A lactate-induced response to hypoxia.

Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

Predictive Synthesis of Transition Metal Carbide via Thermochemical Oxocarbon Equilibrium.

Fabricating nanoscale metal carbides is a great challenge due to them having higher Gibbs free energy of formation (ΔG°) values than other metal compounds; additionally, these carbides have harsh calcination conditions, in which metal oxidation is preferred in the atmosphere. Herein, we report oxocarbon-mediated calcination for the predictive synthesis of nanoscale metal carbides. The thermochemical oxocarbon equilibrium of CO-CO2 reactions was utilized to control the selective redox reactions in multiatomic systems of Mo-C-O, contributing to the phase-forming and structuring of Mo compounds. By harnessing the thermodynamically predicted processing window, we controlled a wide range of Mo phases (MoO2, α-MoC1-x, and ß-Mo2C) and nanostructures (nanoparticle, spike, stain, and core/shell) in the Mo compounds/C nanofibers. By inducing simultaneous reactions of C-O (selective C combustion) and Mo-C (Mo carbide formation) in the nanofibers, Mo diffusion was controlled in C nanofibers, acting as a template for the nucleation and growth of Mo carbides and resulting in precise control of the phases and structures of Mo compounds. The formation mechanism of nanostructured Mo carbides was elucidated according to the CO fractions of CO-CO2 calcination. Moreover, tungsten (W) and niobium (Nb) carbides/C nanofibers have been successfully synthesized by CO-CO2 calcination. We constructed the thermodynamic map for the predictive synthesis of transition metal carbides to provide universal guideline via thermochemical oxocarbon equilibrium. We revealed that our thermochemical oxocarbon-mediated gas-solid reaction enabled the structure and phase control of nanoscale transition metal compounds to optimize the material-property relationship accordingly.

CXCL12 Neutralizing Antibody Promotes Hair Growth in Androgenic Alopecia and Alopecia Areata.

We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (αCXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases. In the AGA model, CXCL12 is highly expressed in DFs. Subcutaneous (s.c.) injection of αCXCL12 significantly induced hair growth in AGA mice, and treatment with αCXCL12 attenuated the androgen-induced hair damage in hair organ culture. Androgens increased the secretion of CXCL12 from DFs through the androgen receptor (AR). Secreted CXCL12 from DFs increased the expression of the AR and C-X-C Motif Chemokine Receptor 4 (CXCR4) in dermal papilla cells (DPCs), which induced hair loss in AGA. Likewise, CXCL12 expression is increased in AA mice, while s.c. injection of αCXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8+, MHC-I+, and MHC-II+ cells in the skin. In addition, injection of αCXCL12 also prevented the onset of AA and reduced the number of CD8+ cells. Interferon-γ (IFNγ) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and αCXCL12 treatment protected the hair follicle from IFNγ in hair organ culture. Collectively, these results indicate that CXCL12 is involved in the progression of AGA and AA and antibody therapy for CXCL12 is promising for hair loss treatment.

Correlation between the inframammary fold and sixth rib: Application to breast reconstruction.

The inframammary fold (IMF) is an essential aesthetic element that influences the outcome of breast surgery. In this study, we introduced a new method for finding the IMF based on retrospective analysis of chest computed tomography (CT) scans of women's breasts. Sagittal sections of 80 female chest CTs were analyzed. Sagittal sections of 80 female chest CTs were analyzed by a single plastic surgeon. The distances between the fifth, sixth, and seventh ribs and the IMF were measured using Photoshop, and the location of the IMF was statistically analyzed according to age and height using paired t tests and Pearson's correlation test. As determined by our new method, the average distance between the IMF and the sixth rib was 5.33 mm, which was less than that between the IMF and any other rib. The IMF was closest to the sixth rib in all age groups (P < 0.001), and all IMFs were located between 39.5 mm superior and 24 mm inferior to the sixth rib. The sixth rib, one of the most visible reference structures in women's surface anatomy, is the "sentinel rib" for the IMF and the most predictive indicator of the location of the IMF. Knowing the original anatomic location of the IMF will enable better outcomes during breast surgery. Clin. Anat. 33:165-172, 2020. © 2019 Wiley Periodicals, Inc.

