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Recent advances of nanoparticles in cancer therapy and diagnosis
Srinivasa rao B, Kanaka Bhushanam, Undurti N Das, Prasad TNVKV, Kakarla Subbarao
Srinivasa rao B1, Kanaka Bhushanam1, Undurti N Das1,2, Prasad TNVKV3, Kakarla Subbarao1
1KIMS Foundation and Research Centre, Minister Road, Secunderabad - 500003, AP, India
2UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA
3Institute of Frontier Technology, Regional Agricultural Research Station, Acharya N. G. Ranga Agricultural University, Tirupathi-517502, India
*Corresponding author: Srinivasa Rao B, M.Sc., Ph.D., KIMS Foundation and Research Centre, Minister Road, Secunderabad - 500003, AP, India, Email: srinumicros@yahoo.com
Received 10 May 2013; Accepted 15 June 2013
Citation: Srinivasarao B, Kanakabhushanam GVVS, Das UN, Prasad TNVKV, Kakarla S. Recent advances of nanoparticles in cancer therapy and diagnosis. J Med Sci Res 2013; 1(2): 95-102. http://dx.doi.org/10.17727/JMSR.2013/1-017
Copyright: © 2013 Srinivasa rao B et al. Published by KIMS Foundation and Research Center. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Recent advances in nanotechnology may offer new hope for significant improvement in the success of cancer treatment, especially in preventing tumor growth and progression. Having grown exponentially, the focus of nanotechnology has been on engineering diversified novel applications that even go beyond therapeutic activity; nanotechnology also offers the ability to detect diseases, such as cancer, much earlier than ever imaginable. Nanoparticles with enhanced surface properties are able to diffuse with greater ease inside the tumor cells delivering a high amount of drug selectively to tumor cells with significant reduced toxicity. The association of chemotherapeutic agents with nanoparticles offers improvement in the solubility and stability of antitumor agents, avoidance of drug degradation, and reductions in therapeutic dose and toxicity, increasing drug levels in tumor tissue and decreasing them in healthy tissue. In this review, we discuss the current state of research on applications of nanoparticles (NPs) for cancer therapy, diagnosis and also advance of nanoparticles.
Keywords: Nanotechnology; Nanoparticles; Liposome; Micelles; Quantum dot; Gold nanoparticles, Magnetic nanoparticles; Carbon nanotubes; Dendrimers; Cancer therapy; Cancer biomarkers
Nanotechnology was first proposed by the Nobel Prize winner Richard Feynman in 1959 [1]. The biomedical application of nanoparticle is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. On the metric scale, a nanometer is one-billionth of a meter. Nanoparticles are structures ranging in size from 1 to 100 nm (Figure 1). Nanoparticles show unique size-dependant physical and chemical properties, which can be optical, magnetic, catalytic, thermodynamic, and electrochemical [2]. These particles have great potential for clinical use, and the National Institute of Health (Bethesda, MD, USA) has referred to this area as nanomedicine.
Figure 1: particle size comparison.
Most cancer therapeutics are small drug molecules that after being ingested or injected into the bloodstream can easily diffuse through vascular pores and the extracellular matrix to reach tumors. Complex therapeutics that involve drug delivery mechanisms or imaging moieties have tended to be much larger. While the exact size of molecules that can easily transverse vascular pores from the bloodstream and reach tumor tissue is unclear, it is probably limited to the size of proteins (<20 nm). Nanoparticles have many potential benefits for diagnosing and treating metastatic cancer, including the ability to transport complex molecular cargoes to the major sites of metastasis, such as the lungs, liver and lymph nodes, as well as targeting to specific cell populations within these organs [3]. The rapid developments in nanostructured materials and nanotechnology will have profound impact in many areas of biomedical applications including delivery of drugs and biomolecules, tissue engineering, detection of biomarkers, cancer diagnosis and cancer therapy.
Different nanotechnology-based nanocarrier systems Based on nanotechnology, nanocarriers synthesized from organic and inorganic materials have been developed, such as liposome, micelles, quantum dots, gold nanoparticles, magnetic nanoparticles, carbon nanotubes and dendrimers [4, 5] (Figure 2). They have shown great potential in cancer therapy by enhancing the performance of medicines and reducing systemic side effect in order to gain therapeutic efficiency.
Figure 2: Examples of nanomaterials and nanocarrier systems (W. Cai et al. [4, 5]).
Liposome: A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Thermosensitive magnetoliposomes (TMs) encapsulated with methotrexate (MTX) prepared by reverse-phase evaporation can achieve a good magnetic targeting effect and rapid drug release in response to hyperthermia, which implies their great potential in cancer therapy [6]. Healthy fibroblast cells and breast cancer (MCF-7) cells were treated with either free phthalocyanine or phthalocyanine bound to either gold nanoparticles or encapsulated in liposomes [7]. A human breast cancer bearing animal model utilizing the liposomes encapsulating taxol injected intravenously showed a better therapeutic effectiveness and a lower hemotoxicity than did free taxol [8]. Liposomes are, up till now, the most used nanocarriers for targeted drug delivery in the clinical setting.
Micelles: Micelles are colloidal dispersions constructed from amphiphilic molecules which tend to be ~20-80 nm in diameter. Their smaller size when compared to larger nanocarriers such as liposomes can limit their ability to carry a substantial dose of the chemotherapeutic agent to the tumor. The use of polymeric micelles for cancer treatment was first reported in the early 1980s by Ringsdorf and coworkers [9]. Micelles containing a folate moiety have been shown to be significantly more cytotoxic to ovarian carcinoma cells than non-targeted micelles [10]. In fact, folate has also been successfully used recently as a targeting ligand in micelles to deliver poorly water-soluble chemotherapeutics (either tamoxifen or paclitaxol) to colon carcinoma cells [11]. In addition, hyaluronic acid (HA)-paclitaxel conjugate micelles have recently been shown to be far more cytotoxic toward HA receptor over expressing cancer cells than for HA receptor deficient cells [12]. The clinical success based on passively delivering chemotherapeutics encapsulated within micelles in cancer treatment have made these nanocarriers particularly attractive candidates for future work involving a more active form of delivery.
Quantum dot: Quantum dots (QDs) are nanometer-size luminescent semiconductor nanocrystals. Their unique optical properties, such as high brightness, long-term stability, simultaneous detection of multiple signals and tunable emission spectra, make them appealing as potential diagnostic and therapeutic systems in the field of oncology. Yezhelyev et al. [13] reported the use of multicolor QDs for quantitative and simultaneous profiling of multiple biomarkers using intact breast cancer cells and clinical specimens and the comparison between the new QDs-based molecular profiling technology with standard western blotting and fluorescence in situ hybridization (FISH). In another study, Gao et al. [14] demonstrated the potential of QDs as a new diagnosis technology for metastasis prostate cancer.
Gold nanoparticles: Gold nanospheres (AuNPs) (also known as gold colloids) of 2 nm to over 100 nm in diameter can be synthesized by controlled reduction of an aqueous HAuCl4 solution using different reducing agents under varying conditions. The properties of AuNPs such as their size, charge and surface chemistry have been shown to affect the uptake of AuNPs into cells as well as their subsequent intracellular fate. In addition, effective drug delivery strategies must take into account the nature of drug-AuNP interaction (covalent/non-covalent binding) as well as the means of drug release following introduction of the drug-AuNP complexes to cells [15].
The utility of AuNPs as novel biosensors for the detection of tumor cells can be demonstrated through the use of a screen-printed carbon electrode (SPCE) coupled with a NP-based electrocatalytic method [16]. Huang et al. [17] have described two methods for tumor targeting: the first involved conjugation of AuNPs to polyethylene glycol (PEG), and the second involved conjugation of AuNPs with specific antibodies which bind unique biomarkers expressed on tumor cells. PEG prevented AuNPs aggregation and lengthened their retention time in blood. This facilitated the preferential accumulation of AuNPs in tumor cells over healthy cells because of the elevated permeability of poorly differentiated blood vessels around tumors following angiogenesis (Figure 3), as well as the decreased clearance rate caused by the deficit of functional lymphatic vessels in tumors [18].
Figure 3: Schematic diagram showing accumulation of ligand-targeted gold nanoparticles conjugated with anticancer drugs in cancer cells mediated via extravasation of the gold nanocarriers through gaps in the endothelial cells ("leaky tumor vasculature") [46].
Magnetic nanoparticles: Magnetic nanoparticles can be produced by a number of physical and chemical routes that differ in the final properties of the products. The common feature of all nanoparticle-based cancer therapies is the need of specific NPs for achieving the desired therapeutic effect. However, each diagnostic/therapeutic technique requires a different chemical or physical property of the particles involved, which depends on the specific function played by the NPs in that therapy (e.g., vector, porous receptacle, heating agent, magnetic moment carrier, etc.). Sometimes the particle function is activated using an external agent (magnetic fields, light, radiation, etc.) that interacts with the NPs. Therefore the requirements for NPs as biomedical agents span a broad range of novel materials, synthesis strategies, and research fields (Table 1). The appeal for using nanoparticles in selective tumor targeting is the potential to deliver a concentrate dose of drug in the vicinity of (or even inside) the target tissue, reducing drug exposure of healthy cells. This could be done by means of physical interactions, or passive/active targeting [19]. The other way to deliver drugs to any desired target involves the functionalization of the surface of nanoparticles with monoclonal antibodies or ligands to tumor-related receptors, taking advantage of the specific binding ability between an antibody and antigen, or between the ligand and its receptor [20, 21].
Carbon nanotubes: A Carbon nanotube (CNT) is a tube-shaped material, made of carbon, having a diameter measuring on the nanometer scale. As a group, Carbon nanotubes typically have diameters ranging from <1 nm up to 50 nm. Their lengths are typically several microns, but recent advancements have made the nanotubes much longer, and measured in centimeters. The shape of the CNT would allow these materials to enter the cell via different methods, such as passive diffusion across the lipid bilayer, or endocytosis, whereby the CNT attaches to the surface of the cell and is subsequently engulfed by the cell membrane. The hollow monolithic structure of CNTs and their ability to bind desired functional groups make CNTs promising drug carriers. They can be functionalized to be more water-soluble and serum-stable, with low toxicity at the cellular level [22, 23].
It has been suggested that CNTs could be used as nanocarriers for delivering drugs into the body via injectable routes [24]. It is beyond the scope of this article to describe all of them in detail, but they have been succinctly summarized in a series of recent reports (Table 2). Drugs can either attach to the outer surface of the CNT via functional groups or be loaded inside the CNT. Attachment of the anticancer drug to the outer surface of the CNT can be through either covalent or noncovalent bonding, including hydrophobic, π–π stacking, and electrostatic interactions [25-27].
Dendrimers: Dendrimers are nano-sized, radially symmetric molecules with well-defined, homogeneous and monodisperse structure consisting of tree-like arms or branches. The properties of dendrimers, in particular the synthetic ability to provide them with many different biological properties, along with their capacity to carry conjugated surface molecules or encapsulated guest molecules, make them immediately attractive as potential vehicles for drug delivery. Once a dendrimer carrying an encapsulated drug reaches the intended site of action, the guest molecule generally must be released to gain bioactivity. The observation that guest molecules could be liberated at different rates demonstrated that viable opportunities exist to tailor the release for either slow or rapid delivery (Figure 4).
