Miracle-dz/UniFAR-FTUs huggingface dataset:
Ultrastructural mitochondrial modifications characteristic of mitofusin 2 mutations (CMT2A)

Dear Editor, The most commonly identified cause of CharcotMarie-Tooth disease type 2A (CMT2A) is a mutation in the mitochondrial fusion protein mitofusin 2 (MFN2) leading to a dominantly, or more rarely recessive, inherited axonal neuropathy. We have reexamined nerve biopsies from three patients from different families with dominant inheritance and MFN2 mutations. Each patient presented with a classical CMT phenotype and had a normal motor nerve conduction velocity in the right median nerve. Case 1, an 8-year-old girl, was first examined 2 years after onset of symptoms and had a peripheral nerve biopsy (PNB). MFN2 analysis disclosed the mutation Thr232Ala in exon 7 (694A>G) in her mother and a first cousin. Case 2, a 47-year-old man, had had a late onset at 30 years and underwent a PNB 5 years later. The mutation Pro123Leu was identified in exon 5 (368C>T). Case 3, a 25-year-old man, had had an early onset at 4 years and was investigated at 16 years with a PNB. The mutation Arg94Glu was disclosed in the exon 4 (281G>A). In Case 1, PNB showed a mixture of chronic axonal degeneration and numerous onion bulb formations. There was a marked loss of myelinated fibers with clusters of regeneration in Case 2, and a dramatic loss of myelinated and unmyelinated fibers in Case 3. Abnormal mitochondria were rather numerous in Case 2 but rare in Cases 1 and 3. Two different patterns of abnormal mitochondria were observed: when located within axons they had a loss of cristae and sometimes appeared almost empty (Fig. 1A), whereas when located in the Schwann cell cytoplasm of myelinated fibers they were greatly enlarged and contained numerous entwined cristae (Fig. 1B and C). Abnormal mitochondria were also visible in the cytoplasm of a few unmyelinated fibers.
Comparison of estrogen receptor determinations by a biochemical ligand‐binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials

The measurement of estrogen receptors (ER) in breast cancer specimens has traditionally been assessed with a dextran‐coated charcoal assay (DCCA). More recently the immunohistochemical staining (IHC) method has gained increasing popularity because of its ability to use fixed tissue, assess needle biopsies, and reduce cost. Controversy exists over the accuracy of IHC compared with that of DCCA in determining ER. We compared these two techniques using tumor tissue obtained from a large group of females with lymph node positive breast carcinoma with long term follow‐up.
CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway

Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells. Moreover, cystine starvation induced mitochondrial fragmentation, dysfunction, and ROS production. A mitochondrial ROS scavenger, Necrox-5, can prevent cystine-starvation-induced cell death. In addition, cystine starvation was found to activate GCN2, but not PERK, to increase the phosphorylation of eIF2α at serine 51, the protein expression of ATF4, and the expression of ATF4 target genes such as CHAC1, which might be downstream of the RIP1/RIP3-MLKL pathway and contribute to cystine-starvation-induced cell death. Knockdown of CHAC1 rescued the cystine-starvation-induced reduction in glutathione (GSH) levels and cell death. Furthermore, N-acetyl-cysteine (NAC), Trolox, and Nec-1 significantly prevented the cystine-starvation-induced increase in intracellular ROS levels, mitochondrial fragmentation and cell death. In summary, these results suggest that CHAC1 degradation of GSH enhances cystine-starvation-induced necroptosis and ferroptosis through the activated GCN2-eIF2α-ATF4 pathway in TNBC cells. Our findings improve our understanding of the mechanism underlying cystine-starvation-induced TNBC cell death.
Micro-tensile tests on micromachined metal on polymer specimens: Elasticity, plasticity and rupture

This study is focused on the mechanical characterization of materials used in microelectronic and micro- electromechanical systems (MEMS) devices. In order to determine their mechanical parameters, a new deformation bench test with suitable micromachined specimens have been developed. Uniaxial tensile tests were performed on ldquolow costrdquo specimens, consisting in electroplated thin copper films and structures, deposited on a polimide type substrate. Moreover, a cyclic mechanical actuation via piezoelectric actuators was tested on the same deformation bench. These experiments validate the device for performing dynamic characterization of materials, and reliability studies of different microstructures.
Industrial clusters: The case for Special Economic Zones in Africa

Firms tend to cluster in close geographic proximity to each other to benefit from reduced transport costs, shared inputs, and productivity spillovers due to learning and technology transfers. Evidence from low-income countries suggests that such agglomeration economies may be substantial in endogenously formed clusters. This raises the question of whether spatial industrial policies can be designed to facilitate clustering. In this paper, we consider the case for creating Special Economic Zones (SEZs) in Africa. We document at the country level the state of current SEZ programmes and the policy measures in place for their promotion. We give an overview of the evidence on their success and provide a set of policy recommendations to improve SEZs performance.
Survey of Current Practice Patterns in the Management of Frontal Sinus Fractures