Subsegmental Osteotomy Technique With Distraction Osteogenesis for Natural Frontal Contouring in Metopic Synostosis.

Vectoring issues occur due to the dynamics of unidirectional procedure that is selected. To circumvent such difficulties, we have devised subsegmental osteotomy with distraction. In our technique, frontal bone flap was divided into 4 segments that were linked to each other by suturing wires in an 8-year-old patient with trigonocephaly. Subsegmental osteotomy and wiring of bone flap enabled us to slide bone in a more curvilinear manner and achieve natural contour. Distraction was initiated on postoperative day 7 at the rate of 1 mm/d for 20-mm gain. At the 9-year follow-up, the patient showed improved head shape and intellectual status.

Hot Deformation Behavior of Hot-Extruded AA7175 Through Hot Torsion Tests.

The hot deformation behavior of hot-extruded AA7175 was investigated with flow curves and processing maps through hot torsion tests. The flow curves and the deformed microstructures revealed that dynamic recrystallization (DRX) occurred in the hot-extruded AA7175 during hot working. The failure strain was highest at medium temperature. This was mainly influenced by the dynamic precipitation of fine rod-shaped MgZn2. The processing map determined the optimal deformation condition for the alloy during hot working.

Evaluation of the Effectiveness of an Alar Transfixion Suture for the Correction of a Vestibular Web and Alar-Facial Groove: A Photogrammetric Analysis.

BACKGROUND: Alar transfixion sutures are commonly used for vestibular web correction. The purpose of this study was to evaluate the long-term results of the use of alar transfixion sutures in patients with a unilateral cleft lip nasal deformity using photogrammetric analysis. METHODS: The study included 42 patients who were divided into child and adult groups. A total of 4 measurement items were evaluated from a basal view by photogrammetry using standardized clinical photographic techniques preoperatively, immediately postoperatively, 3 months postoperatively, and 6 months postoperatively. RESULTS: When the preoperative and last postoperative values were compared, no significant changes in any measurement items were noted in the adult group. In the child group, the proportional index (the ratio of the cleft side to the noncleft side) of the alar slope line inclination was significantly increased, but other measurement items showed no significant change. When the measurement items were compared between time points, no significant changes in any measurement items were noted in the adult group. In the child group, the proportional indexes of the alar length, the width between the subnasale and the alare, and the webbing degree were significantly decreased immediately postoperatively compared with the preoperative values. However, these significant changes were diminished at 3 months postoperatively. The proportional index of the alar slope line inclination was significantly increased at 3 months postoperatively compared with the preoperative value, but the significant change was diminished at 6 months postoperatively. CONCLUSIONS: The alar transfixion suture procedure is not effective for correcting a vestibular web and alar-facial groove.

Comparison of Pedal Soft Tissue Thickness Between Those With and Without Diabetes.

Ulceration is a serious consequence of diabetes that can lead to disability in patients with diabetes. One of the risk factors for ulceration is high foot pressure. The thickness of the pedal soft tissue is important because it has a cushioning effect. Soft tissue atrophy causes elevation in the plantar pressure, which, in turn, causes ischemia. Therefore, we investigated the severity of pedal soft tissue atrophy caused by diabetes and aging. From February 2009 to February 2016, we examined the feet of 261 patients treated in our hospital using magnetic resonance imaging. We divided the patients enrolled in the study into 2 groups. The first group included 52 patients with diabetes but without peripheral arterial disease and the second group included 47 patients without diabetes. We measured the vertical distances under all patients' metatarsal heads using T1-weighted magnetic resonance imaging and measured the pedal soft tissue thickness using the PACS workstation (m-view). We compared the soft tissue thicknesses of the 2 groups and performed statistical analyses of the relationships between these data and other parameters using 2-way analysis of variance. The soft tissue under the first to fourth metatarsal heads was thinner in the diabetic patients than in the nondiabetic patients (first metatarsal, 6.4 versus 8.69; second metatarsal, 8.85 versus 10.64; third metatarsal, 8.15 versus 9.21; fourth metatarsal, 7.38 versus 8.54; p < .05). Aging had no effect on pedal soft tissue atrophy in either group. In conclusion, our study confirmed that diabetic patients experience more severe plantar soft tissue atrophy than nondiabetic patients. We have developed a standard procedure to enable the prediction of pedal soft tissue atrophy severity in diabetic patients.

