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Hi-Ho Silver! Away!

Hi-Ho Silver! Away!

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Silver Climbs Higher

The Lone Ranger galloped into town upon Silver overnight and precious metals markets are seeing fireworks this morning after plenty was also seen yesterday. Silver prices exploding higher, threatening to drag gold out of its multi-week malaise—more on this below.

Meanwhile, the buy-everything trade was back with a vengeance overnight and perhaps rightly so. Markets were booster shot-ed by positive news from Astra-Zeneca regarding the progress of their Covid-19 vaccine. The European Union also lent a helping hand, edging towards a workable pandemic recovery package. The net effect immune boosted equities and commodities, and spurred a new wave of US dollar rotation, as the street priced in more light at the end of the pandemic economic tunnel.

The vaccine news was particularly welcome, capping a slew of positive news from that sector over the past week. My reverse Black Swan continues to be that a vaccine arrives in Q3 with distribution beginning shortly after that. The world won’t have dodged an economic bullet but may get away with a flesh wound that can be staunched without surgery.

The news, however, isn’t all positive. Far too many people around the world are still testing positive for Covid-19, and the situation in the United States, a particular concern. Fears of extended or new lockdowns saw Amazon and Zoom outperform overnight, lifting the Nasdaq to an outsized outperformance day. The bearish outside reversal formation on the Nasdaq which I highlighted last week is well and truly consigned to the dustbin. Momentum rules and big tech has plenty of it.

China stock markets outperformed yesterday, rising by over 3.0% on the day. The regulator lifted the cap on the amount of domestic equities; Chinese insurers can hold. That increased from 30 to 45% of total assets, as at the end of the previous quarter. It caps a busy month for central government involvement in the onshore equity markets. They were firstly urging retail investors to get long to partake in China’s recovery, then getting cold feet a week later after a 13% rally. That led to an almost equally precipitous drop. And now, allowing insurers to buy more equities. The latter makes complete sense, even if the previous two don’t. Retail flows dominate equity volumes on the Mainland and allowing more institutional money to participate may help smooth out the headless charges back and forth by the retail crowd.

Today’s data calendar is incredibly light. The RBA minutes were released, and unsurprisingly, the RBA is happy with monetary policy where it is, isn’t concerned about the exchange rate and is watching developments in the world. Japan’s inflation data this morning showed that inflation is still missing in action after 25 years. Operations normal. Singapore’s inflation data will tell a similar story this afternoon, with MoM rising slightly by 0.50%, but the YoY number firmly anchored in negative territory at -0.80%.

A slew of business and consumer confidence will hit the wires across Europe and today and tomorrow. It should show a generally improving trend as the Eurozone rebounds from its Covid-19 lockdowns. Markets, though, will continue to focus on the pandemic recovery package details, which should maintain the bullish mode for both the euro and European equities.

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A next-generation therapeutic approach for patients after spinal cord injuries

NurExone (TSXV:NRX) has created an exosome-based drug-delivery platform and is developing a novel therapy for acute spinal cord injuries.
The post A next-generation…

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NurExone has created ExoTherapy, a cutting-edge exosome-based drug-delivery platform and is developing its lead product, ExoPTEN, as a novel therapy for acute spinal cord injuries.

Over the past two decades, exosomes – small, extracellular vesicles that are naturally released by many cell types and can carry a variety of molecular cargoes – have become the subject of increasingly intense scientific investigation. Studies suggest exosomes are important messengers for cells and organs, with as-yet unexplored diagnostic and therapeutic potential.

Today, NurExone Biologic Inc. (TSXV:NRX), headquartered in Haifa, Israel, is at the forefront of developing exosomes into next-generation nanocarriers for drug delivery. Drawing on deep expertise in exosome biology, NurExone has created the ExoTherapy technology platform, which comprises proprietary methods for the production, isolation and loading of molecules into exosomes for therapeutic purposes. NurExone is applying the ExoTherapy platform to create the company’s lead product, ExoPTEN, an intra-nasally administered exosome-based ExoTherapy to promote neuro-regeneration for the treatment of acute spinal cord injuries.

Harnessing the properties of exosomes for therapeutic applications

Many cells produce extracellular vesicles (EVs), which are organized into subtypes with different sizes and biological functions. EVs generally fall into two categories: ectosomes, which pinch off from the cell membrane by outward budding; and much smaller exosomes, which have an endosomal origin and are created when endocytotic multivesicular bodies fuse with the plasma membrane, releasing the vesicles they contain as exosomes.