The management of frontal sinus fractures has evolved in the endoscopic era. The development of functional endoscopic sinus surgery (FESS) has been incorporated into management algorithms proposed by otolaryngologists, but the extent of its influence on plastic surgeons and oral and maxillofacial surgeons is heretofore unknown. A cross-sectional survey was performed to assess the practice pattern variations in frontal sinus fracture management across multiple surgical disciplines. A total of 298 surveys were reviewed. 33.5% were facial plastic surgeons with otolaryngology training, 25.8% general otolaryngologists, 25.5% plastic surgeons, and 15.1% oral and maxillofacial surgeons. 74.8% of respondents practiced in an academic setting. 61.7% felt endoscopic sinus surgery changed their management of frontal sinus fractures. 91.8% of respondents favored observation for uncomplicated, nondisplaced frontal sinus outflow tract fractures. 36.4% favored observation and 35.9% favored endoscopic sinus surgery for uncomplicated, displaced frontal sinus outflow tract fractures. For complicated, displaced frontal sinus outflow tract fractures, obliteration was more frequently favored by plastic surgeons and oral and maxillofacial surgeons than those with otolaryngology training. The utility of FESS in managing frontal sinus fractures appears to be recognized across multiple surgical disciplines.
Urban water demand, climatic variation, and irrigation-water insecurity: interactive stressors and lessons for water governance from the Angat River basin (Philippines)

ABSTRACT Climatic variation and intersectoral water competition increasingly challenge the effective provision of irrigation services. This article explores their combined effects on irrigation allocation from the Angat Reservoir (Philippines), where domestic water use in Metro Manila has overtaken regional irrigation as the dominant right-holder. Rules protecting Metro Manila’s large right to water ‘interact’ with dry spells to affect irrigation security in wet and dry seasons. Historically, irrigators were uncompensated because re-allocation’s cause was contested as (1) an unforeseeable climatic event (releasing domestic utilities of liability), or (2) produced by urban demand (requiring compensation). Trade-off rules must be prepared to navigate combinatory effects.
Testing for Speculative Bubbles Using Spot and Forward Prices

The probabilistic structure of periodically collapsing bubbles creates a gap between future spot and forward (or futures) asset prices in small samples. By exploiting this fact, we use two econometric methods, namely, the recursive unit root method of Phillips, Shi, and Yu (2015a,b) and the rolling regression method of Fama (1984), for detecting bubbles. Both methods do not rely on a particular model of asset price determination, they are robust to an explosive root in the process for market fundamentals, and are accompanied by a date-stamping strategy. By applying these methods to the German mark-US dollar and British pound-US dollar exchange rates, we provide evidence in favor of speculative bubbles in the foreign exchange market during the interwar German hyperinflation, but not during the recent floating-rate period. A further application to the S&P 500 index supports the existence of speculative bubbles in the US equity market.
Industrial policy and economic geography: evidence from China

ABSTRACT This paper investigates the trends and determinants of geographic concentration and industrial specialization in China, using provincial panel data for the period 1999–2010. It is shown that after 2005, both geographic concentration and industrial specialization began to decline, resulting in an increased similarity of industrial structure among provinces. This paper posits that the industrial policies of the provincial governments are the cause of this phenomenon. The result is robust when using instrumental variables to deal with possible reverse causality. The underlying mechanism is that the policy of the central government, which is set to steer the direction of industrial development for several years to come, is an important reference document for all provincial planners. It therefore causes the less developed regions to deviate from their comparative advantages and results in a combination of insufficient geographic concentration and inverse specialization in China.
Telangiectatic osteogenic sarcoma: A clinicopathologic study of 124 patients

One hundred‐twenty‐four patients with this rare and special variant of osteogenic sarcoma were treated at Memorial Sloan‐Kettering Cancer Center from 1921 through 1979, representing 11% of all of osteogenic sarcomas. The lesions were predominantly lytic, destructive tumors with only minimal sclerosis on roentgenograms and soft as well as cystic on gross examination. Histologically, aneurysmally dilated spaces lined or traversed by sarcoma cells producing osteoid were noted. The differential diagnosis both radiographically and histologically included several benign lesions like aneurysmal bone cyst and giant cell tumor, among many others. It was found that telangiectatic osteogenic sarcoma is relatively frequent in the femoral diaphysis and in the distal end of the femur. Twenty‐nine percent of the patients present with pathologic fracture, or this develops later. Age and sex distribution, or clinical signs or symptoms were those of ordinary osteogenic sarcomas. No differences in survival rates were found in lesions that were purely lytic or those with minimal sclerosis. Similarly, no differences in survival were noted when comparing patients with telangiectatic or ordinary osteogenic sarcoma. As a matter of fact, definite increase in survival was found in patients treated since 1975 with preoperative multidrug chemotherapy employing high‐dose methotrexate, Adriamycin, and the combination of bleomycin, cyclophosphamide, and dactinomycin.
Residents' ethical disagreements with attending physicians: an unrecognized problem

