The Eyes As a Window into Alzheimer’s

Retinal Scans Tie Blood Vessel Deterioration to Genetic Marker for Alzheimer’s Disease

By Vicky Stein, University of California San Francisco

May 13, 2021 -- While it has been said that the eyes are a window to the soul, a new study shows they could be a means for understanding diseases of the brain. According to new research by scientists at the UCSF Weill Institute for Neurosciences, retinal scans can detect key changes in blood vessels that may provide an early sign of Alzheimer’s disease, while offering important insights into how one of the most common Alzheimer's risk genes contributes to the disease. 

“The most prevalent genetic risk for Alzheimer’s disease is a variant of the APOE gene, known as APOE4,” said lead author Fanny Elahi, MD, PhD. “We still don’t fully understand how this variant increases risk of brain degeneration, we just know that it does, and that this risk is modified by sex, race, and lifestyle. Our research provides new insights into how APOE4 impacts blood vessels and may provide a path forward for early detection of neurodegenerative disease.” 

Studies in mice have explored the effect of APOE4 on capillaries in the brain. Elahi, an assistant professor of neurology and member of the UCSF Memory and Aging Center (MAC), has long suspected these tiny blood vessels may play a significant role in Alzheimer’s disease, since they deliver nutrients and oxygen, carry away waste, and police immune system responses through the protective shield known as the blood–brain barrier. Damage to these blood vessels could cause a host of problems, she says, including the protein buildup and cognitive decline seen in individuals affected by Alzheimer’s disease. 

Because the technology does not exist to visualize individual capillaries in living people’s brains, Elahi and colleagues turned to the eye. In the new study, which publishes May 15, 2021, in the journal Alzheimer’s and Dementia: Diagnosis, Assessment & Disease Monitoring, Elahi and her team have shown that APOE4-associated capillary changes can be detected in humans through an easy, comfortable eye scan. As a light-penetrating tissue that shares biology with the brain, the retina, researchers believe, may help determine what APOE4 variants may be doing to similar capillaries inside the brain, even in those without dementia. 

The team – which includes Ari Green, MD, a neuro-ophthalmologist, professor, and director of the UCSF Neurodiagnostic Center, and Amir Kashani, MD, PhD, associate professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute – used an advanced retinal imaging technique known as optical coherence tomography angiography (OCTA) to peer into the eyes of aging people with and without APOE4 mutations to evaluate the smallest blood vessels at the back of the eye.  

The team leveraged the well-characterized cohorts of people enrolled in ongoing studies of brain aging and neurodegenerative disease at the MAC. By adding OCTA scans to existing MRI and PET scan data, they gain comparative insights without putting volunteer participants through additional discomfort. “That’s the beauty of this technique,” Elahi said. “It’s very easy, noninvasive and participant-friendly.” 

Analyzing the retinal scans, the researchers found reduced capillary density in APOE4 carriers, an effect that increased with participant age. To test whether those scans accurately reflected what was happening in the brain, the team then compared the abnormalities seen in OCTA scans of retinal capillaries to measurements of brain perfusion, or the flow of blood through the brain, as measured via MRI. They found that people with higher retinal capillary density also had greater blood flow in the brain. 

Finally, the team looked to participants with prior PET scans of beta-amyloid, the protein associated with Alzheimer’s disease, to see how their retinal capillary measurements related to the burden of amyloid plaques in the brain, which is the major focus of Alzheimer’s disease diagnosis, research and treatment to date. They found that capillary density did not differ between groups with and without amyloid plaques, nor did it vary along with amyloid burden. According to Elahi, that independence suggests that capillary abnormalities are unlikely to be driven by amyloid pathology, or that their relation may at most be indirect.  

“This is the first time that we have demonstrated in living, asymptomatic humans that the smallest blood vessels are affected in APOE4 gene carriers,” said Elahi. That’s important, she added, because it suggests that the increased risk of brain degeneration and Alzheimer’s disease in APOE4 carriers may be through its effect on blood vessels.  

