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Fas, a member of the death receptor family, plays a central role in initiating cell death, a biological process crucial for immune homeostasis. However, the immunological and pathophysiological impacts to which enhanced Fas signaling gives rise remain to be fully understood. Here we demonstrate that TGF-β–activated kinase 1 (TAK1) works as a negative regulator of Fas signaling in macrophages. Upon Fas engagement with high concentrations of FasL, mouse primary macrophages underwent cell death, and, surprisingly, Fas stimulation led to proteolytic cleavage of gasdermin (GSDM) family members GSDMD and GSDME, a hallmark of pyroptosis, in a manner dependent on caspase enzymatic activity. Remarkably, TAK1-deficient macrophages were highly sensitive to even low concentrations of FasL. Mechanistically, TAK1 negatively modulated RIPK1 kinase activity to protect macrophages from excessive cell death. Intriguingly, mice deficient for TAK1 in macrophages (TAK1mKO mice) spontaneously developed tissue inflammation, and, more important, the emergence of inflammatory disease symptoms was markedly diminished in TAK1mKO mice harboring a catalytically inactive RIPK1. Taken together, these findings not only revealed an unappreciated role of TAK1 in Fas-induced macrophage death but provided insight into the possibility of perturbation of immune homeostasis driven by aberrant cell death.

A 73-year-old man presented with muscle weakness and atrophy of his right arm. Atrophy of his left brachia and left calf had occurred 13 years before without any improvement or deterioration. His sister and cousin had a history of paralytic poliomyelitis. Serum poliovirus type 2 neutralizing antibody was elevated to 128×. Electromyography revealed chronic denervation potentials not only in the muscles affected previously but also in the unaffected muscles. Acute and chronic denervation potentials were found in the newly affected muscle. Postpolio syndrome should be considered in patients with unilateral muscular atrophy even when they have no history of paralytic poliomyelitis.

Clinicopathological features of 86 patients with invasive breast cancer.

Effects of TGF-β1 stiumlation on α-SMA expression in fibroblasts isolated from WT and SA mice.

PI3K–Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. Cancer Res; 75(5); 813–23. ©2015 AACR.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

The concept of zero-energy building (ZEB) has attracted global attention in recent years as it involves offsetting the primary energy usage of a building on an annual base by the energy generated from renewable resources. The performance of wall-mounted photovoltaics (PV) for building applications has great potential for ZEB. In this study, we compared wall-mounted and common roof-mounted PV systems using a combination of experimental and theoretical studies. The wall-mounted PV system exhibited an unusual performance behavior depending on the season. Winter is a suitable season for energy production from the wall-mounted PV system because of the low solar altitude and resulting lower incident angle of the sun. However, the performance ratio (PR) had twin peaks throughout the day that could not be explained by the classical model that uses irradiance and temperature variation. In summer, there was less irradiance on the vertical wall and the PR had triple peaks that were also hard to explain using the conventional model. We established a detailed output power model of the wall-mounted PV using spectrum variation on a vertical plane. Our approach is the development of spectrum model that can be applied to all-climate and computed the performance variation according to the sun’s orientation and incident angle. Our model quantitatively explains unique seasonal and daily efficiency variations for the wall-mounted PV system (twin peaks in winter and triple peaks in summer). Our validated model can be utilized to map a suitable location for a wall-mounted PV system.

The first law for entanglement entropy in CFT in an odd-dimensional asymptotically AdS black hole is studied by using the AdS/CFT duality. The entropy of CFT considered here is due to the entanglement between two subsystems separated by the horizon of the AdS black hole, which itself is realized as the conformal boundary of a black droplet in even-dimensional global AdS bulk spacetime. In $(2+1)$-dimensional CFT, the first law is shown to be always satisfied by analyzing a class of metric perturbations of the exact solution of a $4$-dimensional black droplet. In $(4+1)$-dimensions, the first law for CFT is shown to hold under the Neumann boundary condition at a certain bulk hypersurface anchored to the conformal boundary of the boundary AdS black hole. From the boundary view point, this Neumann condition yields there being no energy flux across the boundary of the boundary AdS black hole. Furthermore, the asymptotic geometry of a $6$-dimensional small AdS black droplet is constructed as the gravity dual of our $(4+1)$-dimensional CFT, which exhibits a negative energy near the spatial infinity, as expected from vacuum polarization., Comment: 15 pages, two figures. Appendix is given for Noether charge formula and discussions are added. To be published in PRD