Figure 4: Requirements for dendrimer-based cancer-targeted drug delivery. (a) Dendrimers with multiple surface functional groups can be directed to cancer cells by tumor-targeting entities that include folate or antibodies specific for tumor-associated antigens. (b) The next step is intake into the cell, which in the case of folate targeting occurs by membrane receptor-mediated endocytosis. (c) Once inside the cell, the drug generally must be released from the dendrimer, which, for the self-immolative method, results in the simultaneous disintegration of the dendritic scaffold (d) (Srinivasa-Gopalan et al.[45]).
The Schluter group examined the impact of peripheral functionality on the cytotoxicity of MCF-7 breast cancer cells in vitro using low generation (G0, G1, and G2) polyamidoamine-like polymers [28]. Paclitaxel was conjugated to PEG or G4-PAMAM to compare the anti-cancer activity of the drug delivered by a linear or dendritic carrier [29]. Studies have shown that folic acid-conjugated dendrimers preferentially target tumor cells that overexpress folic acid receptors [30]. A recent study by Hong et al. explicitly quantified the binding avidity of multi-valent targeted G5- PAMAM containing different numbers of folic acid molecules [31]. The conjugates were prepared and evaluated against a cancer cell line (HeLa) and healthy cells (non-transformed mouse embryonic fibroblasts or MEFs) [32]. The importance of the high architectural control characteristic of dendrimers has been increasingly supported by positive outcomes from in vitro and in vivo studies. Studies have indeed demonstrated that a well-designed dendrimer structure can be potentially tuned simultaneously for desired biocompatibility, bioavailability, pharmacokinetics, and localized delivery of therapeutics to malignancies. Continued research in the area will bring compositions and architectures tailored for increasing specificity and efficacy towards the diagnoses and treatment of cancer in the clinic.
Nanoparticle platforms for Cancer Stem Cell targeted drug delivery
The intratumoral heterogeneity of cancer cells presents a major challenge to the development of effective cancer therapies. However, a growing body of evidence suggests that tumors may be driven by a small population of transformed stem-like cells with the ability to undergo both self-renewal and differentiation into the diverse cancer cell population that constitutes the bulk of the tumor [33, 34, 35]. Nanoscale drug delivery technologies offer fundamental advantages over contemporary small molecule pharmaceuticals used in clinical practice. These advantages include increased bioavailibity, extended drug half-life and reduced off-target toxicities [36].
Biomarkers of cancer
Identification of biological markers of cancer is a major area of research. Every cell type has a unique molecular signature, referred to as biomarkers, which are identifiable characteristics such as levels or activities (the abilities of genes or proteins to perform their functions) of a myriad of genes, proteins or other molecular features. Biomarkers have tremendous therapeutic impact in clinical oncology, especially if the biomarker is detected before clinical symptoms or enable real-time monitoring of drug response. Protein signatures in cancer provide valuable information that may be an aid to more effective diagnosis, prognosis, and response to therapy. More than 11 million people are diagnosed with cancer every year [37].
Alterations primarily in three main classes of genes viz., (proto) oncogenes, tumour suppressor genes and DNA repair genes collectively contribute to the development of cancer genotype and phenotype that resists the natural and inherent death mechanism(s) embedded in cells (apoptosis and like processes), coupled with dysregulation of cell proliferation events (Figure 5). There is a critical need for expedited development of biomarkers and their use to improve diagnosis and treatment for cancer [38]. Just recently, scientists have begun identifying microRNAs (miRNAs) as cancer biomarkers [39, 40]. In fact, miR-141 levels could identify prostate cancer patients with high sensitivity and perfect accuracy [40]. Peng et al. reported that a tailor-made array of cross-reactive sensors based on organically functionalised gold nanoparticles discriminates between breath Volatile Organic Compounds (VOCs) of healthy controls and of patients suffering from lung, breast, colorectal, and prostate cancers [41].
Figure 5: The process of carcinogenesis, showing opportunities of identifying biomarkers.
Nanomaterials: future drugs for cancer chemotherapy
During the past few decades, various chemotherapeutic agents, such as cyclophosphamide, fluorouracil, platinum-based compounds, anthracycline, hydroxycamptothecin and paclitaxel, have been designed and proved to be effective toward cancer cells. However, regrettably, these drugs are non-targeted to cancer, and thus serious side effects to normal cells or tissues are unavoidable [42]. Therefore, new drugs with selective cytotoxicity become an important research focus in cancer chemotherapy. Nanotechnology-based approaches are anticipated to provide a new breakthrough for targeting cancer cells and bypassing their multidrug resistance [43].
On the other hand, in the clinical cancer therapy process, anticancer drugs are simply employed to kill cancer cells. Unfortunately, nontargeted drugs may be rapidly and widely distributed in healthy organs and tissues. As a result, a high dose of anticancer drugs is normally needed to obtain favorable therapy efficacy. Moreover, the patients have to suffer from severe side effects or even from the drug toxicity far earlier than the tumor burden. Presently, these clinical difficulties have largely impeded successful cancer therapy.
Cancer detection
Conventional: Conventional detection of the cancer is done by observing the physical growth/changes in the organ by X-rays and/or CT Scans and is confirmed by biopsy through cell culture. However the limitation of this method is that it is not very sensitive and the detection is possible only after substantial growth of the cancerous cells. Often the treatment is also not possible once the cancer is in such an advanced stage.
Nanotechnology detection: As mentioned before, nanoparticles are of a few of nm and the cells are of the size of few microns. So NP can enter inside the cells and can access the DNA molecules/Genes and, there is a possibility that the defect in the genes can be detected. DNA molecules can be detected in their incipient stage. This could be possible in vivo or in vitro. It will be shown latter that NPs do show potential of cancer detection in its incipient stage.
Conventional: One of the treatment options is surgery. That is, remove the cancerous part. However, the limitation is that one loses the organ and the cancer may appear again. Further, the surgery is not possible for all types of cases of the cancer. Second option is radiation therapy. In this the cancerous cells are burnt by radiation of specific frequency band and the intensity. The limitation of this method is that even the healthy cells get burnt, cancerous cells burning is not uniform and the burnt part may become dead and non functional. The third option is chemotherapy. That is, cancerous cells are killed by drugs toxic to cells or by stopping cells from taking nutrients needed to divide the cells or stop the mechanism responsible for division of the cell. Normally a combination of drugs is given so that drugs affect all the three aspects of the cancer treatment. The limitation of this approach is that treatment is harmful to healthy cells, approach is gross and rarely successful if the cancer is in advanced stage.
Nanotechnology: Certain nanoparticles can be designed to absorb preferentially certain wave length of radiation and gets heated. Such a NPs if enters in the cancerous cell will burn it if irradiated by suitable wavelength radiation. This is kind of the analogue of radiation therapy. As mentioned before, nanotechnology can be used to create therapeutic agents that target specific cells and deliver toxin to kill them. The NP will circulate through the body, detect cancer associated molecular changes, assist with imaging release a therapeutic agent and then monitor the effectiveness of the intervention.
Nanotechnology is definitely a medical boon for diagnosis, treatment and prevention of cancer disease. A number of approaches for successful applications of nanomaterial-based cancer drugs will be possible because of their unusual characteristics. Areas of greatest clinical impact likely include novel, targeted drug-delivery vehicles, molecularly targeted contrast agents for cancer imaging, targeted thermal tumor ablation, and magnetic field targeting of tumors. However, there are still challenges to the development and application of nanotechnology platforms in cancer therapy, such as limited knowledge of the cancer cell physiology, small variety and poor functionalization of medical nanomaterials, and deficiency of clinical evaluation criteria. Nonetheless, with further advances in functionalization base on thorough understanding of the physiological features of cancer cells, nanotechnology platforms hold the promise of essentially changing the practice of oncology, allowing easy and effective targeted therapies. The clinical success of various nanocarrier constructs in cancer therapy have made these and similar systems promising drug delivery vehicles for future work aimed to further improve their overall drug delivery efficacy. Nanoparticles will likely serve as the norm rather than an exception in the majority of all areas of future conventional cancer treatments.
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A series of workshops and special training sessions for future therapists, teachers and trainers, or those eager to intensify their flower power experience.
Taking flower essences is a very profound experience. There are deep seated issues that can be triggered during intake. My workshops and seminars are designed to intensify your Flower Power Experience, by teaching not only about the flowers and their great virtues, but also letting you experience them safely and on a deep level, using techniques such as meditation, mantra chanting and group work.
First-hand knowledge is a must when you choose to make this type of therapeutic work your own. When working with clients, a therapist must be there for them and handle their very personal life-stories with solid knowledge, profound understanding and lots of respect.
In order to safely guide you, I have provided the NaturEssence Basic, Intermediate and Advanced Workshop of one day each. Participants completing the 3 courses have a possibility to receive their therapist- certificates after submitting their case-studies, those who do not wish to work with the essences may skip this step.
The Basic Flower Power Workshop* informs you about the making, history and pioneers of Flower Essences as well as about the currently 27 NaturEssences and 7 Sprays. After completing it, you will be aware of the most common methods available for finding your personal flower-elixir and be confident in using it for yourself.
The Intermediate Workshop* is all about learning how to determine the method of choosing the essences that suits you best and using it for family and friends. You will furthermore have a first go at making your own essence-mix which you will then take home and use. After completion, you'll be actively working with your own set of NaturEssences, which you can buy for a reduced price right after the workshop.
In order to be admitted to the Advanced Workshop and become a NaturEssence-certified Flower Power therapist, you must provide me with case-studies, of about 200 words each, of 3 family-members and/or friends who have taken one or several flower essences proposed by you.
The Advanced Workshop*is an active training on client-therapist relations, essence-mixing and working with the flower meditation, after completion of which you will get a certificate.
As a registered and certified therapist, you can buy stock bottles, elixirs and sprays for a special therapist rate.
The AniMagic Training Class* is a day-course; introducing you to the world of our friends from the Animal Kingdom, finding what they need, the gifts they have for us and how we can communicate with them on a deeper level. Case studies for admission to the Advanced Workshop may include AniMagic Elixirs, as they consist of NaturEssence mixes.
CORESSENCES day *or weekend courses are available to discover the fascinating world of these very powerful and intense elixirs. Find your very own way to a balanced, harmonious lifestyle, enhanced wellbeing, and a deeper understanding of the elements surrounding us.
Businesses, hotels and therapy centres offering my seminars as staff training might benefit from a reduced fare, as I am an MQA-approved therapist in Mauritius.


