Ferried Albumin-Inspired Bioadhesive With Dynamic Interfacial Bonds for Emergency Rescue.

Emergency prehospital wound closure and hemorrhage control are the first priorities for life-saving. Majority of bioadhesives form bonds with tissues through irreversible cross-linking, and the remobilization of misalignment may cause severe secondary damage to tissues. Therefore, developing an adhesive that can quickly and tolerably adhere to traumatized dynamic tissue or organ surfaces in emergency situations is a major challenge. Inspired by the structure of human serum albumin (HSA), a branched polymer with multitentacled sulfhydryl is synthesized, then, an instant and fault-tolerant tough wet-tissue adhesion (IFA) hydrogel is prepared. Adhesive application time is just 5 s (interfacial toughness of ≈580 J m-2), and favorable tissue-adhesion is maintained after ten cycles. IFA hydrogel shows unchangeable adhesive performance after 1 month of storage based on the internal oxidation-reduction mechanism. It not only can efficiently seal various organs but also achieves effective hemostasis in models of the rat femoral artery and rabbit-ear artery. This work also proposes an effective strategy for controllable adhesion, enabling the production of asymmetric adhesives with on-demand detachment. Importantly, IFA hydrogel has sound antioxidation, antibacterial property, hemocompatibility, and cytocompatibility. Hence, the HSA-inspired bioadhesive emerges as a promising first-aid supply for human-machine interface-based health management and non-invasive wound closure.

The unique properties of tear film breakup process in patients with nasal unilateral pterygium.

SIGNIFICANCE: This study found that the unique properties of tear film breakup process in eyes with pterygium, combined with ocular surface parameters, further revealed specific dynamic mechanism. It suggested that the thickness of pterygium was especially valuable in deciding the necessity of surgical management. PURPOSE: This study aimed to explore the dynamic mechanism of tear film instability in eyes with pterygium. METHODS: A paired-eye controlled cross-sectional study was conducted. Seventy-eight patients with nasal pterygium were enrolled. Fluorescein tear film breakup was observed. Several key parameters related to tear film quality were defined and analyzed, including total breakup area (mathematically derived from pixel size using MATLAB), breakup velocity, fluorescein breakup time, breakup location and pattern, tear meniscus height, score of fluorescein corneal staining, and meiboscore. RESULTS: With comparable tear meniscus height, score of fluorescein corneal staining, and meiboscore between paired eyes (p > 0.05), eyes with pterygium had shorter breakup time, larger breakup area, and faster breakup velocity (p < 0.05). In eyes with pterygium, a positive correlation between meiboscore and pterygium parameters including length, thickness, and size was observed (p > 0.001). As the thickness increased, difference of breakup time and area between paired eyes increased (p = 0.02 and 0.046). Eyes with pterygium had more fixed inferonasal breakup location and often presented as dimple break (60%), whereas random break was the most common in contralateral normal eyes (62%). A unique breakup pattern named pterygium-induced local dimple break was found. It displayed as an irregular but vertical line-like shape appearing after lipid layer spreading, which was adjacent to the lower margin of pterygium and presented with unique properties including inferonasal breakup location, local breakup area, shorten breakup time, and faster breakup velocity. CONCLUSIONS: Eyes with pterygium showed a unique tear film breakup process and novel breakup pattern named pterygium-induced local dimple break . Dynamic mechanism played a significant role in tear film instability of eyes with pterygium rather than aqueous deficiency and increased evaporation.

Nanomechanical-based classification of prostate tumor using atomic force microscopy.

BACKGROUND: The loss of mechanical homeostasis between tumor cells and microenvironment is an important factor in tumor metastasis. In the process, mechanical forces affect cell proliferation, differentiation, migration and tissue development. AIMS: Using high spatial resolution of Atomic force microscopy (AFM) technology, our study provides the direct measurement of the nanomechanical properties of prostate cancer clinical tissue specimens. MATERIALS AND METHODS: AFM was used to determine the biomechanical properties of prostate tissue with different grade scores. K-means clustering method and fuzzy C-means were used to distinguish the cellular component in prostate tissue from non-cellular component based on their viscoelasticity. Futhermore, AFM measurements in vitro cells, including metastatic prostate cells (PC-3) and normal human prostate cells (PZ-HPV-7) were carried out. RESULTS: The Young's modulus was decreased in prostate cancer progression, and the elasticity of cellular component in prostate cancer tissue was smaller than that of normal prostate tissue. PC-3 cells were softer than PZ-HPV-7 cells. Further mechanism investigation showed that the difference in modulus between cancerous and normal prostate tissue may be associated with a greater actin cytoskeleton distribution inside the cancer cells. CONCLUSION: The results suggests that the nanomechanical properties can classify the prostate tumor, which could be used as an index for the identification and classification of cancer at cellular level.