Scientific understanding of the origins and functions of exosomes is advancing, but there is widespread recognition that, far from being cellular waste products as once thought, exosomes play an important biological role in intercellular communication and transmission of macromolecules between cells. Further, through their cargo-carrying capacity, exosomes facilitate the spread of proteins, lipids, mRNA, miRNA, and DNA, which can contribute to their general therapeutic effects.

Beyond their normal biological roles, exosomes have increasingly gained attention as vehicles for the delivery of active pharmaceutical ingredients (APIs), from small molecules and peptides to proteins and nucleic acids, as an alternative not only to other kinds of nanocarriers such as lipid vesicles, but also cell-based gene therapies.

Exosomes offer a number of advantages as drug-delivery vehicles. As naturally occurring biological entities harvested from cells, exosomes have completely natural membranes that are better tolerated than many other types of drug-delivery vesicles synthesized from scratch in the laboratory. At the same time, exosomes do not seem to elicit the strong immune responses that often hamper allogeneic cell-based therapies used to deliver therapeutic molecules and genes to patients. In contrast to alternative therapeutic approaches, exosome therapies do not require expensive and time-consuming personalization, but can be used as “off-the-shelf” therapies suitable for all patients.

Exosomes have additional benefits as EV-based delivery vehicles for therapeutic agents. First, exosomes, including those produced by the ExoTherapy platform, can cross the blood–brain barrier (BBB), while other nanoparticles, such as most liposomes, cannot. ExoTherapy opens up the possibility of targeting different cell types – and, by extension, therapeutic indications – that are beyond the reach of non-BBB-crossing EVs1,2. Second, unmodified exosomes, even those carrying no molecular payload, have intrinsic properties that can be therapeutically beneficial, such as anti-inflammatory effects. Finally, exosomes can be administered intra-nasally.

Exosomes originate from many sources. NurExone’s ExoTherapy platform employs exosomes derived from mesenchymal stem cells, which are effective in targeting neuronal cells. The ExoTherapy platform overcomes the many technical challenges involved in producing, purifying, and loading exosomes with APIs of almost any type (Fig. 1). Through its ability to carry a wide variety of therapeutic modalities, ExoTherapy stands as a true platform technology for creating “off-the-shelf” therapies that can be administered non-invasively.

Fig. 1 | From exosome to ExoTherapy: NurExone’s technology platform. NurExone is developing a platform for large-scale production of exosomes and loading of molecular cargo to create biologically guided ExoTherapy. The company’s vision is to restore motor function in patients after a spinal cord injury. siRNA, small interfering RNA. Development of a non-invasive therapy for functional recovery after SCI

The ExoTherapy platform sits at the heart of NurExone’s long-term business plan, providing a tool for creating a rich pipeline of novel therapeutic assets. In the near term, NurExone’s ambitious goal is to bring to market a novel treatment for acute spinal cord injuries (SCIs) derived from the ExoTherapy platform, ExoPTEN.

Globally, an estimated 250,000–500,000 people experience an SCI annually3, with roughly 17,000 new cases in the United States4 and 10,000 in Europe3 each year, bringing the potential market to ~50,000 new cases per year. Vehicular accidents and falls account for the majority of SCIs; sports and recreational accidents are another relatively common cause of SCI. Although the incidence of SCI is low compared with major disease such as cancer or heart disease, the effects are often devastating for patients, irreversible, and expensive to manage.

Depending on the location of the SCI, the consequences can be loss of sensory or motor control of both lower limbs (paraplegia), lower limbs and trunk, or both lower and upper limbs (tetraplegia). SCIs can also affect autonomic regulation of the body, affecting breathing, heart rate, blood pressure, temperature and bowel and bladder function.

Patients with an SCI typically spend almost two weeks in an intensive care unit, followed by a month in a rehabilitation unit. Fewer than 1% of people with an SCI experience full neurological recovery by the time of discharge, and have reduced quality of life and overall life expectancy4. SCI patients are also often frequently re-hospitalized, on average for almost three weeks, principally due to diseases of the genitourinary system, but also resulting from respiratory, circulatory and musculoskeletal problems.

In addition to the enormous physical toll SCIs exert on patients, they are also costly for health service providers. Depending on the location of the SCI, estimates place the cost of managing patients recovering from SCI at between $300,000 and >$1 million, representing a huge burden on health services and the families of new SCI patients.

There are two major obstacles to recovery from SCI. First is the poor innate regenerative capacity of the central nervous system. A major impediment to axonal growth is phosphatase and tensin homolog (PTEN), which downregulates the mammalian target of rapamycin (mTOR) activity and as a result restricts the synthesis of protein required for axonal growth. Second, SCI healing is hampered by the inflammation, myelin-associated inhibitors, glial scar components and compromised blood supply that typically surround SCIs and create a hostile environment for recovery.