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies., Highlights • Patients with hereditary demyelinating neuropathy could die suddenly. • Demyelination of the phrenic and recurrent laryngeal nerves might be relevant. • Pathology of these nerves has been rarely reported.

Reactions of molybdenum-silyl hydrido complex 2 ([MoH3{Si(Ph)[Ph2PCH2CH2P(Ph)C6H4-o]2}]) with 1.5 equiv of 1-alkynes RC≡CH occur readily at room temperature giving σ-acetylide complexes ([MoH2{Si(P...

A 48-year-old woman with a 3-month history of spontaneously resolving stiff leg symptom at the age of 43 years presented with progressive onset of leg rigidity, walking difficulty, and myoclonic jerks. On admission she had marked stiffness in her foot joints with symmetric sustained dorsiflexion of the ankles and toes, with spontaneous and reflex myoclonic jerks easily provoked by knee tendon tap. She appeared to have a spastic gait due to stiffness in her legs. Needle electromyogram (EMG) examination revealed continuous motor unit activity in the tibialis anterior muscle at rest even when voluntary contraction of the gastrocnemius muscle was instructed, but no myokimic discharge or acute denervation sign was seen. The laboratory tests were unremarkable, including glutamic acid decarboxylase antibody. Cerebrospinal fluid (CSF) examination was also normal, without oligoclonal bands or elevated IgG index. She was diagnosed with stiff-limb syndrome based on neurologic examination and needle EMG findings, and she was treated with intravenous high-dose methylprednisolone (500 mg/day, 3 days), resulting in marked improvement in her symptoms. Anti-glycine receptor antibodies were subsequently identified in her archived serum and CSF obtained before immunotherapy. She was then started on oral prednisolone (30 mg/day) and had been free of symptoms.

We study the compatibility of the AdS/CFT duality with the bulk and boundary causality, and derive a conformally invariant averaged null energy condition (CANEC) for quantum field theories in 3 and 5-dimensional curved boundaries. This is the generalization of the averaged null energy condition (ANEC) in Minkowski spacetime to curved boundaries, where null energy is averaged along the null line with appropriate weight for conformal invariance. For this purpose we take, as our guiding principle, the no-bulk-shortcut theorem of Gao and Wald, which essentially asserts that when going from one point to another on the boundary, one cannot take a "shortcut through the bulk". We also discuss the relationship between bulk vs boundary causality and the weak cosmic censorship., 27 pages, 2 figures. v2: section 5 corrected. references added

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

Japanese people born before World War II learned Japanese kana (Japanese syllabograms) writing in a style that is not currently used. These individuals had to learn the current style of kana orthography after the war. An 85-year-old man was taken to our hospital by his family who were surprised by his diary. It was written with kanji (Japanese ideograms) and katakana using the prewar style. A neuropsychological examination revealed impaired recall of hiragana. Neuroimaging studies revealed atrophy of the left fronto-parietal lobe and hypoperfusion of the left frontal lobe. His allographic agraphia might have resulted from the disturbance of the current style of kana orthography.

Dystypia without aphasia, agraphia, or apraxia is a rare symptom and has been suggested to result from a lesion in the left middle frontal cortex. We herein describe a man with dystypia with agraphia due to infarction of the left angular gyrus. His dystypia seemed to result from the convergence failure of the kana into the alphabetical spellings. During dystypia, hypoperfusion of the bilateral middle frontal cortices was discovered. However, after his symptoms improved, blood flow in the middle frontal cortices returned to normal. This case suggests that the middle frontal cortex is downstream of the angular gyrus in the dictating pathway and a lesion in the left middle frontal cortex could cause pure dystypia.

Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) was originally reported in the Okinawa1 and Shiga2 prefectures of Japan. Some families carrying the disease immigrated abroad to countries such as Brazil.3 The causative gene has been identified as the TRK-fused gene ( TFG ).4 TFG is localised to the endoplasmic reticulum exit sites and plays an important role in protein secretion.4 HMSN-P is inherited in an autosomal dominant manner. Its symptoms include weakness and atrophy of the limb, which start from the proximal muscles. Muscle atrophy expands to the tongue and respiratory muscles, and patients develop bulbar palsy and respiratory failure. Additionally, they do not usually develop pyramidal tract signs, and sensory symptoms are minimal. The natural course lasts approximately 20 years or longer. There is only one single case report in which immunohistochemistry using anti-TFG antibody was performed.4 According to that report, cytoplasmic inclusion containing TFG was found in neurons of the precentral gyrus, spinal anterior horn and dorsal root ganglion (DRG). We present the case of a patient with HMSN-P who died of respiratory failure within 4 years after onset. Part of his clinical course has been described previously.5 We herein report the findings of his pathological examination. A 38-year-old man presented with weakness in his left upper limbs. He worked as a course maintainer in a golf field. His mother, who had the same symptoms, developed to respiratory failure and died in her 40s. His maternal uncle also had the same disease. He was case V-4 of Family 2 described in Ishiura et al ’s report.4 Patients with HMSN-P in his family, including him, had a heterozygous missense mutation, c.854C>T (p.Pro285Leu), in TFG . His external ocular movement was normal. There was neither facial weakness nor bulbar palsy. The …

We consider a pair of two-level Unruh-DeWitt detectors accelerated uniformly in the Minkowski vacuum of a massless neutral scalar field, and analyze, within the perturbation theory, the entanglement extracted from the vacuum into the Unruh-DeWitt detectors when the switching of the detectors are performed adiabatically enough at the asymptotic past and future. We consider the cases where the detectors are accelerated parallelly, anti-parallelly, and in differently orientated directions. We show that entanglement is extracted if they are accelerated anti-parallelly and the ratios of the excitation energy to the magnitude of the acceleration coincide between the two detectors. On the other hand, we find the detectors are not entangled when the detectors are accelerated parallelly or in orientated directions. We discuss these results from the viewpoint of the energy conservation associated with the timelike boost Killing vector fields tangent to the worldlines of the detectors., Comment: 18 pages, 7 figures; Ver.2, to appear in P.R.D

Akinetopsia is a quite rare symptom. Two types of akinetopsia have been reported: one is cinematographic vision, and the other is invisibility of moving objects. These symptoms are thought to occur due to dysfunction of the MT/V5 area at the occipitoparietal region. I herein describe a 54-year-old man who collided with a car parked on the left side of the road while driving. He complained that the parked car looked to be moving forwards and he could not stop his car when he noticed that it was parked. Magnetic resonance imaging disclosed the fresh infarction on the right temporoparietal region involving the MT/V5 area. His symptom during driving was considered cinematographic vision and it was the cause of the traffic accident. Akinetopsia resulted in illusory kinetopsia on driving and the traffic accident.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult 1–8, but skin biopsy realized its ante-mortem diagnosis 9,10 and many NIID cases have been diagnosed by skin biopsy11,12. Most cases of NIID are sporadic, but several familial cases are known. Using a large NIID family, we conducted linkage mapping, found a 58.1-Mb linked-region at 1p22.1-q21.3 with a maximum logarithm of odds (LOD) score of 4.21, and successfully identified a GGC repeat expansion in the 5’ portion of NOTCH2NLC in all affected members by long-read sequencing, but not in unaffected members. We further found the similar expansions in additional 8 unrelated families with NIID as well as 39 sporadic NIID patients. Repeat-primed PCR consistently detected the GGC repeat expansion in all the familial and sporadic patients diagnosed by skin biopsy, but never in unaffected family members nor 200 controls. This shows that pathogenic changes in a human-specific gene evolutionarily generated by segmental duplication indeed causes a human disease.