The role of HIF-1α-mediated autophagy in ionizing radiation-induced testicular injury.

Testis, as a key organ for maintaining male fertility, are extremely sensitive to ionizing radiation (IR). IR-induced testicular dysfunction and infertility are common adverse effects of radiation therapy in patients with pelvic cancer. To study the phenotype and mechanism of IR-induced testicular injury, the mice were irradiated with different radiation doses (0, 2 and 5 Gy) below the semi-lethal dose for one month. Our present results showed that testicular weight and the serum testosterone levels significantly decreased with the structural injury of the testis in an IR dose-dependent manner, indicating that IR caused not only the structural damage of the testis, but also the functional damage. Further analysis by TUNEL staining and Western blotting found that IR induced the apoptosis in a dose-dependent manner as indicated by increased expressions of cleaved caspase3, p53 and Bax on Day 15 after IR treatment. Combined with significantly increased oxidative stress, these results indicated that IR-induced testicular damage may be a long-term, progressively aggravated process, accompanied by apoptosis. Given the role of autophagy in apoptosis, the present study also detected and analyzed the localization and expressions of autophagy-related proteins LC-3I/II, beclin1, p62 and Atg12 in testicular cells, and found that LC-3II, beclin1 and Atg12 expressions significantly increased in the testicular cells of mice irradiated with 2 Gy and 5 Gy, while p62 expression significantly decreased with 5 Gy, implying autophagy was involved in the apoptosis of testicular cells induced by IR. Furthermore, the expressions of HIF-1α and BNIP3 were significantly enhanced in the testis cells of mice irradiated with 2 Gy and 5 Gy, suggesting the potential role of HIF-1α/BNIP3-mediated autophagy in the apoptosis of testicular cells induced by IR. Taken together, our findings demonstrated that HIF-1α/BNIP3-mediated autophagy not only plays a protective effect on the testicular cells of mice irradiated with 2 Gy, but also induces the apoptosis of the testicular cells of mice irradiated with 5 Gy, indicating the double effects on apoptosis, which will help us further understanding the molecular mechanisms of IR-induced testicular injury, and will facilitate us further studies on testicular radioprotection.

Robust but On-Demand Detachable Wet Tissue Adhesive Hydrogel Enhanced with Modified Tannic Acid.

Adhesives with robust but readily detachable wet tissue adhesion are of great significance for wound closure. Polyelectrolyte complex adhesive (PECA) is an important wet tissue adhesive. However, its relatively weak cohesive and adhesive strength cannot satisfy clinical applications. Herein, modified tannic acid (mTA) with a catechol group, a long alkyl hydrophobic chain, and a phenyl group was prepared first, and then, it was mixed with acrylic acid (AA) and polyethylenimine (PEI), followed by UV photopolymerization to make a wet tissue adhesive hydrogel with tough cohesion and adhesion strength. The hydrogel has a strong wet tissue interfacial toughness of ∼1552 J/m2, good mechanical properties (∼7220 kPa cohesive strength, ∼873% strain, and ∼33,370 kJ/m3 toughness), and a bursting pressure of ∼1575 mmHg on wet porcine skin. The hydrogel can realize quick and effective adhesion to various wet biological tissues including porcine skin, liver, kidney, and heart and can be changed easily with triggering urea solution to avoid tissue damage or uncomfortable pain to the patient. This biosafe adhesive hydrogel is very promising for wound closure and may provide new ideas for the design of robust wet tissue adhesives.

Tough and On-Demand Detachable Wet Tissue Adhesive Hydrogel Made from Catechol Derivatives with a Long Aliphatic Side Chain.