ExoPTEN, which comprises exosomes loaded with small interfering RNA (siRNA) that inhibits the production of the PTEN protein, addresses both of these obstacles. The exosome component of ExoPTEN possesses intrinsic anti-inflammatory properties, which helps create a more hospitable recovery environment at the SCI site. Meanwhile, the anti-PTEN siRNA counters the suppressive effects of PTEN, activating downstream pathways necessary for the protein synthesis underlying axonal growth and regeneration (Fig. 2).

Fig. 2 | ExoPTEN for the treatment of acute spinal cord injury. a, ExoPTEN: MSC-derived exosomes are loaded with PTEN siRNA (left). b, Non-invasive delivery. c, Mechanism of action: PTEN siRNA inhibits PTEN, downregulating PTEN-related pathways and promoting cell growth and proliferation. d, NurExone’s ambitious goal for ExoPTEN is to induce at least partial functional recovery in patients with acute spinal cord injuries. MSC, mesenchymal stem cell; PTEN, phosphatase and tensin homolog; siRNA, small interfering RNA.

ExoPTEN has been tested as an intra-nasally administered formulation in an extreme rat model of acute SCI: complete transection of the spinal cord resulting in paraplegia. In an internal preclinical study carried out by NurExone, untreated rats remained almost totally paralyzed eight weeks after surgical transection, whereas rats receiving ExoPTEN for a maximum of two weeks showed significant partial functional recovery. No ExoPTEN human trials have yet taken place but NurExone believes the therapy could translate to improvements in quality of life. (Unloaded exosomes also demonstrated a mild effect on post-operation recovery, highlighting the dual-effect nature of ExoPTEN.) ExoPTEN also partially restored healthy electrophysiological traces, indicative of axonal rewiring and regeneration, and improved sensory recovery and urinary reflex restoration.

ExoTherapy’s applications beyond spinal cord injury

The regenerative effects observed with ExoPTEN in the severe spinal cord transection model suggest it may also have therapeutic applications in situations in which cell regeneration is a limiting factor for recovery. One major potential application of ExoPTEN identified by NurExone is traumatic brain injury, which affects more people than SCI and for which there are no effective pharmacological treatments that reduce mortality or improve functional recovery. Other potential therapeutic areas in which ExoPTEN may have a powerful impact include cardiac ischemia/reperfusion injury and associated disease, wound repair, and infertility.

While ExoPTEN employs exosomes to deliver siRNA, the ExoTherapy platform can just as easily be used to deliver other drug modalities. Moving forward, NurExone is planning to continue the development of in-house candidates such as ExoPTEN, and will also explore licensing possibilities for pharma companies looking for an enhanced delivery system for their drug(s) of various modalities, as well as opportunities to form partnerships and collaborations to jointly develop novel ExoTherapy-based medicines.

References Guo, S., Redenski, I. & Levenberg, S. Cells 10, 1872 (2021). Guo, S. et al. ACS Nano. 13, 10015–10028 (2019). World Health Organization. Factsheet: Spinal cord injury (2013). Available from: https://www.who.int/news-room/fact-sheets/detail/spinal-cord-injury National Spinal Cord Injury Statistical Center, Facts and figures at a glance. Birmingham, AL: University of Birmingham at Alabama (2016).

This is third-party provided content issued on behalf of NurExone Biologic, please see full disclaimer here.

Join the discussion: Find out what everybody’s saying about this stock on the NurExone Biologic Inc. Bullboard investor discussion forum, and check out the rest of Stockhouse’s stock forums and message boards.

The post A next-generation therapeutic approach for patients after spinal cord injuries appeared first on The Market Herald Canada.

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Geopolitical Risks May Accelerate A Debt Crisis

Geopolitical Risks May Accelerate A Debt Crisis

Authored by Daniel Lacalle,

Many investors are warning of the risk of a debt crisis, but governments…

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Geopolitical Risks May Accelerate A Debt Crisis

Authored by Daniel Lacalle,

Many investors are warning of the risk of a debt crisis, but governments are ignoring all the signals.

In an inflationary crisis, the government should reduce expenditures to help curb price increases while also anticipating a significant increase in borrowing costs. However, in this crisis, the United States administration is ignoring all the warning signs and continuing to borrow at a record pace.

Debt crises always happen when even the most conservative investors refuse to add to a sovereign bond portfolio that is loss-making to begin with. Central banks may decide to purchase those unwanted government bonds, but then the inflation problem worsens and the losses at the central bank accumulate.

The enormous problem created by the monetary and fiscal insanity of 2020 is difficult to solve. Central banks are already publishing losses in their assets, and those negative results must be covered by taxpayers.