We examine the quantum null energy condition (QNEC) for a $2+1$-dimensional conformal field theory (CFT) at strong coupling in the background of a wormhole spacetime by employing the AdS/CFT correspondence. First, we numerically construct a novel $3+1$-dimensional vacuum AdS black hole solution with non-trivial topology, which is dual to a wormhole geometry connecting two flat universes. Although the bulk null energy condition (NEC) is not violated, the NEC for the holographic stress-energy tensor is violated near the wormhole throat. Next, we investigate the entanglement entropy for a half-space anchored to the boundary wormhole throat. We propose a natural prescription for regularizing the IR divergent part of the entanglement entropy and show that the QNEC is violated at the throat. This is the first counterexample to the QNEC, indicating that IR effects are crucial., Comment: 8 pages, 7 figures, published version

We examine the achronal averaged null energy condition (ANEC) for a class of conformal field theories (CFT) at strong coupling in curved spacetime. By applying the AdS/CFT duality, we find holographic models which violate the achronal ANEC for 3+1 and 4+1-dimensional boundary theories. In our model, the bulk spacetime is an asymptotically AdS vacuum bubble solution with neither causality violation nor singularities. The conformal boundary of our bubble solution is asymptotically flat and is causally proper in the sense that a “fastest null geodesic” connecting any two points on the boundary must lie entirely on the boundary. We show that conversely, if the spacetime fails to have this causally proper nature, then there must be a naked singularity in the bulk.

We herein report a sporadic Creutzfeldt-Jakob disease (sCJD) patient followed from the presymptomatic phase to death. A 67-year-old woman had abnormal hyperintense cortical lesions on diffusion-weighted magnetic resonance imaging (MRI) one year before the onset. The levels of 14-3-3 protein and total tau protein, and findings from a real-time quaking-induced conversion test were normal at first but became abnormal after disease onset. Although there are four reports of presymptomatic sCJD identified by MRI, this is the first case report in which all three biomarkers had been assessed before and after the disease onset. MRI might be the most sensitive modality for detecting presymptomatic sCJD patients.

We consider entanglement extraction into two two-level Unruh-DeWitt detectors from a vacuum of a neutral massless quantum scalar field in a four-dimensional spacetime, where the general monopole coupling to the scalar field is assumed. Based on the reduced density matrix of the two detectors derived within the perturbation theory, we show that the single copy of the entangled pair of the detectors can be utilized in quantum teleportation even when the detectors are separated acausally, while we observe no violation of the Bell-CHSH inequality. In the case of the Minkowski vacuum, in particular, we find that entanglement usable in quantum teleportation is extracted due to the special relativistic effect when the detectors are in a relative inertial motion, while it is not when they are comoving inertially and the switching of the detectors is executed adiabatically at infinite past and future., Comment: 23 pages, 3 figures; ver.2: 21 pages, format and appearance of Fig. 1 improved, reference added, along with minor corrections; ver.3 (final version): title and appearance of figures improved, note added in proof and a new reference added along with minor corrections

Japanese people born before World War II learned Japanese kana (Japanese syllabograms) writing in a style that is not currently used. These individuals had to learn the current style of kana orthography after the war. An 85-year-old man was taken to our hospital by his family who were surprised by his diary. It was written with kanji (Japanese ideograms) and katakana using the prewar style. A neuropsychological examination revealed impaired recall of hiragana. Neuroimaging studies revealed atrophy of the left fronto-parietal lobe and hypoperfusion of the left frontal lobe. His allographic agraphia might have resulted from the disturbance of the current style of kana orthography.