Wet adhesion is critical in cases of wound closure, but it is usually deterred by the hydration layer on tissues. Inspired by dopamine-mediated underwater adhesion in mussel foot proteins, wet tissue adhesives containing catechol with 2-3 carbons side chains are reported mostly. To make wet adhesion of this type of adhesives much tougher, catechol derivatives with a long aliphatic side chain (≈10 atoms length) are synthesized. Then, a series of strong wet tissue adhesive hydrogels are prepared through photoinduced copolymerization of acrylic acid with synthetic monomers. The adhesive hydrogel has a high cohesion strength, that is, tensile strength and strain, and toughness of ≈1800 kPa, ≈540%, and ≈4100 kJ m-3 , respectively. Its interfacial toughness on wet and underwater porcine skin is respectively ≈1300 and ≈1100 J m-2 , and its adhesion strength to wet porcine skin is ≈153 kPa. These values are much higher than those of dopamine-based adhesives in the same conditions, demonstrating that the long aliphatic side chain on catechol can greatly improve the wet tissue-adhesion. Additionally, the tough interfacial adhesion can be broken on demand with 5 wt.% aqueous urea solution. This adhesive hydrogel is highly promising in safe wound closure.

Contribution of HIF-1α/BNIP3-mediated autophagy to lipid accumulation during irinotecan-induced liver injury.

Irinotecan is a topoisomerase I inhibitor which has been widely used to combat several solid tumors, whereas irinotecan therapy can induce liver injury. Liver injury generally leads to tissue hypoxia, and hypoxia-inducible factor-1α (HIF-1α), a pivotal transcription factor, mediates adaptive pathophysiological responses to lower oxygen condition. Previous studies have reported a relationship between HIF-1α and autophagy, and autophagy impairment is a common characteristic in a variety of diseases. Here, irinotecan (50 mg/kg) was employed on mice, and HepG2 and L-02 cells were cultured with irinotecan (10, 20 and 40 µM). In vivo study, we found that irinotecan treatment increased final liver index, serum aminotransferase level and hepatic lipid accumulation. Impaired autophagic flux and activation of HIF-1α/BNIP3 pathway were also demonstrated in the liver of irinotecan-treated mice. Moreover, irinotecan treatment significantly deteriorated hepatic oxidative stress, evidenced by increased MDA and ROS contents, as well as decreased GSH-Px, SOD and CAT contents. Interestingly, protein levels of NLRP3, cleaved-caspase 1 and IL-1ß were enhanced in the liver of mice injected with irinotecan. In vitro study, irinotecan-treated HepG2 and L-02 cells also showed impaired autophagic flux, while HIF-1α inhibition efficaciously removed the accumulated autophagosomes induced by irinotecan. Additionally, irinotecan treatment aggravated lipid accumulation in HepG2 and L-02 cells, and HIF-1α inhibition reversed the effect of irinotecan. Furthermore, HIF-1α inhibition weakened irinotecan-induced NLRP3 inflammasome activation in HepG2 cells. Taken together, our results suggest that irinotecan induces liver injury by orchestrating autophagy via HIF-1α/BNIP3 pathway, and HIF-1α inhibition could alleviate irinotecan-induced lipid accumulation in HepG2 and L-02 cells, which will provide a new clue and direction for the prevention of side effects of clinical chemotherapy drugs.

Diabetes-Induced Autophagy Dysregulation Engenders Testicular Impairment via Oxidative Stress.