PURPOSE: To evaluate the frequency and nature of ethical disagreements over patient care between housestaff and attending physicians. METHOD: During the spring of 1994, a cross-sectional survey about ethical disagreements was conducted of all 42 internal medicine housestaff at the West Virginia University Hospitals and all 51 faculty in the Department of Medicine at the West Virginia University School of Medicine. Chi-square analysis was used to compare categorical variables. RESULTS: Thirty-six (86%) of the residents and 41 (80%) of the faculty responded. The housestaff recounted 127 ethical disagreements between attending physicians and housestaff in the previous year; the attending physicians reported 19. A total of 32 residents reported at least one ethical disagreement with an attending physician during the previous year. When asked about their most troubling disagreement, 27 (84%) of these residents reported they had been distressed because they considered the treatment ordered by the attending physician to be futile. Only 11 residents (34%) had discussed their most troubling disagreement with the attending physician. Of the 24 residents who correctly identified that a formal process to resolve ethical disagreements with a physician did not exist, 17 desired one. CONCLUSION: The residents' disagreements with attending physicians over ethical aspects of patient care were common and usually concerned issues of overtreatment. Since most of the housestaff did not express their concerns, the attending physicians were largely unaware of them. The findings suggest that residency directors need to encourage housestaff to discuss their ethical conflicts with attending physicians.
Do firm sizes matter for R&D efficiency: evidence for a stochastic metafrontier model

This paper employs the concepts of metafrontier, group frontiers and technology gap ratio for the purpose of investigating differences in R&D efficiency across groups of firms. The study finds that R&D employees, physical capital, R&D expenditure and patent citations are important to produce patents. Large firms with more R&D manpower are associated with higher R&D efficiency. The estimated output elasticity for R&D expenditure input and physical capital input for large firms is higher than that for small firms. The estimated output elasticity for patent citation input in a large firm sample is slightly smaller than that in a small firm sample. Small firm groups are much closer to metafrontier than large firm groups. Small firms have higher R&D efficiency than large firms. The results provide new insights into R&D efficiency and the first step of policymaking to improve R&D environment.
Comparison between a 3D UTD model and near field chamber measurements in the presence of a dielectric circular cylinder

This paper is related to the comparison between a 3D UTD (Uniform Theory of Diffraction) propagation model and NFC (Near Field Chamber) measurements, in a context of an antenna disturbed by a dielectric circular cylinder, referring to a “Scattering” case [1], i.e. a Transmitter and a Receiver “off” the cylinder. After the determination of the UTD model validity domain in terms of frequency and “antenna-cylinder” distance, the benefits and limitations of the model are highlighted thanks to the comparison with the measurements.
Improved renal transplantation in the rat with a nonsplinted ureteroureterostomy

Orthotopic renal transplantation in the rat is a widely used model in immunology and transplantation‐related research. Although numerous modifications of the surgical technique of ureteric reconstruction were evaluated, ureter complications following this reconstruction still occurred frequently. Instead of dividing the ureter in the middle between kidney and bladder (method 1), the anastomosis was performed close to the renal pelvis after cutting the ureter obliquely (method 2), which enlarged the diameter of the ureteral anastomosis 2‐fold. The incidence of stenosis of ureteric anastomosis was 12.5% (3/24) using method 1, whereas this complication was avoided completely (0/45) using method 2. Furthermore, the risk of injury to the ureter was reduced, as isolation of the ureter was limited. These modifications improved the last delicate step in the procedure of rat kidney transplantation. © 2002 Wiley‐Liss, Inc. MICROSURGERY 22:204–210 2002
Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users.