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GUIDED TOURS IN SEVERAL LANGUAGES (1/31/2019 até 12/31/2019)
History Tellers
Guided tour to the Legislative Assembly of Madeira
Friday at 3:00 p.m.
All those who wish to partake should contact: 935 010 779 or visit@aauma.pt
Guided tour to Quinta Vigia - Presidency of Regional Government of Madeira
EXHIBITION BY CATARINA BRANCO: EM PAISAGEM (2/1/2019 até 6/15/2019)
MUDAS.Museum of Contemporary Art of Madeira
This exhibition is the result of a joint organization between MUDAS.Museum of Contemporary Art of Madeira and the Archipelago-Centre of Contemporary Arts of the Azores, a partnership established under the protocol of cooperation signed by the representatives of the respective governments with the bureau of the Culture, during the Madeira - Azores Summit in 2016.
In this project Catarina Branco, presents us with a selection of work
The Educational Service of MUDAS.Museum of Contemporary Art of Madeira. (2/1/2019 até 12/31/2019)
It provides to the population, through prior appointment, pedagogical mediation services that include, in addition to the traditional visits oriented to the exhibitions, workshop visits, thematic visits, expression workshops, awareness raising activities in the Schools, among other activities.
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ANNUAL ACTIVITIES OF MADEIRA ETHNOGRAPHIC MUSEUM (2/1/2019 até 12/31/2019)
WORKSHOP "HANDS THAT GIVE ME AFFECTION AND WEAVE THREADS"
Weaving activity is here approached in a motivating and interactive manner. Through practicing, making flowers and carpets with the museum's loom, sharing knowledge and led by the local weaver.
Target Audience: All publics
Schedule: By prior booking by email or telephone.
Aims: To allow a better understanding of the "know how" of weavers, a forgotten profession, always preserving and conveying t
"THE MUSEUM GOES TO THE STREET"
1st Wednesday of every month | 2:30 P.M. – 15:00 P.M.
To promote the museum-school-community relationship and raise the awareness towards the Madeira's ethnographic heritage.
Target audience: Schools, libraries, occupational centres and other interested institutions.
Tuesday to Friday | 2:30 P.M. – 5:00 P.M.
Learning how to differentiate the "Observing" from the "Seeing".
Drawing of museum pieces.
Target audience: Primary and secondary school students.
EDUCATIONAL GARDEN
Aromatic and Medicinal Herbs Garden.
Tuesday to Friday | 2:30 P.M.– 4:30 P.M.
To make the museum's educational garden know to all and promote the importance of cultivation of aromatic and medicinal herbs.
Target audience: General public
"ILUMINAÇÃO A VELA"
Tuesday to Friday | 10:30 A.M. - 12:30 P.M.
Get acquainted with the history and evolution of lighting, as a household equipment.
Target Audience: Seniors.
Thematic guided tours:
"Sardas Discovers the Museum"
Throughout the year, at the opening hours of the museum.
Proposed activity for children and young visitors to the museum.
Pedagogical exploration game about the museum for young people visiting the museum, designed by Deebook Publisher for the Museum Educational Services.
"PLAYING LIKE IN THE OLD DAYS"
This activity will be developed in OTL - "Museum, Leisure Place", in the museum's garden.
Aims: "Playing like in the old days" is a project of the Educational Services, which aims to make known, value and encourage the practice of traditional games.
Encouraging children and young people to practice these games, with centuries-old traditions in our archipelago and with them enjoy moments of fun and joy, is the first intention of this
History Tellers - Discovering the City (2/1/2019 até 12/31/2019)
Monday to Friday, from 10:00 a.m. to 5:00 p.m.
Guided tour through the streets of the city promoted by the University of Madeira Students' Union
Target audience: childreen and youngsters (until 16 years old)
Meeting-point: La Vie Shopping Centre
All those who wish to partake should contact: 291 705 060
" DEDO NA FERIDA" (4/3/2019 até 5/28/2019)
Visual Collective Exhibition
Rua do Esmeraldo, 10-Funchal
"PLAYGROUD" (4/24/2019 até 6/20/2019)
By Filipa Venâncio
Galeria Marca de Água
Monday to Friday – 10:30 am / 6:30 pm
Rua da Carreira, 119 - Funchal
Workshop on Project Preparation and Applications Preparation for Financing (4/29/2019 até 5/4/2019)
Centro de Estudos História do Atlântico Doutor Alberto Vieira
2nd formation cycle
Duration: [five days]
Trainer: Dr. Vítor Martelo
Maximum number of trainees: 15
More information / registration form at: https://goo.gl/NTReHu
Regional Directorate for Culture - 291 211 830
Regional Secretariat for Tourism and Culture / Department of Culture