Government bonds have been an atrocious investment in 2022 and continue to generate negative results for investors in 2023. Furthermore, sovereign debt is rising at a record pace, ignoring the wall of maturities that the global fixed-income world is facing in 2024 and 2025.

The United States national debt has soared by $550 billion in less than a month. Total debt was $31.4 trillion in July and soared to $33.5 trillion in less than four months. This happened while the 10-year Treasury yield increased from 3.7% to 4.6%. Imagine a government that massively increases debt and does so at a record speed when there is a $500 billion investment-grade maturity wall in 2025 and the government faces $7.6 trillion of maturities of public debt in the next twelve months, according to Goldman Sachs. At the same time, Goldman Sachs also noted that CFTC figures show that U.S. Treasury net long positions in 2-year and 10-year notes have fallen to the lowest level since October 2018. This is truly a dangerous scenario in the middle of geopolitical tensions reaching new highs.

The United States government is counting on rising global demand for US dollars to offset the increased fiscal imbalances and on the Fed to change its monetary policy if needed. This is a dangerous bet when China, Saudi Arabia, and other nations’ Treasury holdings are dropping to multi-year lows. It is also extremely imprudent to believe that the world will absorb the United States’ fiscal imbalances at any cost in the middle of a global geopolitical conflict. Furthermore, it is reckless to believe that the Federal Reserve will buy all the Treasury bonds required when the central bank is already loss-making. Such a level of irresponsibility may put the U.S. dollar in danger in the long term.

The United States’ fiscal imbalances are enormous, but so are the deficit levels of many other developed nations, and the combination of rising rates, losses at the central bank, and impending giant maturity walls happens as well in the euro area.

All of this is evidence of the monetary debasement process that started in 2009 but accelerated in 2020. Governments are destroying the purchasing power of their currencies to disguise their enormous debt and deficit levels, and inflation is eroding citizens’ savings and wages. In this environment, sovereign bonds never protect investors.

Governments do not want to pay for the risk they take and will absorb others’ wealth via negative real rates or price losses in the issued bonds. The inflationary spiral is likely to remain persistent, and the prospect of another round of quantitative easing may not offset the accumulated losses in bond portfolios and certainly will not modify the currency debasement scenario. In a period like this, gold becomes the cheapest asset by far. It is inexpensive relative to its historical purchasing power and monetary qualities, but it is even more attractive relative to the fiat currencies whose monetary value is dissolved by massive printing. The current debt problem and the geopolitical risk tell us that gold is a safe bet in a volatile world.

Tyler Durden Tue, 10/17/2023 - 06:30

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Australian dollar calm after RBA minutes

RBA releases minutes Investors eye Israel-Hamas war The Australian dollar has extended its gains on Tuesday. AUD/USD is trading at 0.6353 in Europe, up…

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  • RBA releases minutes
  • Investors eye Israel-Hamas war

The Australian dollar has extended its gains on Tuesday. AUD/USD is trading at 0.6353 in Europe, up 0.18%.

It has been a rough patch for the Australian dollar lately. The Aussie hasn’t managed a winning week since September and dropped close to a one-year low last week. The Australian dollar has rebounded this week, gaining close to 1%, as the US dollar has lost some steam.

We’ve been hearing a lot about the Fed’s “higher for longer” stance and the markets are less confident that the Fed is done with the current tightening cycle than they were a few months ago. The fighting in the Middle East has created a new “higher for longer” in terms of uncertainty, which could result in elevated volatility in the currency markets.

The US dollar, a trusted safe-haven asset, has not benefited from the latest turmoil in the Middle East, at least not yet. There is widespread concern that the Israel-Hamas war could spread to Lebanon and even to Iran. The US is determined to halt any contagion and has dispatched aircraft carriers to the region.

The Reserve Bank of Australia released the minutes of this month’s meeting earlier today. The central bank held rates at 4.10% for a fourth straight time, but the minutes showed that there was consideration to raise rates by a quarter-point.

The board members noted that inflation was well above the 2%-3% target and “was expected to do so for some time”, with rising fuel prices adding to headline inflation. The minutes noted that the current tightening cycle continued to filter through the economy and the full effects were yet to be felt.

The RBA meets next on November 3rd and members will have plenty of data to chew on ahead of the rate decision. Australia releases an employment report on Thursday, inflation next week and economic forecasts prior to the meeting. The RBA has said that rate decisions will be data-dependent, and these releases will determine whether the RBA extends its pause phase or delivers a rate hike.

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AUD/USD Technical

With the Australian dollar showing limited movement, the support and resistance levels are unchanged from Monday:

  • AUD/USD continues to test resistance at 0.6343. Above, there is resistance at 0.6399
  • 0.6240 and 0.6184 are providing support

 

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