BACKGROUND The benefits of highly active antiretroviral therapy (HAART) for the treatment of HIV infection are well documented, but concerns regarding access and adherence to HAART are growing. We evaluated virological responses to HAART among HIV-1 infected patients who were injection drug users (IDUs) in a population-based setting where HIV/AIDS care is delivered free of charge. METHODS We evaluated previously untreated HIV-1 infected men and women who initiated HAART between Aug. 1, 1996, and July 31, 2000, and who were followed until Mar. 31, 2002, in a province-wide HIV treatment program. We used Kaplan-Meier methods and Cox proportional hazards regression in our evaluation of time to suppression (i.e., less than 500 copies/mL) and rebound (i.e., 500 copies/mL or more) of plasma HIV-1 RNA, with patients stratified according to whether or not they had a history of injection drug use. RESULTS Overall, 1422 patients initiated HAART during the study period, of whom 359 (25.2%) were IDUs. In Kaplan-Meier analyses, the cumulative suppression rate at 12 months after initiation of HAART was 70.8% for non-IDUs and 51.4% for IDUs (p < 0.001) (these values include people who achieved suppression before 12 months but who might not have been followed for the full 12-month period). Among patients who achieved suppression of plasma HIV-1 RNA, the cumulative rebound rate at 12 months after initial suppression was 23.8% for non-IDUs and 34.7% for IDUs (p < 0.001). However, after adjustment for adherence and other covariates, the rates of HIV-1 RNA suppression (adjusted relative hazard 0.9, 95% confidence interval [CI] 0.7-1.0) and HIV-1 RNA rebound (adjusted relative hazard 1.3, 95% CI 1.0-1.6) were similar between non-IDUs and IDUs. Differences between non-IDUs and IDUs were even less pronounced in subanalyses that considered only therapy-adherent patients (p > 0.1). INTERPRETATION Non-IDUs and IDUs had similar rates of HIV-1 RNA suppression and rebound after the initiation of HAART, once lower levels of adherence were taken into account. Nevertheless, the lower virological response rates among IDUs suggest that, unless interventions are undertaken to improve adherence, these patients may experience elevated rates of disease progression and use of medical services in our setting.
The protease inhibitor UCF‐101 ameliorates streptozotocin‐induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP‐activated protein kinase

5‐[5‐(2‐Nitrophenyl) furfuryliodine]‐1,3‐diphenyl‐2‐thiobarbituric acid (UCF‐101) is a protease inhibitor which was reported to protect against ischaemic heart damage and apoptosis. This study evaluated the impact of UCF‐101 on steptozotocin (STZ)‐induced diabetic cardiomyocyte dysfunction. Adult FVB mice were made diabetic with a single injection of STZ (200 mg kg−1). Two weeks after STZ injection, cardiomyocytes from control and STZ‐treated mice were isolated and treated with UCF‐101 (20 μm for 1 h). Cardiomyocyte contractile properties were analysed, including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time to PS (TPS) and time to 90% relengthening (TR90). Steptozotocin‐induced diabetes depressed PS and ±dL/dt and prolonged TPS and TR90 in cardiomyocytes, all of which were significantly alleviated by UCF‐101. Immunoblotting analysis showed that UCF‐101 significantly alleviated STZ‐induced loss of phospholamban phosphorylation without affecting sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA2a) and phospholamban. Steptozotocin reduced AMP‐activated protein kinase (AMPK) phosphorylation at Thr172 of the catalytic subunit without affecting total AMPK expression, which was restored by UCF‐101. Short‐term exposure to UCF‐101 did not change the expression of X‐linked inhibitor of apoptosis protein (XIAP) and Omi stress‐regulated endoprotease, high temperature requirement protein A2 (Omi/HtrA2), favouring an apoptosis‐independent mechanism. Both the AMPK activator resveratrol and the antioxidant N‐acetylcysteine mimicked the UCF‐101‐induced beneficial effect in STZ‐induced diabetic cardiomyocytes. In addition, UCF‐101 promoted the phosphorylation of p38 mitogen‐activated protein kinases and c‐Jun N‐terminal kinase (JNK) after 15 min of incubation, while it failed to affect the phosphorylation of extracellular signal‐regulated kinase (ERK) and glycogen synthase kinase‐3β (GSK‐3β) within 120 min in H9C2 myoblasts. Taken together, these results indicate that UCF‐101 protects against STZ‐induced cardiomyocyte contractile dysfunction, possibly via an AMPK‐associated mechanism.
Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells

The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is critical for cell survival, especially for neurons that rarely regenerate cell bodies. We first describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current flow and dye barriers can, if appropriately used, provide more accurate assessments. We describe the effects of various substances (calcium, calpains, cytoskeletal proteins, ESCRT proteins, mUNC-13, NSF, PEG) and biochemical pathways (PKA, PKC, PLC, Epac, cytosolic oxidation) on plasmalemmal sealing probability, and suggest that substances, pathways, and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution. During sealing, calcium ion influx mobilizes vesicles and other membranous structures (lysosomes, mitochondria, etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes. Furthermore, we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal leaflets, or in a single step involving the fusion of one large wound vesicle with the nearby, undamaged plasmalemma. We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon. Finally, we speculate on relationships between plasmalemmal sealing, Wallerian degeneration, and the ability of polyethylene glycol (PEG) to seal cell membranes and rejoin severed axonal ends – an important consideration for the future treatment of trauma to peripheral nerves. A better knowledge of biochemical pathways and cytoplasmic structures involved in plasmalemmal sealing might provide insights to develop treatments for traumatic nerve injuries, stroke, muscular dystrophy, and other pathologies.