redpajama_set_name: RedPajamaCommonCrawl


(Ecofin Agency) - In 2018, private equity firms invested $3.5 billion in Africa against $3.9 billion in 2017, the African Private Equity and Venture Capital Association (AVCA) revealed in a report published recently.
According to the same source, private equity investments in the continent reached $25.7 billion between 2013 and 2018.
The report reveals that during the period under review (2018) the number of private equity transactions reached 186 while in 2017, they were 171 and 1022 for the 2013-2018 period.
In 2018, the volume of funds raised by equity funds active in the continent Reached $2.7 billion against $2.7 billion in 2017.
On the other hand, the number of disinvestments dropped from 52 in 2017 to 46 in 2018 mainly because of the decrease in disinvestments recorded in South Africa (amid economic uncertainties).
Shares transfer to trade buyers represented 39% of the divestiture recorded in 2018 against 37% for share transfers to other private equity funds or financial institutions. 2% were management buy-out and 2% for IPOs.


text:
The influence of cigarette smoking on a population of infertile men and women
Donatella Caserta, Giulia Bordi, Noemi Di Segni, Angelo D'Ambrosio, Maddalena Mallozzi, Massimo Moscarini
Ospedale Pediatrico Bambino Gesu
Purpose: This study aimed at investigating the effect of cigarette smoking on semen parameters in infertile men and on antral follicle count (AFC) and reproductive hormone levels in infertile women. Methods: In 648 men (200 smokers and 448 non-smokers) sperm concentration, motility and morphology were compared according to smoking status. In the female population, AFC and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured in 296 women (102 smokers and 194 non-smokers). Statistical analysis of data was performed using t test, χÂ-test and Spearman's correlation. Results: Among the male population, smokers had significantly lower sperm concentration and motility than non-smokers. Sperm normal morphology was reduced in smokers, although this difference did not reach statistical significance. No significant correlation was found between sperm parameters and the intensity of smoking. In the female population, AFC was reduced in smokers compared with non-smokers. Women who smoked had significantly higher FSH levels. No significant difference was found in LH and estradiol levels according to smoking status. The number of pack-years was negatively correlated to AFC and positively correlated to FSH levels. Conclusion: Cigarette smoking is associated with damaging effects on sperm parameters in infertile men and with ovarian reserve alteration in infertile women, as reflected by reduced AFC and increased FSH levels. Every smoker should be encouraged to stop smoking to prevent the damage of the toxins contained in cigarette smoking and preserve their own reproductive potential.
Antral follicle count
Semen parameters
Dive into the research topics of 'The influence of cigarette smoking on a population of infertile men and women'. Together they form a unique fingerprint.
Cigarette Smoking Medicine & Life Sciences 100%
Antral Medicine & Life Sciences 95%
Smokers Medicine & Life Sciences 85%
Follicle Stimulating Hormone Medicine & Life Sciences 74%
Non-Smokers Medicine & Life Sciences 68%
Smoking Medicine & Life Sciences 48%
Spermatozoa Medicine & Life Sciences 46%
Sperm Motility Medicine & Life Sciences 40%
Caserta, D., Bordi, G., Di Segni, N., D'Ambrosio, A., Mallozzi, M., & Moscarini, M. (2013). The influence of cigarette smoking on a population of infertile men and women. Archives of Gynecology and Obstetrics, 287(4), 813-818. https://doi.org/10.1007/s00404-012-2643-5
The influence of cigarette smoking on a population of infertile men and women. / Caserta, Donatella; Bordi, Giulia; Di Segni, Noemi et al.
In: Archives of Gynecology and Obstetrics, Vol. 287, No. 4, 04.2013, p. 813-818.
Caserta, D, Bordi, G, Di Segni, N, D'Ambrosio, A, Mallozzi, M & Moscarini, M 2013, 'The influence of cigarette smoking on a population of infertile men and women', Archives of Gynecology and Obstetrics, vol. 287, no. 4, pp. 813-818. https://doi.org/10.1007/s00404-012-2643-5
Caserta D, Bordi G, Di Segni N, D'Ambrosio A, Mallozzi M, Moscarini M. The influence of cigarette smoking on a population of infertile men and women. Archives of Gynecology and Obstetrics. 2013 Apr;287(4):813-818. doi: 10.1007/s00404-012-2643-5
Caserta, Donatella ; Bordi, Giulia ; Di Segni, Noemi et al. / The influence of cigarette smoking on a population of infertile men and women. In: Archives of Gynecology and Obstetrics. 2013 ; Vol. 287, No. 4. pp. 813-818.
@article{f4cf7b4a9e5c47cdbffe19aa93f94d7b,
title = "The influence of cigarette smoking on a population of infertile men and women",
abstract = "Purpose: This study aimed at investigating the effect of cigarette smoking on semen parameters in infertile men and on antral follicle count (AFC) and reproductive hormone levels in infertile women. Methods: In 648 men (200 smokers and 448 non-smokers) sperm concentration, motility and morphology were compared according to smoking status. In the female population, AFC and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured in 296 women (102 smokers and 194 non-smokers). Statistical analysis of data was performed using t test, χ{\^A}-test and Spearman's correlation. Results: Among the male population, smokers had significantly lower sperm concentration and motility than non-smokers. Sperm normal morphology was reduced in smokers, although this difference did not reach statistical significance. No significant correlation was found between sperm parameters and the intensity of smoking. In the female population, AFC was reduced in smokers compared with non-smokers. Women who smoked had significantly higher FSH levels. No significant difference was found in LH and estradiol levels according to smoking status. The number of pack-years was negatively correlated to AFC and positively correlated to FSH levels. Conclusion: Cigarette smoking is associated with damaging effects on sperm parameters in infertile men and with ovarian reserve alteration in infertile women, as reflected by reduced AFC and increased FSH levels. Every smoker should be encouraged to stop smoking to prevent the damage of the toxins contained in cigarette smoking and preserve their own reproductive potential.",
keywords = "Antral follicle count, Cigarette smoking, Infertility, Reproductive hormones, Semen parameters",
author = "Donatella Caserta and Giulia Bordi and {Di Segni}, Noemi and Angelo D'Ambrosio and Maddalena Mallozzi and Massimo Moscarini",
journal = "Archives of Gynecology",
T1 - The influence of cigarette smoking on a population of infertile men and women
AU - Caserta, Donatella
AU - Bordi, Giulia
AU - Di Segni, Noemi
AU - D'Ambrosio, Angelo
AU - Mallozzi, Maddalena
AU - Moscarini, Massimo
N2 - Purpose: This study aimed at investigating the effect of cigarette smoking on semen parameters in infertile men and on antral follicle count (AFC) and reproductive hormone levels in infertile women. Methods: In 648 men (200 smokers and 448 non-smokers) sperm concentration, motility and morphology were compared according to smoking status. In the female population, AFC and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured in 296 women (102 smokers and 194 non-smokers). Statistical analysis of data was performed using t test, χÂ-test and Spearman's correlation. Results: Among the male population, smokers had significantly lower sperm concentration and motility than non-smokers. Sperm normal morphology was reduced in smokers, although this difference did not reach statistical significance. No significant correlation was found between sperm parameters and the intensity of smoking. In the female population, AFC was reduced in smokers compared with non-smokers. Women who smoked had significantly higher FSH levels. No significant difference was found in LH and estradiol levels according to smoking status. The number of pack-years was negatively correlated to AFC and positively correlated to FSH levels. Conclusion: Cigarette smoking is associated with damaging effects on sperm parameters in infertile men and with ovarian reserve alteration in infertile women, as reflected by reduced AFC and increased FSH levels. Every smoker should be encouraged to stop smoking to prevent the damage of the toxins contained in cigarette smoking and preserve their own reproductive potential.
AB - Purpose: This study aimed at investigating the effect of cigarette smoking on semen parameters in infertile men and on antral follicle count (AFC) and reproductive hormone levels in infertile women. Methods: In 648 men (200 smokers and 448 non-smokers) sperm concentration, motility and morphology were compared according to smoking status. In the female population, AFC and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured in 296 women (102 smokers and 194 non-smokers). Statistical analysis of data was performed using t test, χÂ-test and Spearman's correlation. Results: Among the male population, smokers had significantly lower sperm concentration and motility than non-smokers. Sperm normal morphology was reduced in smokers, although this difference did not reach statistical significance. No significant correlation was found between sperm parameters and the intensity of smoking. In the female population, AFC was reduced in smokers compared with non-smokers. Women who smoked had significantly higher FSH levels. No significant difference was found in LH and estradiol levels according to smoking status. The number of pack-years was negatively correlated to AFC and positively correlated to FSH levels. Conclusion: Cigarette smoking is associated with damaging effects on sperm parameters in infertile men and with ovarian reserve alteration in infertile women, as reflected by reduced AFC and increased FSH levels. Every smoker should be encouraged to stop smoking to prevent the damage of the toxins contained in cigarette smoking and preserve their own reproductive potential.
KW - Antral follicle count
KW - Cigarette smoking
KW - Infertility
KW - Reproductive hormones
KW - Semen parameters
JO - Archives of Gynecology
JF - Archives of Gynecology


text:
\section{Introduction}
\label{sec:intro}

In many speech-to-text (STT) applications, the message-carrying speech signal $s(t)$ is corrupted by room reverberations $n(t)$, yielding the reverberated signal $o(t)=s(t) \ast n(t)$ where $\ast$ is the convolution operator and $t$ denotes time. According to the convolution theorem of Fourier transform, convolutions in time domain, turn into multiplication in the spectral domain and thereby additions in log spectral domain shown in equation \ref{eq:main_idea}.
\begin{eqnarray}
\label{eq:main_idea}
    \log \mathcal{F}(o(t)) &=&  \log \mathcal{F}(o(t)) \\ \nonumber
          &=& \log \mathcal{F}(s(t) \ast n(t))  \\ \nonumber
    &=& \log ( \mathcal{F}(s(t)) \times \mathcal{F}(n(t))) \\ \nonumber
    &=&\log \mathcal{F}(s(t)) + \log  \mathcal{F}(n(t))
\end{eqnarray}
$\mathcal{F}$ indicates the Fourier transform operator. Thus, for known $n(t)$, the original signal $s(t)$ could easily be recovered as
\begin{equation}
\label{eq:main_idea2}
    s(t)=\mathcal{F}^{-1} ( \exp (\log  \mathcal{F}(o(t)) -\log  \mathcal{F}(n(t))) )
\end{equation},
where $\mathcal{F}^{-1}$ is the inverse Fourier transform operator.

However, a few practical issues arise in this analysis.
\begin{itemize}
    \item Even though $n(t)$ has infinite duration, in digital signal processing, it can only be represented as a finite length discrete time signal.
    \item In order to use equation \ref{eq:main_idea2} with digital signals, we need equal length discrete Fourier transforms of the digitized versions of the signals $o(t)$ and $n(t)$.
    \item As we shall show, arithmetic operations done in the log spectral domain needs phase unwrapping operations to remove phase ambiguity.
    \item $n(t)$ is typically not known.
\end{itemize}

\section{Proposed Technique}
Suppose that the infinitely long impulse response $n(t)$ can be approximated by its truncated digital version $n^{\prime}=\{n^{\prime}_k\}_{k=1}^S$. Even though $n^{\prime}$ is unknown, it can be assumed to be a constant vector of real numbers.