STAP Refinement of the NMR database: a database of 2405 refined solution NMR structures.

According to several studies, some nuclear magnetic resonance (NMR) structures are of lower quality, less reliable and less suitable for structural analysis than high-resolution X-ray crystallographic structures. We present a public database of 2405 refined NMR solution structures [statistical torsion angle potentials (STAP) refinement of the NMR database, http://psb.kobic.re.kr/STAP/refinement] from the Protein Data Bank (PDB). A simulated annealing protocol was employed to obtain refined structures with target potentials, including the newly developed STAP. The refined database was extensively analysed using various quality indicators from several assessment programs to determine the nuclear Overhauser effect (NOE) completeness, Ramachandran appearance, χ(1)-χ(2) rotamer normality, various parameters for protein stability and other indicators. Most quality indicators are improved in our protocol mainly due to the inclusion of the newly developed knowledge-based potentials. This database can be used by the NMR structure community for further development of research and validation tools, structure-related studies and modelling in many fields of research.

VnD: a structure-centric database of disease-related SNPs and drugs.

Numerous genetic variations have been found to be related to human diseases. Significant portion of those affect the drug response as well by changing the protein structure and function. Therefore, it is crucial to understand the trilateral relationship among genomic variations, diseases and drugs. We present the variations and drugs (VnD), a consolidated database containing information on diseases, related genes and genetic variations, protein structures and drug information. VnD was built in three steps. First, we integrated various resources systematically to deduce catalogs of disease-related genes, single nucleotide polymorphisms (SNPs), protein mutations and relevant drugs. VnD contains 137,195 disease-related gene records (13,940 distinct genes) and 16,586 genetic variation records (1790 distinct variations). Next, we carried out structure modeling and docking simulation for wild-type and mutant proteins to examine the structural and functional consequences of non-synonymous SNPs in the drug-related genes. Conformational changes in 590 wild-type and 4437 mutant proteins from drug-related genes were included in our database. Finally, we investigated the structural and biochemical properties relevant to drug binding such as the distribution of SNPs in proximal protein pockets, thermo-chemical stability, interactions with drugs and physico-chemical properties. The VnD database, available at http://vnd.kobic.re.kr:8080/VnD/ or vandd.org, would be a useful platform for researchers studying the underlying mechanism for association among genetic variations, diseases and drugs.

A simplified homology-model builder toward highly protein-like structures: an inspection of restraining potentials.

A homology model builder using simple restraining potentials based on spline-interpolated quadratic functions is developed and interfaced with CHARMM package. The continuity and stability of the potential function were validated, and the parameters were optimized using the CASP7 targets. The performance of the model builder was benchmarked to the Modeller program using the template-based modeling targets in CASP9. The benchmark results show that, while our builder yields the structures with slightly lower packing, backbone, and template modeling scores, our models show much better protein-like scores in terms of normalized discrete optimized protein energy, dipolar distance-scaled finite-ideal gas reference, Molprobity clash, Ramachandran appearance Z-score, and rotamer Z-score. As our model builder is interfaced with CHARMM, it is advantageous to directly use other CHARMM functionality and energy functions to refine the model structures or to use the models for other computational studies using CHARMM.

Trigger Wrist with Carpal Tunnel Syndrome Accompanied with Trifid Median Nerve: A Case Report and Literature Review.

Trigger wrist, characterized by a clicking or snapping sensation around the wrist joint during finger or wrist motion, and bifid or trifid median nerve, which occurs in carpal tunnel syndrome along with anatomical variation of median nerve, are rare conditions. We report the case of a patient with a thickened tendon caused by severe tenosynovitis and flexor tendon subluxation to the hamate hook due to bowing of the flexor retinaculum, thereby resulting in trigger wrist as well as an anatomical median nerve variation (bifid median nerve in the right wrist and trifid median nerve in the left wrist). A 59-year-old housewife visited our hospital with bilateral fingertip numbness, tingling sensation, and aggravated severe night cramping that began 2 months ago. She also complained about trigger wrist during small finger flexion. Based on magnetic resonance imaging, ultrasonography, and nerve conduction study, trifid median nerve and bilateral severe median nerve neuropathy of the wrist were diagnosed; therefore, transverse carpal tunnel release and exploration under wide-awake anesthesia were planned. Intraoperative findings showed trifid and bifid median nerves in left and right wrists, respectively. Additionally, bowing of flexor retinaculum and severe flexor tendon tenosynovitis were observed. Tenosynovitis with thickened flexor sheath resulted in subluxation of the small finger flexor tendon above the hamate hook. After transverse carpal ligament release with antebrachial fascia release and tenosynovectomy, subluxation of the flexor tendon was resolved. At 6 months postoperatively, the tingling and dullness in fingertips also resolved, and no trigger wrist or any other complications were noted.

