as the initiating factor and the potential therapeutic target of knee osteoarthritis (KOA). Acupotomy, the biomechanical therapy guided by traditional Chinese meridians theory, alleviates cartilage deterioration by correcting abnormal mechanics. Whether this mechanical effect of acupotomy inhibits KOA subchondral bone lesions is indistinct. This study aimed to investigate the effects of acupotomy on inhibiting subchondral bone resorption and to define the possible mechanism in immobilization-induced KOA rabbits. After KOA modeling, 8 groups of rabbits (4w/6w acupotomy, 4w/6w electroacupuncture, 4w/6w model, and 4w/6w control groups) received the indicated intervention for 3 weeks. Histological and bone histomorphometry analyses revealed that acupotomy prevented both cartilage surface erosion and subchondral bone loss. Further, acupotomy suppressed osteoclast activity and enhanced osteoblast activity in KOA subchondral bone, showing a significantly decreased expression of tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinases-9 (MMP-9), and cathepsin K (Ctsk) and a significantly increased expression of osteocalcin (OCN); this regulation may be mediated by blocking the decrease in osteoprotegerin (OPG) and the increase in NF-κB receptor activated protein ligand (RANKL). These findings indicated that acupotomy inhibited osteoclast activity and promoted osteoblast activity to ameliorate hyperactive subchondral bone resorption and cartilage degeneration in immobilization-induced KOA rabbits, which may be mediated by the OPG/RANKL signaling pathway. Taken together, our results indicate that acupotomy may have therapeutic potential in KOA by restoring the balance between bone formation and bone resorption to attenuate subchondral bone lesions.

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection.

In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or ß-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G+ and CD68+ cells, while increasing the relative amount of IgGκ+ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.

The effect and mechanism of N-(Z)-9-octadecenyl-2-propanesulfonamide in treatment of insulin resistance in type 2 diabetic mice / 药学学报

This study was designed to investigate the therapeutic effect and mechanisms of action of novel compound N-(Z)-9-octadecenyl-2-propanesulfonamide (N15) on type 2 diabetes (T2DM). A mouse model of T2DM was established with multiple injection of streptozotocin (STZ) at a low dose. N15 at different doses (50, 100 and 200 mg·kg-1·d-1) and pioglitazone (6 mg·kg-1·d-1) were administrated orally for 6 weeks. The level of fasting blood glucose (FBG) and fasting insulin (FIns) were measured in the course of the experiment for insulin resistance index (HOMA-IR). Oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were determined in the treated mice. The expression of Akt, AMPK and Glut4 in liver were analyzed by Western blot. N15 was found to reduce the level of FBG, FIns and HOMA-IR (P P P P P > 0.05). These results suggested that the novel compound N15 can ameliorate insulin resistance and the potential mechanism may be associated with increased insulin signaling in liver and promotion of phosphatidyl inositol 3 phosphate phosphorylation.

Intensity modulated radiation therapy with simultaneous integrated boost based dose escalation on neoadjuvant chemoradiation therapy for locally advanced distal esophageal adenocarcinoma.

AIM: To evaluate impact of radiation therapy dose escalation through intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB). METHODS: We retrospectively reviewed the patients who underwent four-dimensional-based IMRT-SIB-based neoadjuvant chemoradiation protocol. During the concurrent chemoradiation therapy, radiation therapy was through IMRT-SIB delivered in 28 consecutive daily fractions with total radiation doses of 56 Gy to tumor and 5040 Gy dose-painted to clinical tumor volume, with a regimen at the discretion of the treating medical oncologist. This was followed by surgical tumor resection. We analyzed pathological completion response (pCR) rates its relationship with overall survival and event-free survival. RESULTS: Seventeen patients underwent dose escalation with the IMRT-SIB protocol between 2007 and 2014 and their records were available for analysis. Among the IMRT-SIB-treated patients, the toxicity appeared mild, the most common side effects were grade 1-3 esophagitis (46%) and pneumonitis (11.7%). There were no cardiac events. The Ro resection rate was 94% (n = 16), the pCR rate was 47% (n = 8), and the postoperative morbidity was zero. There was one mediastinal failure found, one patient had local failure at the anastomosis site, and the majority of failures were distant in the lung or bone. The 3-year disease-free survival and overall survival rates were 41% (n = 7) and 53% (n = 9), respectively. CONCLUSION: The dose escalation through IMRT-SIB in the chemoradiation regimen seems responsible for down-staging the distal esophageal with well-tolerated complications.

A novel homogenization procedure to model the skin layers in LF numerical dosimetry.