Assume a digitized observed reverberated speech utterances $o=\{o_k\}_{k=1}^{S+T-1}$, obtained by convolving a source signal $s=\{s_k\}_{k=1}^T$ with $n^{\prime}$. Appropriate number of zeros can be appended to the signals to make them uniform length sequences leading to the equation
\begin{equation}
\label{eq:discrete_main}
    \log \mathbb{F}(o) =\log \mathbb{F}(s) + \log \mathbb{F}(n^{\prime})
\end{equation},
where $\mathbb{F}$ is the discrete Fourier transform operator. Since $n^{\prime}$ is assumed to be a constant vector, so is $\log \mathbb{F}(n^{\prime})$. Computing the expected values on both sides of equation \ref{eq:discrete_main}, we get
\begin{equation}
\label{eq:discrete_main_extecpted}
    \mathbb{E}\log \mathbb{F}(o) =\mathbb{E} \log \mathbb{F}(s) + \log \mathbb{F}(n^{\prime})
\end{equation}
Thus, an estimate of the unchanging logarithmic spectra of the room impulse response can simply be obtained as
\begin{equation}
\label{eq:get_rir}
    \log \mathbb{F}(n^{\prime}) = \mathbb{E}\log \mathbb{F}(o) -\mathbb{E} \log \mathbb{F}(s)
\end{equation}
Equation \ref{eq:get_rir} forms the basis of our algorithm where the expected values are replaced with \textit{empirical sums} computed over a finite number of speech utterances to obtain an estimate $\phi$ of the log spectrum of the room impulse response $\log \mathbb{F}(n^{\prime})$. This estimate can be used to normalize the log spectrum of the observed speech to estimate the clean speech as

\begin{equation}
\label{eq:main_idea2_discrete}
    \hat{s}=\mathbb{F}^{-1} ( \exp (\log  \mathbb{F}(o) - \phi ) )
\end{equation}

\subsection{Relation to prior work}
This principle follows Stockham et al. \cite{1451730} with several important differences, which come from our application to dereverberation. Stockham et al. aimed for mitigating effects of distortions, which resulted from use of a primitive recording machine. Impulse response of such a machine was relatively short comparing to our longer response of the reverberant room. Therefore, unlike Stockham  et al. , who were dealing with deconvolving rather short impulse responses, we are dealing with much longer impulse responses of rooms. Subsequently, our applied time segments are significantly scaled up. While they worked with 500 millisecond segments and averaged over several minutes of the recording on the old-fashioned gramophone plate, we used speech segments representing whole utterances and use as much as 180 hours of reverberant speech for computing the averages. Dealing with large room impulse responses also forces us to work with spectral subtractions in complex domain, while Stockham  et al. worked with magnitude spectra and used phases which were computed from recovered magnitude spectra under minimum-phase assumption. This is unsatisfactory in our application.

\subsection{The algorithm}
Our algorithm is requires the availability of two sets of speech data.
\begin{itemize}
    \item \textbf{Data1}: $P_o$ utterances $o^{(i)}$, $i=1,2,\dots P_o$ from the domain of interest which generally will be a reverberant environment. For the baseline experiment, this can also be clean speech data as we explain in section \ref{sec:exp}.\\
    \item \textbf{Data2}: $P_s$ utterances $s^{(i)}=1,2,\dots P_s$ of high quality clean speech data. This data does not need to be related to \textbf{Data1}.
\end{itemize}
Additionally, the room impulse response $n^{\prime}$ is assumed to be a fixed vector for all $P_o$ utterances in \textbf{Data1}.
\subsubsection{Computing the normalization vector $\phi$}
We compute $\phi$ following three simple steps.
\begin{itemize}
    \item Append zeros to each utterance from \textbf{Data1} and \textbf{Data2} to make all of them have uniform number of samples $N_{uniform}$.
    \item Compute Fourier transforms of each zero appended utterance $\mathbb{F}( o^{(i)} )$, $i=1,2,\dots P_o$ and $\mathbb{F}( s^{(i)} )$, $i=1,2,\dots P_s$
    \item Compute the normalizing vector \\
    $\phi=\frac{1}{P_o} \sum_{i=1}^{P_o}\log \mathbb{F}( o^{(i)} ) - \frac{1}{P_s}  \sum_{i=1}^{P_s} \log \mathbb{F}( s^{(i)} )$
\end{itemize}
During operation $\phi$ can be used to dereverberate speech utterances.
\subsubsection{Utterance-wise log spectrum normalization}
\label{sec:normalized_speech}
\begin{enumerate}
    \item Consider an observed test utterance $o^{test}$. Append zeros to make it $N_{uniform}$ samples long
    \item Compute Fourier transform $\mathbb{F} (o^{test})$
    \item Compute normalized speech \\
    $\hat{s}^{test}=\mathbb{F}^{-1} (\exp (\log \mathbb{F} (o^{test})-\phi)$ )
\end{enumerate}
This normalized speech utterance can be used for extract features for speech recognition. However, this leads to a processing delay amounting to the duration of each utterance. Alternately, we can directly compute FDLP-spectrograms from 1.5 seconds long windowed speech leading to lesser delays.

\subsubsection{Frame-wise log spectrum normalization and direct FDLP-spectrogram feature extraction }
\label{sec:asr_feats}
\begin{enumerate}
    \item For an observed test utterance $o^{test}$, generate von Hann windowed frames covering samples over 1.5 second of speech with 50\% overlap.
    \item Considering there are $M$ of these frames $o^{test,m}$, $m=1,2,\dots M$, append each frame with zeros to make them $N_{uniform}$ samples long.
    \item Compute Fourier transform of each frames $\mathbb{F} ( o^{test,m} )$, $m=1,2,\dots M$
    \item Compute normalized speech frames \\
    $\hat{o}^{test,m}=\mathbb{F}^{-1} (\exp (\log \mathbb{F}(o^{test,m})-\phi)$ )
    \item Use $\hat{o}^{test,m}$, $m=1,2,\dots M$ to compute complex FDLP-spectrogram\cite{sadhu2022complex}.
\end{enumerate}
Elegantly combining feature extraction with dereverberation, frame-wise normalization requires the analysis window to be significantly larger than the length of the room impulse response.
\subsubsection{Phase wrapping issues for computing $\phi$}
For any $i \in \{ 1,2, \dots P_o\}$, the discrete Fourier transform $\mathbb{F} (o^{(i)})$ written in exponential form is given by \\ $\mathbb{F} (o^{(i)})=|\mathbb{F} (o^{(i)})| \exp ( j \angle \mathbb{F} (o^{(i)}) )$, where $|*|$ and $\angle *$ indicates the standard magnitude and phase operators on any complex number respectively. In the log domain, this exponential form becomes
\begin{equation}
    \log \mathbb{F} (o^{(i)})= \log |\mathbb{F} (o^{(i)})| + j \angle \mathbb{F} (o^{(i)})
\end{equation}
and hence
\begin{equation}
\label{eq:the_issue}
    \frac{1}{P_o} \sum_{i=1}^{P_o}\log \mathbb{F}( o^{(i)} ) = \frac{1}{P_o} \sum_{i=1}^{P_o}\log |\mathbb{F}( o^{(i)} )| + j \frac{1}{P_o} \sum_{i=1}^{P_o} \angle \mathbb{F}( o^{(i)} )
\end{equation}.
 Although computing the first term on the right hand side of equation \ref{eq:the_issue} is straight forward, the second term is highly ambiguous because of phase wrapping. Since phase is an angular variable, it takes on values between 0 to $2 \pi$. Phase angles beyond that are reduced to this range by adding or subtracting appropriate multiples of $2\pi$ from it. For example, two complex numbers $1\angle j\pi$ and $1\angle j3\pi$ are identical. However, averaging the phases of $1\angle j2\pi$ and $1\angle j\pi$ gives us $1.5\pi$, whereas average phase of $1\angle j2\pi$ and $1\angle j3\pi$ is $2.5\pi$. A detailed description of this phase wrapping problem can be found in \cite{oppenheim1968nonlinear}.