Testes produce sperms, and gamete generation relies on a proper niche environment. The disruption of hierarchical regulatory homeostasis in Leydig or Sertoli cells may evoke a sterile phenotype in humans. In this study, we recapitulated type 2 diabetes mellitus by using a high-fat diet- (HFD-) fed mouse model to identify the phenotype and potential mechanism of diabetes-induced testicular impairment. At the end of the study, blood glucose levels, testosterone structure, testicular antioxidant capacity, and testosterone level and the expression of hypoxia-inducible factor- (HIF-) 1α, apoptosis-related protein cleaved-caspase3, and autophagy-related proteins such as LC3I/II, p62, and Beclin1 were evaluated. We found that long-term HFD treatment causes the development of diabetes mellitus, implicating increased serum glucose level, cell apoptosis, and testicular atrophy (P < 0.05 vs. Ctrl). Mechanistically, the results showed enhanced expression of HIF-1α in both Sertoli and Leydig cells (P < 0.05 vs. Ctrl). Advanced glycation end products (AGEs) were demonstrated to be a potential factor leading to HIF-1α upregulation in both cell types. In Sertoli cells, high glucose treatment had minor effects on Sertoli cell autophagy. However, AGE treatment stagnated the autophagy flux and escalated cell apoptosis (P < 0.05 vs. Ctrl+Ctrl). In Leydig cells, high glucose treatment was adequate to encumber autophagy induction and enhance oxidative stress. Similarly, AGE treatment facilitated HIF-1α expression and hampered testosterone production (P < 0.05 vs. Ctrl+Ctrl). Overall, these findings highlight the dual effects of diabetes on autophagy regulation in Sertoli and Leydig cells while imposing oxidative stress in both cell types. Furthermore, the upregulation of HIF-1α, which could be triggered by AGE treatment, may negatively affect both cell types. Together, these findings will help us further understand the molecular mechanism of diabetes-induced autophagy dysregulation and testicular impairment, enriching the content of male reproductive biology in diabetic patients.

Water-driven noninvasively detachable wet tissue adhesives for wound closure.

Tissue adhesive with on-demand detachment feature is critically important since it can minimize hurt to patient when it is stripped away. Herein, a water-driven noninvasively detachable wet tissue adhesive hydrogel (w-TAgel) was produced by UV-initiated radical copolymerization of N-isopropylacrylamide (NIPAM), acrylamide (AAm), gelatin methacrylate (GelMA), and urushiol. As a w-TAgel, its robust and tough mechanical property makes it suitable for dynamic wound tissue. The polyurushiol segments of it are crucial to the formation of tough adhesion interface with various wet tissues, while polyNIPAM units play an indispensable role in on-demand detachment via thermo-responsive swelling behavior because the hydrophobic aggregation among isopropyl groups is destroyed upon water treatment with temperature of 25 â€‹°C or less. Additionally, it exhibits multiple merits including good hemocompatibility, cytocompatibility as well as pro-coagulant activity and hemostasis. Therefore, our w-TAgel with strong adhesion and facile detachment is an advanced prospective dressing for wound closure and rapid hemostasis. The wet tissue adhesion and water-driven detachable mechanism may shed new light on the development of on-demand noninvasively detachable wet tissue adhesives.

Action Sites and Clinical Application of HIF-1α Inhibitors.

Hypoxia-inducible factor-1α (HIF-1α) is widely distributed in human cells, and it can form different signaling pathways with various upstream and downstream proteins, mediate hypoxia signals, regulate cells to produce a series of compensatory responses to hypoxia, and play an important role in the physiological and pathological processes of the body, so it is a focus of biomedical research. In recent years, various types of HIF-1α inhibitors have been designed and synthesized and are expected to become a new class of drugs for the treatment of diseases such as tumors, leukemia, diabetes, and ischemic diseases. This article mainly reviews the structure and functional regulation of HIF-1α, the modes of action of HIF-1α inhibitors, and the application of HIF-1α inhibitors during the treatment of diseases.

Catechol modification of non-woven chitosan gauze for enhanced hemostatic efficacy.

Development of efficient hemostatic gauze is critical to increasing survival rate by quick bleeding control of life-threatening hemorrhage. Herein, a novel chitosan non-woven hemostatic gauze is made by slightly surface modification with a special catechol compound, i.e. 3-(9,11,13-pentadecatrienyl)-1,2-benzenediol with a long side hydrophobic alkyl chain. Its wettability, interaction with red blood cell and platelet, and hemostatic efficacy on rat injuries are evaluated. This chitosan-catechol gauze demonstrates impressive hemostatic performances on rat femoral artery and liver laceration injury models (blood loss of this modified chitosan gauze is less than 17% of that of pristine chitosan gauze). Additionally, it is biodegradable, and maintains non-cytotoxicity. It integrates three structure and function effects together, i.e., anchoring effect between catechol and tissue, blood repelling effect from hydrophobic alkyl chain, and blood wicking effect from hydrophilic chitosan. Therefore, a new hemostatic mechanism is proposed for the excellent hemostatic potentials of this chitosan gauze.