Elahi and her colleagues plan to follow their study participants to better understand blood vessel dysfunction at a molecular level. That work could help detect the onset of Alzheimer’s disease before significant damage occurs to the brain and identify new vascular targets for early treatment.  

“This is just the beginning,” Elahi said. "But the implications for early detection and possible intervention can be significant in combatting Alzheimer’s disease and other neurodegenerative disorders. It's much harder to regenerate neurons than to stop their degeneration from happening in the first place. Similar to cancer, early detection can save lives,"  

https://www.ucsf.edu/news/2021/05/420526/eyes-offer-window-alzheimers-disease

The Startling Intelligence of Elephants

Elephant cognition is the study of animal cognition as present in elephants. Most contemporary ethologists view the elephant as one of the world's most intelligent animals. With a mass of just over 5 kg (11 lb), an elephant's brain has more mass than that of any other land animal, and although the largest whales have body masses twenty times those of a typical elephant, a whale's brain is barely twice the mass of an elephant's brain. In addition, elephants have around 257 billion neurons.  Elephant brains are similar to humans' and many other mammals' in terms of general connectivity and functional areas, with several unique structural differences. Although initially estimated to have as many neurons as a human brain, the elephant's cortex has about one-third of the number of neurons as a human brain.

Elephants manifest a wide variety of behaviors, including those associated with grief, learning, mimicry, play, altruism, use of tools, compassion, cooperation, self-awareness, memory, and communication.  Further, evidence suggests elephants may understand pointing: the ability to nonverbally communicate an object by extending a finger, or equivalent.  It is thought they are equal with cetaceans and primates in this regard. Due to such claims of high intelligence and due to strong family ties of elephants, some researchers argue it is morally wrong for humans to cull them.  Aristotle described the elephant as "the animal that surpasses all others in wit and mind."

Elephant Society

The elephant has one of the most closely knit societies of any living species. Elephant families can only be separated by death or capture.  Cynthia Moss, an ethologist specializing in elephants, recalls an event involving a family of African elephants.

Two members of the family were shot by poachers, who were subsequently chased off by the remaining elephants. Although one of the elephants died, the other, named Tina, remained standing, but with knees beginning to give way. Two family members, Trista and Teresia (Tina's mother), walked to both sides of Tina and leaned in to hold her up. Eventually, Tina grew so weak, she fell to the ground and died. However, Trista and Teresia did not give up but continually tried to lift her. They managed to get Tina into a sitting position, but her body was lifeless and fell to the ground again. As the other elephant family members became more intensely involved in the aid, they tried to put grass into Tina's mouth. Teresia then put her tusks beneath Tina's head and front quarters and proceeded to lift her. As she did so, her right tusk broke completely off, right up to the lip and nerve cavity. The elephants gave up trying to lift Tina but did not leave her; instead, they began to bury her in a shallow grave and throw leaves over her body. They stood over Tina for the night and then began to leave in the morning. The last to leave was Teresia.

Because elephants are so closely knit and highly matriarchal, a family can be devastated by the death of another (especially a matriarch), and some groups never recover their organization. Cynthia Moss has observed a mother, after the death of her calf, walk sluggishly at the back of a family for many days.

Edward Topsell stated in his publication The History of Four-Footed Beasts in 1658, "There is no creature among all the Beasts of the world which hath so great and ample demonstration of the power and wisdom of almighty God as the elephant."  Elephants are believed to be on par with chimpanzees with regard to their cooperative skills.

Elephant Altruism

Elephants are thought to be highly altruistic animals that even aid other species, including humans, in distress. In India, an elephant was helping locals lift logs by following a truck and placing the logs in pre-dug holes upon instruction from the mahout (elephant trainer). At a certain hole, the elephant refused to lower the log. The mahout came to investigate the hold-up and noticed a dog sleeping in the hole. The elephant only lowered the log when the dog was gone.  When an elephant is hurt, other elephants (even if they are unrelated) aid them.