 To disambiguate the second term in eq. \ref{eq:the_issue}, we unwrap the phases \cite{schafer1969echo} of \textit{all} computed spectra using the following simple algorithm. Consider a wrapped discrete phase sequence $p=\{p_k\}_{k=1}^N$ where $0 \leq p_k \leq 2\pi$ $\forall k \in \{1,2,\dots N\}$. To compute the unwrapped phase $\hat{p}$, we follow algorithm \ref{algo:1}.

\begin{algorithm}
\caption{Phase Unwrapping $p \xrightarrow[]{} \hat{p} $} \label{algo:1}
Initialize unwrapped phase $\hat{p}_k=0$ $\forall k \in \{1,2,\dots N\}$ \;
 $\hat{p}_1=p_1$ \;
\For{$k=2 \to N$}
{
$\hat{p}_k=p_k+2\pi t$ \;
$t$ \text{chosen s.t.} $|\hat{p}_k- \hat{p}_{k-1}| \leq \pi$  \;
}
\end{algorithm}

\section{Experimental Details}
\label{sec:exp}
\subsection{Data sets}
\subsubsection{Training data}
For our experiments we obtain the following \textit{mutually exclusive} segments from the Librispeech \cite{librispeech} data.
\begin{itemize}
    \item \textbf{High quality clean speech data set}: 180 hours of clean speech that is used as \textbf{Data2} for all our experiments.
    \item \textbf{Four different reverberated data sets}: 180 hours of clean speech data that is convolved with four different room impulse responses to generate four separate reverberated speech data sets. Each of them are used as \textbf{Data1} for computing the normalization vector $\phi$ when testing the ASR performance under a specific reverberant condition.
    \item \textbf{ASR training data set}: 50 hours of clean speech data that is used for ASR training. In order to keep the speech features consistent across our experiments, we also normalize utterance-wise log spectrum of this data with $\phi_{clean}$, computed by using this 50 hours of clean data as \textbf{Data1}.
\end{itemize}

\subsubsection{Room impulse responses}
In our experiments, four different types of room impulse responses provided with the REVERB data set are used, two of which are large room impulse responses with reverberation time $T_{60}=0.7$ seconds and another two medium sized room impulse responses with reverberation time $T_{60}=0.5$ seconds. $T_{60}$ is the time taken for the impulse response power to decay by 60dB. In all four cases, the source is located 250 cm away from the microphone at two different angles.

\subsubsection{Test data}
To evaluate the performance of the ASR under clean test condition, we use the original clean Librispeech test set. Additionally, this clean test set is convolved with the same four room impulse responses in use to obtain respective test sets under each of the four reverberant conditions. $\phi_{clean}$ is used as the ``default" normalization vector under various testing conditions to obtain baseline ASR results on various test sets.

\subsection{ASR setup}

\subsubsection{Front-end}

Our front-end uses FDLP-spectrogram features \cite{sadhu2021radically} using complex FDLP \cite{sadhu2022complex} to extract modulations from raw speech waveform. Speech utterances are segmented with 1.5 seconds long analysis windows with 50\% overlap.

\subsubsection{ASR architecture}
In our experiments, a Connectionist Temporal Classification (CTC) ASR acoustic model is used with 12 Transformer layers together along with a neural language model with 6 Transformer layers all trained with ESPnet \cite{watanabe2018espnet} speech recognition toolkit.
\subsection{Generalized weighted prediction error based dereverberation}
Weighted Prediction Error (WPE) \cite{yoshioka2010speech} based blind dereverberation works by estimating the theoretically obtainable signal from only the first $\Delta$ taps of the room impulse response and optimizing for a prediction filter that eliminates the late reverberation effects. An improved optimization loss is called for in the more widely used Generalized WPE \cite{wpe} which is used in Section \ref{sec:results} for comparing recognition results with regards to our technique.

\section{Results}
\label{sec:results}
Figure \ref{fig:comapre_clean_and_noisy_spectrogram} shows an example large room reverberant speech utterance and the dereverberation result when its log spectrum is utterance-wise normalized (as per Section \ref{sec:normalized_speech}).  The CTC ASR when tested on clean librispeech test set using utterance-wise $\phi_{clean}$ normalization yields a Word Error Rate (WER) of 26.2\%. This provides a lower bound on ASR performance under any of the reverberant conditions.

\begin{figure}[H]

\centering
\begin{subfigure}[b]{0.5\textwidth}
   \includegraphics[width=1\linewidth]{largeroom_original_clean.jpg}
   \caption{Original clean speech spectrogram}
   \label{fig:Ng1}
\end{subfigure}

\begin{subfigure}[b]{0.5\textwidth}
   \includegraphics[width=1\linewidth]{largeroom.jpg}
   \caption{Reverberated speech spectrogram}
   \label{fig:Ng1}
\end{subfigure}

\begin{subfigure}[b]{0.50\textwidth}
   \includegraphics[width=1\linewidth]{largeroom_cleaned.jpg}
   \caption{Spectrogram of same utterance after dereverberation}
   \label{fig:Ng2}
\end{subfigure}

\caption[x]{Result of dereverberating large room reverberated speech using the utterance-wise normalization described in Section \ref{sec:normalized_speech} }.
\label{fig:comapre_clean_and_noisy_spectrogram}
\end{figure}

\subsection{Recognition results with utterance-wise normalization}
Table \ref{table:recognition_comparison_uttwise} compares the results of three different speech recognition pipelines under various reverberant test conditions. Not surprisingly, using our ASR as an off-the-shelf speech recognizer over the four reverberant conditions yields significantly inferior recognition results. Recognition accuracy is universally benefited to a certain degree by the addition of generalized WPE dereverberation front-end to the ASR. However, the improvements offered by our method is remarkable and closest to the clean test set error rate of 26.2\%.

\begin{table}[h]
\centering
\begin{tabular}{@{}lccc@{}}
\toprule
\multirow{2}{*}{\begin{tabular}[c]{@{}l@{}}reverberant\\ condition\end{tabular}} & \begin{tabular}[c]{@{}c@{}}default \\ normalization\end{tabular} & \begin{tabular}[c]{@{}c@{}}default\\ normalization \\ +WPE\end{tabular} & \begin{tabular}[c]{@{}c@{}}our  \\ method\end{tabular} \\ \cmidrule(l){2-4}
                                                                                & \multicolumn{3}{c}{WER \%}                                                                                \\ \midrule
\multicolumn{1}{l|}{large room 1}                                                & 75.7                                                                    & 70.2                                                                            & 29.4                                                   \\
\multicolumn{1}{l|}{large room 2}                                                & 80.2                                                                    & 78.4                                                                            & 30.2                                                   \\
\multicolumn{1}{l|}{medium room 1}                                               & 62.8                                                                    & 56.3                                                                            & 29.2                                                   \\
\multicolumn{1}{l|}{medium room 2}     &    76.3            &       70.9            &   29.3                                                     \\ \bottomrule
\end{tabular}
\caption{ASR test results under four reverberant conditions are shown. The \textbf{first column} of results shows the recognition result with no extra front-end processing except utterance-wise speech log spectrum normalization by $\phi_{clean}$. The \textbf{second column} shows the results with WPE front-end dereverberation of the raw waveform before $\phi_{clean}$ normalization. The \textbf{third column} shows the recognition result of obtaining normalized speech utterances using the appropriate normalization vector as described in Section \ref{sec:normalized_speech}.}
\label{table:recognition_comparison_uttwise}
\end{table}

\subsection{Recognition results with frame-wise normalization}
Table \ref{table:recognition_comparison_phramewise} shows that speech recognition with frame-wise normalization works slightly inferior to utterance-wise normalization. When using windowed speech frames, our foundational idea expressed in equation \ref{eq:discrete_main} approximately holds true when the window length is considerably larger than the length of the room impulse response \cite{1451730}. In our case, a compromise is reached with an analysis window of 1.5 seconds. This is twice the $T_{60}$ value of the longest room impulse response at hand and also allows for fast FDLP-spectrogram feature extraction with appropriate resolution in modulation frequency domain. This explains the reduction is recognition accuracy, although still significantly better than WPE dereverberation seen in table \ref{table:recognition_comparison_uttwise}.

\begin{table}[h]
\centering
\begin{tabular}{@{}lc@{}}
\toprule
\multirow{2}{*}{\begin{tabular}[c]{@{}l@{}}reverberant\\ condition\end{tabular}} & \begin{tabular}[c]{@{}c@{}}recognition using FDLP-spectrograms  \\  with 1.5 second long  \\ normalized log spectrum \end{tabular} \\ \cmidrule(l){2-2}
                                                                                & WER \%                                                                                \\ \midrule
\multicolumn{1}{l|}{large room 1}                                                & 37.5                                                                                \\
\multicolumn{1}{l|}{large room 2}                                                & 39.1                                                                                \\
\multicolumn{1}{l|}{medium room 1}                                               & 37.2                                                                                \\
\multicolumn{1}{l|}{medium room 2}                                               &  43.9                                                                                \\ \bottomrule
\end{tabular}
\caption{ASR test results under four reverberant conditions using normalized log spectrum of 1.5 seconds long windowed speech directly used for computing FDLP-spectrogram. (see  Section \ref{sec:asr_feats})}
\label{table:recognition_comparison_phramewise}
\end{table}

\section{Discussions and conclusions}
A straightforward method to remove stationary reverberations from speech signal is described in this paper. Our method utilizes fundamental concepts from convolution theorem of Fourier transform and empirically computed expectations of log spectrum to obtain a normalizer that can remove effect of reverberations from whole utterances as well as speech frames.

\begin{table}[H]
\centering
\begin{tabular}{@{}lc@{}}
\toprule
\multirow{2}{*}{\begin{tabular}[c]{@{}l@{}}amount of \\ reverberated \\ data used\end{tabular}} & \begin{tabular}[c]{@{}c@{}}recognition under \\ large room reverberant \\ condition\end{tabular} \\ \cmidrule(l){2-2}
                                                                                & WER \%                                                                                \\ \midrule
\multicolumn{1}{l|}{50 hours}                                                                   & 42.9                                                                                \\
\multicolumn{1}{l|}{100 hours}                                                                  &   31.9                                                                                \\ \bottomrule
\end{tabular}
\caption{ASR recognition results under a large room reverberant condition with variable amounts of reverberant data (\textbf{Data1}) used for computing the normalization vector. }
\label{table:amount_of_data}
\end{table}

Dereveberation does not require any labelled training data. For the unlabeled data requirements, the clean speech data is abundant. However, reverberant data collected from a fixed microphone setup from the same room, could be more difficult to collect. In the idealized laboratory situation presented in this paper, the signal was artificially reverberated so the convolving system was fixed for each database whereas in practical applications, the reverberations may be changing their character. To get the average logarithmic spectrum, 180 hours of reverberant data was used which might not be available from one fixed reverberant condition. Table \ref{table:amount_of_data} shows the degradation in recognition performance for reduced amount of reverberant data. It is apparent that our method depends on significant amount of reverberant data to be effective. This is clearly a current drawback of our technique for most practical situations and further efforts are under way to better understand this aspect.