We test the cosmic censorship conjecture for a class of polarized AdS black branes (holes) in the Einstein-Maxwell theory at large number of dimensions $D$. We first derive a new set of effective equations describing the dynamics of the polarized black branes (holes) to leading order in the $1/D$ expansion. In the case of black branes, we construct `mushroom-type' static solutions from the effective equations, where a spherical horizon is connected with an asymptotic planar horizon through a `neck' which is locally black-string shape. We argue that this neck part (of black string) cannot be pinched off dynamically from the perspective of thermodynamical stability. In the case of black holes, we show that the equatorial plane on the spherical horizon cannot be sufficiently squashed unless the specific heat is positive. We also discuss that the solutions are stable against linear perturbation, agreeing with the thermodynamical argument. These results suggest that Gregory-Laflamme type instability does not occur at the neck, in favor of the cosmic censorship., Comment: 10 pages, 4 figures

Supersymmetry arises in certain theories of fermions coupled to gauge fields and gravity in a spacetime of 11 dimensions. The dynamical brane background has mainly been studied for the class of purely bosonic solutions only, but recent developments involving a time-dependent brane solution have made it clear that one can get more information by asking what happens on supersymmetric systems. In this proceeding, we construct an exact supersymmetric solution of a dynamical M-brane background in the 11-dimensional supergravity and investigate supersymmetry breaking, the geometric features near the singularity and the black hole horizon.

Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders.

Vascular permeability is regulated by intercellular junction organization of endothelial cells, the dysfunction of which is implicated in numerous pathological conditions. Molecular mechanisms of how endothelial cells regulate intercellular junction in response to extracellular signals, however, have so far remained elusive. This study identified that Girdin (also termed GIV), an Akt substrate functioning in post natal angiogenesis, was expressed in a mature endothelial monolayer, where it regulated VE-cadherin trafficking to maintain vascular integrity. Girdin depletion abrogated VEGF-induced VE-cadherin endocytosis and the disassembly of adherens junctions in a monolayer of endothelial cells, thus leading to a significant decrease in the permeability. We also showed that activated R-Ras, a member of the Ras family GTPase, known to be a master regulator of transendothelial permeability, interacts with Girdin, and facilitates the complex formation between Girdin and VE-cadherin in endothelial cells. However, the increased permeability mediated by the loss of R-Ras was rescued by Girdin depletion, thus suggesting that the interaction of Girdin with R-Ras functions in VE-cadherin trafficking pathways distinct from endocytosis. The recycling of VE-cadherin was promoted by the exogenous expression of the active mutant of R-Ras, which was attenuated in the Girdin-depleted endothelial cells. These results show that Girdin regulates transendothelial permeability in synergy with R-Ras and VE-cadherin in an endothelial monolayer.

Statin therapy moderately increases high-density lipoprotein cholesterol (HDL-C) levels. Contrary to this expectation, a paradoxical decrease in HDL-C levels after statin therapy is seen in some patients. We evaluated 724 patients who newly started treatment with statins after acute myocardial infarction (AMI). These patients were divided into 2 groups according to change in HDL-C levels between baseline and 6 to 9 months after initial AMI (ΔHDL). In total, 620 patients had increased HDL-C levels and 104 patients had decreased HDL-C levels. Both groups achieved follow-up low-density lipoprotein cholesterol levels100 mg/dl. Adverse cardiovascular events (a composite of all-cause death, myocardial infarction, and stroke) have more frequently occurred in the decreased HDL group compared with the increased HDL group (15.4% vs 7.1%, p = 0.01). Multivariate analysis showed that decreased HDL, onset to balloon time, and multivessel disease were the independent predictors of adverse cardiovascular events (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.08 to 3.52; HR 1.05, 95% CI 1.01 to 1.09; and HR 2.08, 95% CI 1.22 to 3.56, respectively). In conclusion, a paradoxical decrease in serum HDL-C levels after statin therapy might be an independent predictor of long-term adverse cardiovascular events in patients with AMI.