Contribution of Oxidative Stress to HIF-1-Mediated Profibrotic Changes during the Kidney Damage.

Hypoxia and oxidative stress are the common causes of various types of kidney injury. During recent years, the studies on hypoxia inducible factor- (HIF-) 1 attract more and more attention, which can not only mediate hypoxia adaptation but also contribute to profibrotic changes. Through analyzing related literatures, we found that oxidative stress can regulate the expression and activity of HIF-1α through some signaling molecules, such as prolyl hydroxylase domain-containing protein (PHD), PI-3K, and microRNA. And oxidative stress can take part in inflammation, epithelial-mesenchymal transition, and extracellular matrix deposition mediated by HIF-1 via interacting with classical NF-κB and TGF-ß signaling pathways. Therefore, based on previous literatures, this review summarizes the contribution of oxidative stress to HIF-1-mediated profibrotic changes during the kidney damage, in order to further understand the role of oxidative stress in renal fibrosis.

HIF-1α Activation Promotes Luteolysis by Enhancing ROS Levels in the Corpus Luteum of Pseudopregnant Rats.

The increase of oxidative stress is one of the important characteristics of mammalian luteal regression. Previous investigations have revealed the essential role of reactive oxygen species (ROS) in luteal cell death during luteolysis, while it is unknown how ROS is regulated in this process. Considering the decrease of blood flow and increase of PGF2α during luteolysis, we hypothesized that the HIF-1α pathway may be involved in the regulation of ROS in the luteal cell of the late corpus luteum (CL). Here, by using a pseudopregnant rat model, we showed that the level of both HIF-1α and its downstream BNIP3 was increased during luteal regression. Consistently, we observed the increase of autophagy level during luteolysis, which is regulated in a Beclin1-independent manner. Comparing with early (Day 7 of pseudopregnancy) and middle CL (Day 14), the level of ROS was significantly increased in late CL, indicating the contribution of oxidative stress in luteolysis. Inhibition of HIF-1α by echinomycin (Ech), a potent HIF-1α inhibitor, ameliorated the upregulation of BNIP3 and NIX, as well as the induction of autophagy and the accumulation of ROS in luteal cells on Day 21 of pseudopregnancy. Morphologically, Ech treatment delayed the atrophy of the luteal structure at the late-luteal stage. An in vitro study indicated that inhibition of HIF-1α can also attenuate PGF2α -induced ROS and luteal cell apoptosis. Furthermore, the decrease of cell apoptosis can also be observed by ROS inhibition under PGF2α treatment. Taken together, our results indicated that HIF-1α signaling is involved in the regression of CL by modulating ROS production via orchestrating autophagy. Inhibition of HIF-1α could obviously hamper the apoptosis of luteal cells and the process of luteal regression.

Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome.

FoxO1 is a member of the forkhead transcription factor family subgroup O (FoxO), which is expressed in many cell types, and participates in various pathophysiological processes, including cell proliferation, apoptosis, autophagy, metabolism, inflammatory response, cytokine expression, immune differentiation, and oxidative stress resistance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in the women of childbearing age, which is regulated via a variety of signaling pathways. Currently, the specific mechanism underlying the pathogenesis of PCOS is still unclear. As an important transcription factor, FoxO1 activity might be involved in the pathophysiology of PCOS. PCOS has been associated with insulin resistance and low-grade inflammatory response. Therefore, the studies regarding the role of FoxO1 in the incidence and associated complications of PCOS will help provide novel ideas for establishing the treatment strategy of PCOS.

HIF-1α Protects Granulosa Cells From Hypoxia-Induced Apoptosis During Follicular Development by Inducing Autophagy.