 Resulting FDLP-spectrogram features are shown to be exceptionally robust to the effects of reverberation for speech recognition.

\section{ACKNOWLEDGMENTS}
\label{sec:ack}
This work was supported  by the Center of Excellence in Human Language Technologies, The Johns Hopkins University.

\bibliographystyle{IEEEbib}

redpajama_set_name: RedPajamaArXiv


How often do sellers get paid?
Do we get paid weekly or on any set dates during a month or set days during a week or does it vary based on when the account was created?
Disbursement date is based on the day you signed up, or from the last "adjustment" due to account issues.
Individual sellers get disbursements every 7 days with a 14 day hold.
Pro sellers get disbursements every 14 days with no hold.
Accounts may have additional holds or restrictions placed on them based on status and sales history.
You're posting a lot of basic questions here in the forums. You might save yourself some time by going to Seller Help, watching the videos, and browsing the Help files. You can also visit [Seller University|https://sellercentral.amazon.com/learn/?ref_=id_xx_shel_home].
Daily for me…depends on when you started your account.
Goodbye, when did you start your account if you don't mind my asking? I heard there was a policy change affecting pro sellers after 2011?


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text:
VA Recognized as Top Employer
Written by Press Room
Categories: Government
In the past year, Montana VA Health Care System (MTVAHCS) has embraced planned and unplanned changes. From the ground breaking of a new clinic, to opening new state-of-the-art clinics, to responding to the COVID-19 pandemic, MTVAHCS has responded with adaptability and innovation. The organization was recently recognized by Forbes in naming the VA as one of Montana's top ten best employers.
Between 2009 to March 2019, four different Executive Directors led MTVAHCS. In June 2019, Dr. Judy Hayman became the MTVAHCS's Executive Director and established a core leadership team committed to identifying and cultivating leaders at each level of the organization. Focusing on the provision of safe, high qualityVeteran centric care, transparency in communications, ensuring high reliability, and identifying continuous process improvement opportunities defines the culture under Dr. Hayman's leadership.
"We have 1,400 staff who serve over 47,000 Veterans at 17 sites across Montana. When the pandemic began this spring, our staff immediately began planning and taking charge to respond. As guidance changed, our staff took the lead to ensure that Veterans were receiving the safest care possible. It is through constant communication and employee engagement that we have been able to overcome many of the challenges related to COVID-19" said Dr. Hayman. In May, MTVAHCS was selected as the lead site within its VA region to increase face-to-face visits for Veterans in the first phase of expanded care during the pandemic. "We have been able to continue serving Veterans during COVID-19 and were selected to lead our region in expanding face-to-face care because of the hard work and dedication of our staff."
In June, a new partnership was announced between MTVAHCS and Billings Clinic and St. Vincent Healthcare to serve rural Veterans and create integrated care between the VA and private healthcare systems. At the beginning of July, MTVAHCS broke ground on a new Veteran clinic in Missoula. At the end of July, MTVAHCS welcomed Veterans into their new state-of-the-art outpatient clinic in Great Falls. MTVAHCS has eight new clinics scheduled to open, across the state, by the end of next year.
MTVAHCS's overall trust scores—which derive from Veteran rankings of their health care experiences—are at a historic high. MTVAHCS provides healthcare to Veterans across Montana through a series of community-based clinics, the Miles City Community Living Center (Montana VA's only nursing home), an acute care medical center, a nationally acclaimed sleep center, and robust telehealth services. One third of Montana VA employees are Veterans.


text:
Хаги́н-Сала́ ( — солёная/засолённая балка; от  и ) — река в России, протекает в Городовиковском и Яшалтинском районах Республики Калмыкия. Река впадает в залив лиман Хагин-Сала озера Маныч-Гудило. Длина реки составляет 64 км, площадь водосборного бассейна составляет 686 км². Река почти на всём своём протяжении перегорожена дамбами и плотинами, образующими ряд прудов, а нижнем течении одноимённый лиман Хагин-Сала.

Река протекает через село Весёлое Городовиковского района и село Ульяновское Яшалтинского района.

Минерализация воды в реке (по результатам проб 2004 года) достигает 15-16 г/л (высокая). Класс воды сульфатный, группа натрий, тип второй.

Бассейн
Бассейн Хагин-Салы расположен на территориях Калмыкии и Ростовской области.

 Хагин-Сала
 б. Джальдже (правая составляющая)
 б. Менгута — (п)
 б. Кашункале — (л)
 б. Кункрюк-Сала — (л)
 р. Джуве — (л)
Притоки, указанные курсивом, фактически впадают в лиман Хагин-Сала, образованный в нижнем течении Хагин-Салы в результате заполнения Пролетарского водохранилища.

Данные водного реестра

По данным государственного водного реестра России относится к Донскому бассейновому округу, водохозяйственный участок реки — Маныч от истока до Пролетарского гидроузла, без рек Калаус и Егорлык, речной подбассейн реки — бассейн притоков Дона ниже впадения Северского Донца. Речной бассейн реки — Дон (российская часть бассейна).

По данным геоинформационной системы водохозяйственного районирования территории РФ, подготовленной Федеральным агентством водных ресурсов:
 Код водного объекта в государственном водном реестре — 05010500712107000016521
 Код по гидрологической изученности (ГИ) — 107001652
 Код бассейна — 05.01.05.007
 Номер тома по ГИ — 07
 Выпуск по ГИ — 0

См. также
 Реки Калмыкии

Примечания

Источник
 Атлас Республики Калмыкия, ФГУП «Северо-Кавказское аэрогеодезическое предприятие», Пятигорск, 2010 г., стр. 108—109

Бассейн Маныча
Реки Городовиковского района Калмыкии
Реки Яшалтинского района

redpajama_set_name: RedPajamaWikipedia


MORE than a third of parents have got into debt to pay for their children's Christmas presents.
According to a survey by the Action for Children charity, many families in Northern Ireland will face money worries at Christmas.
Of the parents surveyed, almost half said they have been cutting back on presents and the amount they spent on a Christmas tree and dinner.
On average, parents said they had been trying to reduce their spending for four years.
However, around 34 per cent said they had got into debt to afford Christmas presents.
The charity said the British government's austerity measures and problems with the new system of benefits, known as universal credit, could leave families in substantial debt.
It said it had seen a 30 per cent rise in parents seeking financial advice over the last three years.
Action for Children's Northern Ireland director Dawn Shaw said many families are struggling.
"When you are a parent who is already struggling to make ends meet, Christmas can be a very stressful time that can lead to increased debt and difficult choices on what you can provide for the family over the festive period," she said.
"Our survey shows that this is the reality for too many families in Northern Ireland and we see this on a daily basis in our services."


University College Dublin Digital Library has advised that it is currently working on the digitisation of the Dublin Metropolitan Police General Register, (1835-1925), and the Civil Guard Temporary Register, 1922-1925.
The registers, which are held by An Garda Síochána Garda Museum and Archives, have already been scanned but it will be a few months before the scans make their way online. They will be launched initially as an image-only collection ie they won't be text searchable.
They will join the Dublin Metropolitan Police (DMP) Prisoners' Books, 1903-18 collection on the free-to-access platform. Once online, researchers will be able to research the prisoners (in the DMP Prisoners Books) and then look up details of the arresting officer (DMP General Register).
The Civic Guard was formed in 1921, after the Royal Irish Constaulary was disbanded; it was renamed the Garda Síochána na hÉireann in August 1923. The Dublin Metropolitan Police merged with An Garda Síochána in 1925.