Anatomical Study of the Close Association between Latissimus Dorsi and Surrounding Muscles. How to Safely Harvest the Muscle?

Background We suggested an easy and effective harvesting technique to avoid injury to tissues adjacent to the latissimus dorsi (LD). Methods Between 2007 and 2017, breast reconstruction was performed with an LD flap using the "bottom-up" technique. Medical records were retrospectively reviewed. Data on postoperative complications, results, and follow-up were obtained. Nine cadaveric dissections were performed to assess positional relationships between LD and adjacent muscles based on the ribs where relevant muscles and LD attach. Overall, 78 LD flaps were harvested without complications. Results Average age was 45.4 years. The mean operation time was 260 minutes. There were no abnormalities or injuries in the adjacent fascia and muscles during the flap harvest. Drains were removed at an average of 21.9 days postoperatively. In all cadavers, there was conjoined fascia between the thoracolumbar and LD fasciae. The average level of the merging point between the LD and external oblique muscle (EOM) was 8.9 to 11.1 ribs. The average level of the overlapping point between the LD and serratus posterior inferior (SPI) was 9.5 to 11.1 ribs. Conclusions There are three dangerous zones during LD flap harvesting. The first zone is where the conjoined fascia encompasses the LD and thoracolumbar fasciae. The second zone is where the LD merges with the EOM and the serratus anterior. The third zone is the lower part where the LD merges with the SPI and EOM. The "bottom-up" technique enables a more meticulous and atraumatic operation by beginner flap surgeons.

Optimal treatment recommendations for diabetes patients using the Markov decision process along with the South Korean electronic health records.

The extensive utilization of electronic health records (EHRs) and the growth of enormous open biomedical datasets has readied the area for applications of computational and machine learning techniques to reveal fundamental patterns. This study's goal is to develop a medical treatment recommendation system using Korean EHRs along with the Markov decision process (MDP). The sharing of EHRs by the National Health Insurance Sharing Service (NHISS) of Korea has made it possible to analyze Koreans' medical data which include treatments, prescriptions, and medical check-up. After considering the merits and effectiveness of such data, we analyzed patients' medical information and recommended optimal pharmaceutical prescriptions for diabetes, which is known to be the most burdensome disease for Koreans. We also proposed an MDP-based treatment recommendation system for diabetic patients to help doctors when prescribing diabetes medications. To build the model, we used the 11-year Korean NHISS database. To overcome the challenge of designing an MDP model, we carefully designed the states, actions, reward functions, and transition probability matrices, which were chosen to balance the tradeoffs between reality and the curse of dimensionality issues.

Deep visual domain adaptation and semi-supervised segmentation for understanding wave elevation using wave flume video images.

Accurate water surface elevation estimation is essential for understanding nearshore processes, but it is still challenging due to limitations in measuring water level using in-situ acoustic sensors. This paper presents a vision-based water surface elevation estimation approach using multi-view datasets. Specifically, we propose a visual domain adaptation method to build a water level estimator in spite of a situation in which ocean wave height cannot be measured directly. We also implemented a semi-supervised approach to extract wave height information from long-term sequences of wave height observations with minimal supervision. We performed wave flume experiments in a hydraulic laboratory with two cameras with side and top viewpoints to validate the effectiveness of our approach. The performance of the proposed models were evaluated by comparing the estimated time series of water elevation with the ground-truth wave gauge data at three locations along the wave flume. The estimated time series were in good agreement within the averaged correlation coefficient of 0.98 and 0.90 on the measurement and 0.95 and 0.85 on the estimation for regular and irregular waves, respectively.