Owing to the avascular structure of the ovarian follicle, proliferation of granulosa cells (GCs) and development of follicles occur under hypoxia, which is obviously different from the cell survival requirements of most mammalian cells. We hypothesized that autophagy may exert an inhibitory effect on GC apoptosis. To decipher the underlying mechanism, we constructed a rat follicular development model using pregnant mare serum gonadotropin and a cell culture experiment in hypoxic conditions (3% O2). The present results showed that the autophagy level was obviously increased and was accompanied by the concomitant elevation of hypoxia inducible factor (HIF)-1α and BNIP3 (Bcl-2/adenovirus E1B 19kDa-interacting protein 3) in GCs during follicular development. The levels of Bax (Bcl2-associated X) and Bcl-2 (B-cell lymphoma-2) were increased, while the activation of caspase-3 exhibited no obvious changes during follicular development. However, inhibition of HIF-1α attenuated the increase in Bcl-2 and promoted the increase in Bax and cleaved caspase-3. Furthermore, we observed the downregulation of BNIP3 and the decrease in autophagy after treatment with a specific HIF-1α activity inhibitor (echinomycin), indicating that HIF-1α/BNIP3 was involved in autophagy regulation in GCs in vivo. In an in vitro study, we also found that hypoxia did not obviously promote GC apoptosis, while it significantly enhanced the activation of HIF-1α/BNIP3 and the induction of autophagy. Expectedly, this effect could be reversed by 3-methyladenine (3-MA) treatment. Taken together, these findings demonstrated that hypoxia drives the activation of HIF-1α/BNIP3 signaling, which induces an increase in autophagy, protecting GC from apoptosis during follicular development.

Time-course of the visual Impact on presbyopes of a low dose miotic.

PURPOSE: To examine the pupil and visual impact of a single early morning drop of a low concentration miotic. METHODS: Pupil size, refraction, visual acuity (VA), near reading performance and intraocular pressure were monitored for 8 h at a wide range of light levels following bilateral instillation of single drops of 0.1% brimonidine tartate in 19 early presbyopes (40-50 years) and 11 mature presbyopes (>50 years). RESULTS: Pupil miosis did not alter distance VA or refraction. Significant pupil miosis peaked at 1-2 h after dosing, which expanded the depth of focus of mature presbyopes with the mean improvement in near logMAR VA of -0.15, -0.07 and -0.03, at 20, 200 and 2000 lux, respectively. One hour after instillation, near reading speed improved by 21, 24 and 5 words per min for text size commonly seen in US newspaper and cellphone text messages, 18, 21 and 19 words per min for text size of grocery labels and 12, 13 and 30 words per min for text size of over-the-counter medications at light levels of 20, 200 and 2000 lux, respectively. No such improvements in near VA and near reading speed were observed in the young presbyopes having some residual accommodation. Most of the pupil miosis remained 8 h after instillation, whereas near VA improvements disappeared after 4 h. CONCLUSION: Low dose miotics can enhance near vision in presbyopic subjects while retaining high quality distance vision over a wide range of light levels. Significant improvements in near vision were observed only during the 1-2 h period after dosing when miosis peaked.

The Impact of IOL Abbe Number on Polychromatic Image Quality of Pseudophakic Eyes.

PURPOSE: The human eye exhibits large amounts (2.5 diopters) of longitudinal chromatic aberration (LCA). Its impact on polychromatic image quality, however, has been shown experimentally and by computer modeling to be small or absent. We hypothesized that modest changes in pseudophakic LCA created by higher and lower Abbe number materials will have little or no impact on polychromatic image quality in pseudophakic eyes. MATERIALS AND METHODS: Using published chromatic and monochromatic aberration data from pseudophakic eyes and higher and lower Abbe number materials (37 and 55), we computed monochromatic point spread functions for 21 wavelengths across the visible spectrum. After weighting by either the RGB spectra of a liquid crystal display or by a flat white spectrum, they were weighted by the human spectral sensitivity function (Vλ) before being added to generate polychromatic PSFs. RESULTS: In the absence of monochromatic aberrations, the reduced LCA due to higher Abbe number intraocular lens (IOL) materials resulted in a reduction of 0.08 diopters in the mean defocus generated by LCA. At the retinal plane, the higher Abbe number pseudophakic model produced improvements in polychromatic modulation transfer functions (MTFs) similar to those generated by a 0.05 diopter reduction in spherical defocus. When monochromatic aberrations were added to make the model more representative of actual pseudophakic eyes, the differences in image quality became sub-threshold for human vision or disappeared completely. CONCLUSION: The anticipated gains in polychromatic image quality from employing higher Abbe number IOL materials with reduced LCA do not materialize in plausible aberrated models of pseudophakic eyes.