Cynthia Moss has often seen elephants going out of their way to avoid hurting or killing a human, even when it was difficult for them (such as having to walk backwards to avoid a person).  Joyce Poole documented an encounter told to her by Colin Francombe on Kuki Gallman's Laikipia Ranch. A ranch herder was out on his own with camels when he came across a family of elephants. The matriarch charged at him and knocked him over with her trunk, breaking one of his legs. In the evening, when he did not return, a search party was sent in a truck to find him. When the party discovered him, he was being guarded by an elephant. The animal charged the truck, so they shot over her and scared her away. The herdsman later told them that when he could not stand up, the elephant used her trunk to lift him under the shade of a tree. She guarded him for the day and would gently touch him with her trunk.

Elephant Mimicry

Recent studies have shown that elephants can also mimicsounds they hear. The discovery was found when Mlaika, an orphaned elephant, would copy the sound of trucks passing by. So far, the only other animals that are thought to mimic sounds are whales, dolphins, bats, primates and birds.  Calimero, an African elephant who was 23 years old, also exhibited a unique form of mimicry. He was in a Swiss zoo with some Asian elephants. Asian elephants use chirps that are different from African elephants' deep rumbling noises. Calimero also began to chirp and not make the deep calls that his species normally would.

Kosik, an Indian elephant at Everland Amusement Park, South Korea can imitate up to five  Korean words, including sit, no, yes and lie down.  Kosik produces these human-like sounds by putting his trunk in his mouth and then shaking it while breathing out, similar to how people whistle with their fingers.

Ecologist O’Connell-Rodwell’s conducted research in 1997 which concluded that elephants create low-frequency vibrations (seismic signals) through their trunks and feet to communicate across long distances.  Elephants use contact calls to stay in touch with one another when they are out of one another's sight. In 2004, Joseph Soltis conducted a study to understand the low-frequency vocalization elephants used to communicate across short-distances. The research found that closely allied female elephants were more likely to produce ‘rumbles’ to other members at twice the rate of those who had lesser integrated members.  Female elephants are able to remember and distinguish the contact calls of female family and bond group members from those of females outside of their extended family network. They can also distinguish between the calls of family units depending upon how frequently they came across them.

Joyce Poole, of the Amboseli Elephant Research Project, Kenya, has demonstrated vocal learning and imitation in elephants of sounds made by each other and in the environment. She is beginning to research whether sounds made by elephants have dialects, a trait that is rare in the animal kingdom.

Use of Tools

Elephants show a remarkable ability to use tools, using their trunks like arms. Elephants have been observed digging holes to drink water and then ripping bark from a tree, chewing it into the shape of a ball, filling in the hole and covering over it with sand to avoid evaporation, then later going back to the spot for a drink. They also often use branches to swat flies or scratch themselves.  Asian Elephants have also been known to drop large rocks onto an electric fence to break the fence or to cut off the electricity.  Asian elephants in India have been known to break electric fences using logs and clear the surrounding wires using their tusks to provide a safe passageway.

                   https://en.wikipedia.org/wiki/Elephant_cognition

Chinese Rover Lands Successfully on Mars

Tianwen-1 (TW-1, literally Heavenly Questions) is an interplanetary mission by the China National Space Administration (CNSA) to send a robotic spacecraft to Mars, consisting of an orbiter, deployable camera, lander and the Zhurong rover.  The spacecraft, with a total mass of nearly five tons, is one of the heaviest probes launched to Mars and carries 13 scientific instruments.

The scientific objectives of the mission relate to the geology of Mars, the current and past presence of water, the internal structure of the planet, identification of minerals and rock types on the surface, as well as characterization of the space environment and atmosphere of Mars.

The mission's three spacecraft was launched from the Wenchang Spacecraft Launch Site on 23 July 2020 on a Long March 5 heavy-lift launch vehicle. After seven months of transit, it entered orbit around Mars on 10 February 2021.  For the next three months the space probe studied the target landing sites from a reconnaissance orbit. On 14 May 2021, the lander successfully landed on Mars.  With the landing, China became the third nation to achieve a successful soft landing on Mars, after the Soviet Union and the United States.  If the deployment of the rover is also successful, China would become only the second nation to accomplish this feat, after the United States, and the first nation to orbit, land and release a rover during its first mission to arrive at Mars.