text:
Updated on Jul 26, 2022
Superclass Cyclostomata
Scientific name Myxini
Rank Class
Higher classification Craniate
Lower classifications Myxine, Myxinidae
Subphylum Vertebrata
Order Myxiniformes
Length Black hagfish: 30 – 89 cm
Clutch size Pacific hagfish: 28
Family MyxinidaeRafinesque, 1815
Eddie and the hagfish
Hagfish, the class Myxini (also known as Hyperotreti), are eel-shaped, slime-producing marine fish (occasionally called slime eels). They are the only known living animals that have a skull but no vertebral column. Along with lampreys, hagfish are jawless; they are the sister group to vertebrates, and living hagfish remain similar to hagfish from around 300 million years ago.
Hagfish sliming video
As Human Food
The classification of hagfish has been controversial. The issue is whether the hagfish is a degenerate type of vertebrate-fish (most closely related to lampreys), or represents a stage that precedes the evolution of the vertebral column (as do lancelets). The original scheme groups hagfish and lampreys together as cyclostomes (or historically, Agnatha), as the oldest surviving class of vertebrates alongside gnathostomes (the now-ubiquitous jawed vertebrates). An alternative scheme proposed that jawed vertebrates are more closely related to lampreys than to hagfish (i.e., that vertebrates include lampreys but exclude hagfish), and introduces the category craniata to group vertebrates near hagfish. Recent DNA evidence has supported the original scheme.
Hagfish average about 0.5 m (19.7 in) in length. The largest known species is Eptatretus goliath with a specimen recorded at 127 cm (4 ft 2 in), while Myxine kuoi and Myxine pequenoi seem to reach no more than 18 cm (7.1 in) (some have been seen as small as 4 cm (1.6 in)).
Hagfish have elongated, eel-like bodies, and paddle-like tails. The skin is naked and covers the body like a loosely fitting sock. They have cartilaginous skulls (although the part surrounding the brain is composed primarily of a fibrous sheath) and tooth-like structures composed of keratin. Colors depend on the species, ranging from pink to blue-grey, and black or white spots may be present. Eyes are simple eyespots, not compound eyes that can resolve images. Hagfish have no true fins and have six or eight barbels around the mouth and a single nostril. Instead of vertically articulating jaws like Gnathostomata (vertebrates with jaws), they have a pair of horizontally moving structures with tooth-like projections for pulling off food. The mouth of the hagfish has two pairs of horny, comb-shaped teeth on a cartilaginous plate that protracts and retracts. These teeth are used to grasp food and draw it toward the pharynx.
Hagfish are long and vermiform, and can exude copious quantities of a milky and fibrous slime or mucus from some 100 glands or invaginations running along its flanks. The typical species Myxine glutinosa was named for this slime. When captured and held, e.g., by the tail, they secrete the microfibrous slime, which expands into up to 20 litres (5¼ gallons) of sticky, gelatinous material when combined with water. If they remain captured, they can tie themselves in an overhand knot, which works its way from the head to the tail of the animal, scraping off the slime as it goes and freeing them from their captor, as well as the slime. This singular behavior may assist them in extricating themselves from the jaws of predatory fish or from the interior of their own "prey", and that the "sliming" might act as a distraction to predators.
Recently, the slime was reported to entrain water in its microfilaments, creating a slow-to-dissipate, viscoelastic substance, rather than a simple gel. It has been proven to impair the function of a predator fish's gills. In this case, the hagfish's mucus would clog up the predator's gills, disabling their ability to breathe. The predator would release the hagfish as it focused less on eating and more on not suffocating. It is because of the mucus that there are very few marine predators that target the hagfish. The other known predators of hagfish are varieties of birds or mammals.
Free-swimming hagfish also "slime" when agitated and later clear the mucus off by way of the same travelling-knot behavior. The reported gill-clogging effect suggests that the travelling-knot behavior is useful or even necessary to restore the hagfish's own gill function after "sliming".
Research is ongoing regarding the properties and possible applications of the components of hagfish slime filament protein, particularly as a renewable alternative to synthetics currently derived from petroleum.
Hagfish generally respire through taking in water through their pharynx, past the velar chamber and bringing the water through the internal gill pouches, which can vary in number from 5 to 16 pairs, depending on species. The gill pouches open individually, but in Myxine the openings have coalesced, with canals running backwards from each opening under the skin, uniting to form a common aperture on the ventral side known as the branchial opening. The esophagus is also connected to the left branchial opening, which is therefore larger than the right one, through a pharyngocutaneous duct (esophageocutaneous duct), which has no respiratory tissue. This pharyngocutaneous duct is used to clear large particles from the pharynx, a function also partly taking place through the nasopharyngeal canal. In other species the coalescence of the gill openings is less complete, and in Bdellostoma each pouch opens separately to the outside like in lampreys. The unidirectional water flow passing the gills is produced by rolling and unrolling velar folds located inside a chamber developed from the naso-hypophyseal tract, and is operated by a complex set of muscles inserting into cartilages of the neurocranium, assisted by peristaltic contractions of the gill pouches and their ducts. Hagfish also have a well-developed dermal capillary network that supplies the skin with oxygen when the animal is buried in anoxic mud, as well as a high tolerance for both hypoxia and anoxia, with a well developed anaerobic metabolism. It has also been suggested that the skin is capable of cutaneous respiration.
The hagfish's eye, which lacks lens, extraocular muscles, and the three motor cranial nerves (III, IV, and VI), is significant to the evolution of more complex eyes. A parietal eye and the parapineal organ are also absent. Hagfish eyespots, when present, can detect light, but as far as is known, none can resolve detailed images. In Myxine and Neomyxine, the eyes are partly covered by the trunk musculature.
Very little is known about hagfish reproduction. Embryos are difficult to obtain for study, although laboratory breeding of the Far Eastern inshore hagfish, Eptatretus burgeri, has succeeded. In some species, sex ratio has been reported to be as high as 100:1 in favor of females. Some hagfish species are thought to be hermaphroditic, having both an ovary and a testicle (there is only one gamete production organ in both females and males). In some cases, the ovary is thought to remain nonfunctional until the individual has reached a particular age or encounters a particular environmental stress. These two factors in combination suggest the survival rate of hagfish is quite high.
Depending on species, females lay from one to thirty tough, yolky eggs. These tend to aggregate due to having Velcro-like tufts at either end. Hagfish are sometimes seen curled around small clutches of eggs. It is not certain if this constitutes actual breeding behavior.
Hagfish do not have a larval stage, in contrast to lampreys, which have a long one.
Hagfish have a mesonephric kidney and are often neotenic of their pronephric kidney. The kidney(s) are drained via mesonephric/archinephric duct. Unlike many other vertebrates, this duct is separate from the reproductive tract. Unlike all other vertebrates, the proximal tubule of the nephron is also connected with the coelom, provided lubrication.
The single testicle or ovary has no transportation duct. Instead, the gametes are released into the coelom until they find their way to the posterior end of the caudal region, whereby they find an opening in the digestive system.
While polychaete marine worms on or near the sea floor are a major food source, hagfish can feed upon and often even enter and eviscerate the bodies of dead and dying/injured sea creatures much larger than themselves. They are known to devour their prey from the inside. Hagfish have the ability to absorb dissolved organic matter across the skin and gill, which may be an adaptation to a scavenging lifestyle, allowing them to maximize sporadic opportunities for feeding. From an evolutionary perspective, hagfish represent a transitory state between the generalized nutrient absorption pathways of aquatic invertebrates and the more specialized digestive systems of aquatic vertebrates.
Like leeches, they have a sluggish metabolism and can survive months between feedings; their feeding behavior, however, appears quite vigorous. Analysis of the stomach content of several species has revealed a large variety of prey, including polychaetes, shrimps, hermit crabs, cephalopods, brittlestars, bony fishes, sharks, birds and whale flesh.
In captivity, hagfish are observed to use the overhand-knot behavior "in reverse" (tail-to-head) to assist them in gaining mechanical advantage to pull out chunks of flesh from carrion fish or cetaceans, eventually making an opening to permit entry to the interior of the body cavity of larger carcasses. A healthy larger sea creature likely would be able to outfight or outswim this sort of assault.
This energetic opportunism on the part of the hagfish can be a great nuisance to fishermen, as they can devour or spoil entire deep-drag-netted catches before they can be pulled to the surface. Since hagfish are typically found in large clusters on and near the bottom, a single trawler's catch could contain several dozen or even hundreds of hagfish as bycatch, and all the other struggling, captive sea life make easy prey for them.
The digestive tract of the hagfish is unique among the chordates because the food in the gut is enclosed in a permeable membrane, analogous to the peritrophic matrix of insects.
Hagfish have also been observed actively hunting the red bandfish, Cepola haastii, in its burrow, possibly using their slime to suffocate the fish before grasping it with their dental plates and dragging it from the burrow.
Originally, Myxine was included by Linnaeus (1758) in Vermes. In recent years, hagfish have become of special interest for genetic analysis investigating the relationships among chordates. Their classification as agnathans places hagfish as elementary vertebrates in between invertebrates and gnathostomes. However, there has been long discussion in scientific literature about whether the hagfish were even non-vertebrate. This position is supported by recent molecular biology analyses, which tend to classify hagfish as invertebrates within the subphylum Craniata, because of their molecular evolutionary distance from Vertebrata (sensu stricto). A single fossil of hagfish shows little evolutionary change has occurred in the last 300 million years.
However, the validity of the taxon "Craniata" was recently examined by Delarbre et al. (2002) using mtDNA sequence data, concluding the Myxini are more closely related to Hyperoartia than to Gnathostomata – i.e., that modern jawless fishes form a clade called Cyclostomata. The argument is that if the Cyclostomata are indeed monophyletic, Vertebrata would return to its old content (Gnathostomata + Cyclostomata) and the name Craniata, being superfluous, would become a junior synonym.
Hagfish are not often eaten, owing to their repugnant looks and sliminess. However the inshore hagfish, found in the Northwest Pacific, is valued as food in Korea. The hagfish is kept alive and irritated by rattling its container with a stick, prompting it to produce slime in large quantities. This slime is used in a similar manner as egg whites in various forms of cookery in the region. The inshore hagfish, known as kkomjangeo (꼼장어) or meokjango (먹장어) in Korean and nuta-unagi (ぬたうなぎ) in Japanese, is the only member of the hagfish family with a seasonal reproductive cycle.
Hagfish skin, used in a variety of clothing accessories, is usually referred to as eel skin. It produces a particularly durable leather, especially suitable for wallets and belts.
Hagfish Wikipedia
Similar TopicsMyxine
Hagfish (band)
Priya Ravichandran
Myxine


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