HIF-1α/BNIP3-Mediated Autophagy Contributes to the Luteinization of Granulosa Cells During the Formation of Corpus Luteum.

During the luteinization after ovulation in mammalian ovary, the containing cells undergo an energy consuming function re-determination process to differentiate into luteal cells under avascular environment. Previous evidences have delineated the contribution of autophagy to the cell differentiation and the catabolic homeostasis in various types of mammalian cells, whereas few interest had been focused on the involvement of autophagy in the luteinization of granulosa cells during the formation of early corpus luteum. Herein, the present study investigated that expression and contribution of autophagy during granulosa cell luteinization and early luteal development through in vivo and in vitro experiments. The results clearly demonstrated that HIF-1α/BNIP3-mediated autophagy plays a vital role in the luteinization of granulosa cells during the early luteal formation in vivo and in vitro. In the neonatal corpus luteum, HIF-1α up-regulated BNIP3 expressions, which contributed to the autophagic initiation by disrupting beclin1 from Bcl-2/beclin1 complex and protected cells from apoptosis by curbing the skew of mitochondria balance under avascular niche. Notably, Inhibition of HIF-1α activity by echinomycin enhanced the levels of cytoplasmic cytochrome c and cell apoptosis in the nascent corpus luteum. These findings revealed that HIF-1α/BNIP3-mediated autophagy enabled the process of granulosa cell luteinization and protected the granulosa-lutein cells from further apoptosis under hypoxia niche. To our knowledge, the present study firstly clarified that HIF-1α/BNIP3-mediated autophagy contributes to the luteinization of granulosa cells during the formation of pregnant corpus luteum, which will help us further understanding the luteal biology and provide us new clues for the treatment of luteal insufficiency.

Ricco's law and absolute threshold for foveal detection of black holes.

Visual detection of small black objects surrounded by a light background depends on background luminance, pupil size, optical blur, and object size. Holding pupil and optics fixed, we measured the minimum background luminance needed for foveal detection of small black targets as a function of target size. For all three observers, absolute threshold varied inversely with target area when disk diameter subtended less than 10' of visual angle. For target diameter ≥10', threshold remained constant at about 0.3 Td, which was also the absolute threshold for detecting light spots 10' or larger in diameter on a black background. These results are consistent with Ricco's law of spatial summation: a "black hole" is just detectable when the background luminance is sufficiently high for its absence inside the Ricco area to reduce 555 nm photon flux by 7500 photons/s, which is the same change needed to detect light spots on a black surround. These results can be accounted for by a differential pair of Ricco detectors, each about the size of the receptive field center of magocellular retinal ganglion cells when projected into object space through the eye's weakly aberrated optical system. Statistical analysis of the model suggests the quantum fluctuations due to internal, biological noise (i.e., "scotons") are a greater handicap than the photon fluctuations inherent in the light stimulus at absolute foveal threshold.

Psychophysical study of the optical origin of starbursts.

Starbursts seen around small bright lights at night have been attributed to optical scatter, diffraction, or aberrations. We manipulated pupil aperture and aberrations to investigate the entopic appearance of perceived starbursts. The impact of circular, annular, and wedge-shaped pupil apertures, and spherical aberration sign and magnitude were used to identify pupil sub-apertures responsible for each radial perceived starburst line. Local intensity distributions within the starbursts mapped onto unique sub-regions of the pupil of both phakic and pseudophakic eyes, consistent with the hypothesis that ocular aberrations are the cause of starbursts. In paraxially focused eyes, the size of starbursts is predicted by the amount of spherical aberration, and starburst orientation is either the same or 180 deg rotated from the pupil region that creates each starburst line. No starbursts are seen when the pupil diameter is smaller than 3 mm. Replacing the eye's natural lens with a radially symmetric and optically homogeneous intraocular lens reduced the observed number of starbursts by 50%. Geometrical optics modeling including the measured aberrations of an individual eye can reveal point spread function structure that captures some of the key elements of the entopic perceptions.