In this study we focus on the validity of the skin layer currently implemented in up-to-date human-body anatomical models employed in low frequency (LF) numerical dosimetry. Indeed, the several layers of the skin structure, i.e. the stratum corneum (SC), dermis, and epidermis are in these models embedded into a unique fairly-thick (2-3 mm) layer encompassing all of them. While a previous work from the authors showed that for normal-standing (or limb-non-touching) postures a single-layer skin model could conservatively estimate the peak electric field induced in the skin, at least a two-layer skin model comprising of the SC and the remaining skin layers should be used for limb-touching exposure scenarios. This implies notable efforts to discretize the tiny SC layer questioning the validity of current anatomical models. A novel strategy based on the homogenization of the several skin layers has been therefore proposed in order to eliminate the SC from the computational domain opening the doors to future LF magnetic applications even for limb-touching scenarios.

TCR and IL-7 Signaling Are Altered in the Absence of Functional GTPase of the Immune Associated Nucleotide Binding Protein 5 (GIMAP5).

GTPase of the immune associated nucleotide binding protein (GIMAP) family of proteins are expressed essentially in cells of the hematopoietic system. Mutation in the founding member of this gene family, Gimap5, results in the lymphopenic phenotype in Bio-Breeding diabetes prone rats. In mice, deletion of functional Gimap5 gene affects the survival and renewal of hematopoietic stem cells in addition to the defects observed in T cells. Here we show that T cells from OTII TCR-transgenic Gimap5sph/sph mice do not proliferate in response to its cognate antigen. Furthermore, T cells from Gimap5 mutant rats and mice show decreased phosphorylation of STAT5 following stimulation with IL-7. Our results suggest that functional Gimap5 is required for optimal signaling through TCR and IL-7R in T cells.

GIMAP5 Deficiency Is Associated with Increased AKT Activity in T Lymphocytes.

Long-term survival of T lymphocytes in quiescent state is essential to maintain their cell numbers in secondary lymphoid organs. In mice and in rats, the loss of functional GTPase of the immune associated nucleotide binding protein 5 (GIMAP5) causes peripheral T lymphopenia due to spontaneous death of T cells. The underlying mechanism responsible for the disruption of quiescence in Gimap5 deficient T cells remains largely unknown. In this study, we show that loss of functional Gimap5 results in increased basal activation of mammalian target of rapamycin (mTOR), independent of protein phosphatase 2A (PP2A) or AMP-activated protein kinase (AMPK). Our results suggest that the constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway may be one of the consequences of the absence of functional GIMAP5.

Human exposure from pulsed magnetic field therapy mats: a numerical case study with three commercial products.

A previous study found that incident magnetic field exposure from pulsed magnetic field therapy (PMFT) mats can exceed ICNIRP 1998 reference levels. Due to the popularity of PMFT mats for private therapeutic use, regulators need to know if the products are compliant with the basic restrictions and how overexposure can be determined. This case study's objective was to test if such products are intrinsically compliant with ICNIRP 1998 and ICNIRP 2010 basic restrictions by evaluating three different commercially-available PMFT products. In the first step, experimentally validated numerical models of these mats were developed. As a second step, the induced fields were evaluated in high-resolution anatomical models of the IT'IS Virtual Population for various lying positions and compared to the safety guidelines. As expected, a strong influence of exposure on the PMFT design, anatomy, lying position and body orientation was found. The maximum exposure of one PMFT exceeds 3.1 times the basic restrictions of ICNIRP 1998 for the central nervous system tissues and 1.36 times the limit of ICNIRP 2010 for the peripheral tissues. Body loops can significantly increase the electric fields close to the skin, e.g., when the hand and thigh are in contact during mat use. In conclusion, PMFT products are not intrinsically compliant with ICNIRP 1998 and ICNIRP 2010 basic restrictions and therefore require special considerations.

Risk Factors Associated with Intraoperative Major Blood Loss during Resection of Hepatocellular Carcinoma.

BACKGROUND/AIMS: Intraoperative blood loss is an independent predictor of recurrence and survival after resection of hepatocellular carcinoma (HCC). The aim of this study was to identify the risk factors associated with intraoperative major blood loss in patients undergoing liver resection for HCC. METHODOLOGY: Clinicopathologic data and perioperative outcomes of 386 patients who underwent liver resection for HCC were retrospectively reviewed. The patients were divided into high (> 1,000 mL) and low (51,000 mL) blood loss groups according to the intraoperative blood loss. Intraoperative blood loss,more than 1,000 mL was defined as major blood loss. The risk factors associated with intraoperative major blood loss were analyzed by univariate and multivariate analyses. RESULTS: Vascular invasion, major hepatectomy and prolonged operation time were risk factors associated with intraoperative major blood loss during resection of HCC on multivariate analysis. Moreover, HCC patients with intraoperative major blood loss had prolonged hospital stay, higher incidence of postoperative complication and mortality compared with patients' with blood loss 1,000 mL. CONCLUSIONS: Vascular invasion, major hepatectomy and prolonged operation time are independent predictors of intraoperative major blood loss during resection of HCC.