Evaluation of the International Society for Cutaneous Lymphoma Algorithm for the Diagnosis of Early Mycosis Fungoides.

The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF cases to validate the ISCL algorithm. We found that CD5 and CD7 expression differed significantly between early MF and non-MF cases, with epidermal discordance of CD7 expression more frequently identified in early MF. Notably, increasing the cut-off value for CD7 expression from 10% to 22.5% improved its sensitivity. Furthermore, TCR-γ and ß chain rearrangements were more frequently detected in early MF than in non-MF cases. Based on these findings, we propose CD5 and CD7 deficiency as mandatory immunopathologic criteria and PCR-based testing for TCR-γ and ß chains as required molecular/biologic criteria to improve the efficiency of early MF diagnosis using the ISCL algorithm.

Open carpal release using local anesthesia without a tourniquet: Does bleeding tendency affect the outcome?

BACKGROUND: The aim of this study was to analyze the clinical results of minimal single palmar-incision carpal tunnel release without a tourniquet. METHODS: We reviewed the medical records of 75 patients (90 cases of carpal tunnel syndrome) who underwent minimal single-palmar incision carpal tunnel release without a tourniquet from June 2010 to January 2018. Ten patients had a bleeding tendency. We compared the preoperative and postoperative Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) scores. We also analyzed outcomes and complications according to the presence of a bleeding tendency. RESULTS: In all cases, there was a complete disappearance or marked improvement in symptoms within 6 months, with no recurrence. The postoperative BCTQ score showed a significant improvement compared to the preoperative score, and no statistically significant difference in BCTQ scores was detected according to the presence of a bleeding tendency. CONCLUSIONS: Carpal tunnel release without a tourniquet using a minimal single palmar incision is effective and reliable. This technique prevents unnecessary pain associated with the tourniquet and is especially helpful in patients with a bleeding tendency or those treated with hemodialysis.

Subsystem Hazard Analysis on an Offshore Waste Disposal Facility.

Offshore waste disposal facilities are unique marine infrastructures that exist only in a few countries. Although the existing facilities in Japan and Singapore have been successfully operated in general, there have been no investigations on the probable hazards they pose on the environment. Considering this, conceivable hazards were identified for an offshore waste disposal facility that has recently been proposed in Korea. The causes and consequences of each of the identified hazards were analyzed to seek countermeasures for reducing the environmental impact in advance. Hazards of waste disposal facilities can be classified according to their design, construction, maintenance, operation, and site utilization. For these areas, except for site utilization, subsystem hazard analysis was performed. In the initial assessment, seven elements were found to be in the extreme risk zone, 30 were in the high-risk zone, and six were in the moderate-risk zone. After applying the alternative mitigation methods, the final risk assessment resulted in 27 moderate-risk and 16 low-risk elements. Therefore, it was confirmed that the potential risks of the proposed offshore waste disposal facility were within acceptable ranges.

Risk of necrosis in the adjacent toe after one-toe fillet flap in diabetic foot: Retrospective study of 107 cases over 5 years.

PURPOSE: Fillet flap is a "spare part" concept. This technique allows the defect to be covered without donor site morbidity. Over the past 5 years, there were 107 diabetic foot cases of one-toe fillet flap in our hospital. After the operation, in some patients, there was necrosis of the adjacent toe that required additional amputation. The aim of our study was to determine the cause of necrosis of the adjacent toe after fillet flap. METHODS: The patients were divided into two groups. One group had no necrosis of the adjacent toe (group A) after the operation, and the other group had necrosis of the adjacent toe that required additional amputation after the operation (group B). Then, to confirm the cause of the additional necrosis of the adjacent toe, χ2 tests, Fisher's tests, and logistic regression tests were performed. RESULTS: A total of 107 patients were included, and 48 patients needed additional amputation. The logistic regression test revealed that a fillet flap at the metatarsophalangeal joint (MTPJ), horizontal sutures, and a fillet flap at the second toe were significant risk factors for developing necrosis. CONCLUSIONS: If a fillet flap with a second toe, fillet flap on MTPJ level and horizontal closure after fillet flap is needed, the chance of developing necrosis of the adjacent toe and additional revisional surgery must be communicated preoperatively.