Downregulation of LncRNAH19 and MiR-675 promotes migration and invasion of human hepatocellular carcinoma cells through AKT/GSK-3ß/Cdc25A signaling pathway.

LncRNAH19 has been implicated as having both oncogenic and tumor suppression properties in cancer. LncRNAH19 transcripts also serve as a precursor for miR-675. However, it is unknown whether LncRNAH19 and miR-675 are involved in the migration and invasion of hepatocellular carcinoma (HCC) cells. The purpose of this study was to investigate the effect and mechanism of LncRNAH19 and miR-675 on migration and invasion of HCC cells. The migration and invasion of HCC cells were measured by Transwell migration and invasion assays after transfection of HCC cells with miR-675 inhibitors and LncRNAH19siRNA. The levels of LncRNAH19 and miR-675 were detected by quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR), and the protein expression of AKT, GSK-3ß and Cdc25A by Western blotting analysis. The expression levels of LncRNAH19 and miR-675 were higher in MHCC-97H cells than in L02, Huh-7 and HepG2 cells. Transwell migration assay revealed that the miR-675 inhibitor and LncRNAH19siRNA could significantly increase the migration of HCC cells (P<0.01) as compared with the control group. Transwell invasion assay demonstrated that the miR-675 inhibitor and LncRNAH19siRNA could significantly increase the invasion of HCC cells (P<0.01) as compared with the control group. Western blotting analysis showed that the expression levels of AKT and Cdc25A were significantly increased (P<0.05), and the expression level of GSK-3ß was significantly decreased (P<0.05) after treatment with miR-675 inhibitors and LncRNAH19siRNA as compared with the control group. These findings suggested that inhibition of LncRNAH19 and miR-675 expression can promote migration and invasion of HCC cells via AKT/GSK-3ß/Cdc25A signaling pathway.

Theoretical assessment of the maximum obtainable power in wireless power transfer constrained by human body exposure limits in a typical room scenario.

In this study, the maximum received power obtainable through wireless power transfer (WPT) by a small receiver (Rx) coil from a relatively large transmitter (Tx) coil is numerically estimated in the frequency range from 100 kHz to 10 MHz based on human body exposure limits. Analytical calculations were first conducted to determine the worst-case coupling between a homogeneous cylindrical phantom with a radius of 0.65 m and a Tx coil positioned 0.1 m away with the radius ranging from 0.25 to 2.5 m. Subsequently, three high-resolution anatomical models were employed to compute the peak induced field intensities with respect to various Tx coil locations and dimensions. Based on the computational results, scaling factors which correlate the cylindrical phantom and anatomical model results were derived. Next, the optimal operating frequency, at which the highest transmitter source power can be utilized without exceeding the exposure limits, is found to be around 2 MHz. Finally, a formulation is proposed to estimate the maximum obtainable power of WPT in a typical room scenario while adhering to the human body exposure compliance mandates.

Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion.

Glioma-associated oncogene homolog-1 (Gli-1) is considered a marker of Hedgehog pathway activation and is associated with the progression of several cancers. We have previously reported that Gli-1 was correlated with invasion and metastasis in hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of Gli-1 in HCC invasion are unclear. In this study, we found that small interfering RNA mediated down-regulation of Gli-1 expression significantly suppressed adhesion, motility, migration, and invasion of both SMMC-7721 and SK-Hep1 cells. Furthermore, down-regulation of Gli-1 significantly reduced expressions and activities of both matrix metalloproteinase (MMP)-2 and MMP-9. In addition, we found that down-regulation of Gli-1 resulted in up-regulation of E-cadherin and concomitant down-regulation of Snail and Vimentin, consistent with inhibition of epithelial-mesenchymal transition (EMT). Taken together, our results suggest that down-regulation of Gli-1 suppresses HCC cell migration and invasion likely through inhibiting expressions and activations of MMP-2, 9 and blocking EMT.

On the issues related to compliance assessment of ICNIRP 2010 basic restrictions.

This article discusses technical issues related to compliance assessment of ICNIRP 2010 basic restrictions. Several difficulties are identified in this study when assessing the spatial average and 99th percentile value of the electric field. These issues are mainly attributed to the lack of clarity in the guideline specifications, which leads to inadequate or irreproducible results. Effects on compliance results due to such ambiguous procedures are hereby investigated, with particular focus on technical issues rather than biological ones. Examples spanning from simple canonical test cases to realistic applications have been selected to highlight the strong variability in dosimetry results. Based on our findings, revisiting the ICNIRP 2010 guidelines is strongly recommended, and proposed alternative solutions are outlined.

IL-15 trans-presentation regulates homeostasis of CD4(+) T lymphocytes.

Interleukin-15 (IL-15) is essential for the survival of memory CD8(+) and CD4(+) T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4(+) T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.Il15(-/-) mice when compared to NOD.scid recipients. The increased accumulation of CD4(+) T cells is also observed in NOD.Il15(-/-) mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the IL-15Rα chain, but not those lacking the common gamma chain, also show increased accumulation of CD4(+) T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4(+) T cells and requires trans-presentation of IL-15. CD4(+) T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4(+) T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-γ production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4(+) T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.

On the issues related to compliance of LF pulsed exposures with safety standards and guidelines.

In this paper, procedures to determine compliance of low-frequency pulsed exposures are investigated. Current methods specified by international standards or guidelines (e.g., from the ICNIRP or IEEE) are recognized to be conservative in order to account for uncertainties coming from the assessment procedures. In this way, protection of workers and the general public should be guaranteed. However, overly conservative procedures could hinder the application of technologies employing complex, intermittent, or pulsed waveforms without improving safety. Besides over conservatism, variabilities among the results of several procedures are examined for the first time. These limits pose several concerns on the applicability of the existing compliance formulae. A more stable technique, which is still easy to implement, is therefore proposed.

Analysis of human brain exposure to low-frequency magnetic fields: a numerical assessment of spatially averaged electric fields and exposure limits.

Compliance with the established exposure limits for the electric field (E-field) induced in the human brain due to low-frequency magnetic field (B-field) induction is demonstrated by numerical dosimetry. The objective of this study is to investigate the dependency of dosimetric compliance assessments on the applied methodology and segmentations. The dependency of the discretization uncertainty (i.e., staircasing and field singularity) on the spatially averaged peak E-field values is first determined using canonical and anatomical models. Because spatial averaging with a grid size of 0.5 mm or smaller sufficiently reduces the impact of artifacts regardless of tissue size, it is a superior approach to other proposed methods such as the 99th percentile or smearing of conductivity contrast. Through a canonical model, it is demonstrated that under the same uniform B-field exposure condition, the peak spatially averaged E-fields in a heterogeneous model can be significantly underestimated by a homogeneous model. The frequency scaling technique is found to introduce substantial error if the relative change in tissue conductivity is significant in the investigated frequency range. Lastly, the peak induced E-fields in the brain tissues of five high-resolution anatomically realistic models exposed to a uniform B-field at ICNIRP and IEEE reference levels in the frequency range of 10 Hz to 100 kHz show that the reference levels are not always compliant with the basic restrictions. Based on the results of this study, a revision is recommended for the guidelines/standards to achieve technically sound exposure limits that can be applied without ambiguity.

SOCS1 prevents potentially skin-reactive cytotoxic T lymphocytes from gaining the ability to cause inflammatory lesions.

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of T lymphocyte homeostasis. SOCS1-deficient mice accumulate CD8(+) T cells, which display a memory-like phenotype and proliferate strongly to IL-15. Socs1(-/-) mice develop inflammatory skin lesions, however, the underlying mechanisms are not well understood. In order to investigate the role of SOCS1 in regulating CD8(+) T cells potentially reactive to tissue antigens (Ags) of the skin, we generated Socs1(-/-) mice expressing MHC-I-restricted Pmel-1 transgenic TCR specific to the melanoma-derived gp100 Ag, which is also expressed by normal melanocytes. Socs1(-/-) Pmel-1 cells express increased levels of memory markers CD44, Ly6C, CD122, and CD62L, and show downregulation of TCR and upregulation of CD5, suggesting in vivo TCR stimulation. However, stimulation of Socs1(-/-)Pmel-1 cells with gp100-derived peptide induced only marginal proliferation in vitro despite eliciting strong effector functions, which was associated with elevated Blimp-1 induction. Following adoptive transfer to Rag1(-/-) mice, Socs1(-/-)Pmel-1 cells underwent lymphopenia-induced proliferation and caused severe skin pathology characterized by inflammatory lesions in ears, muzzle, extremities, and eyes. These findings underscore the importance of SOCS1 in regulating potentially skin-reactive cytotoxic T lymphocytes, which could get activated under conditions that promote Ag-nonspecific, cytokine-driven proliferation.