The Tianwen-1 mission was the second of three Martian exploration missions launched during the July 2020 window, with missions also launched by the national space agencies of the United Arab Emirates (Emirates Mars Mission with the Hope orbiter) and the United States (Mars 2020 with the Perseverance rover and Ingenuity helicopter drone).

Landing on Mars May 14

At 23:18 UTC, on 14 May 2021, the Tianwen-1 lander successfully landed in the preselected landing area in the southern part of the Mars Utopia Planitia.  The landing phase began with the release of the protective capsule containing the lander/rover. The capsule made an atmospheric entry followed by a descent phase under parachute, after which the lander used retro-propulsion to soft-land on Mars.

Current plans call for the lander to deploy the rover Zhurong on 22 May 2021. The rover is designed to explore the surface for 90 sols; its height is about 1.85 m (6.1 ft) and it has a mass of about 240 kg (530 lb). After the planned rover deployment, the orbiter would serve as a telecommunications relay for the rover while continuing to conduct its own orbital observations of Mars.

Chinese President Xi Jinping stated in response to the landing, "You were brave enough for the challenge, pursued excellence and placed our country in the advanced ranks of planetary exploration.  Your outstanding achievement will forever be etched in the memories of the motherland and the people.

                    https://en.wikipedia.org/wiki/Tianwen-1

Early Cancer Detection Did Not Save Lives

Screening for ovarian cancer did not reduce early deaths

From: University College, London

May 13, 2021 -- The latest analysis looked at data from more than 200,000 women aged 50-74 at recruitment who were followed up for an average of 16 years. The women were randomly allocated to one of three groups: no screening, annual screening using an ultrasound scan, and annual multimodal screening involving a blood test followed by an ultrasound scan as a second line test.

A large-scale randomised trial of annual screening for ovarian cancer, led by UCL researchers, did not succeed in reducing deaths from the disease, despite one of the screening methods tested detecting cancers earlier.

Results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) have been published in a report in the medical journal The Lancet.

In the UK, 4,000 women die from ovarian cancer each year. It is not usually diagnosed until it is at a late stage and hard to treat. UKCTOCS was designed to test the hypothesis that a reliable screening method that picks up ovarian cancer earlier, when treatments are more likely to be effective, could save lives.

The latest analysis looked at data from more than 200,000 women aged 50-74 at recruitment who were followed up for an average of 16 years. The women were randomly allocated to one of three groups: no screening, annual screening using an ultrasound scan, and annual multimodal screening involving a blood test followed by an ultrasound scan as a second line test.

The researchers found that, while the approach using multimodal testing succeeded in picking up cancers at an early stage, neither screening method led to a reduction in deaths.

Earlier detection in UKCTOCS did not translate into saving lives. Researchers said this highlighted the importance of requiring evidence that any potential screening test for ovarian cancer actually reduced deaths, as well as detecting cancers earlier.

Professor Usha Menon (MRC Clinical Trials Unit at UCL), lead investigator of UKTOCS, said: "UKCTOCS is the first trial to show that screening can definitely detect ovarian cancer earlier. However, this very large, rigorous trial shows clearly that screening using either of the approaches we tested did not save lives. We therefore cannot recommend ovarian cancer screening for the general population using these methods.

"We are disappointed as this is not the outcome we and everyone involved in the trial had hoped and worked for over so many years. To save lives, we will require a better screening test that detects ovarian cancer earlier and in more women than the multimodal screening strategy we used."

Women aged between 50 and 74 were enrolled in the trial between 2001 and 2005. Screening lasted until 2011 and was either an annual blood test, monitoring changes in the level of the protein CA125, or a yearly vaginal ultrasound scan. About 100,000 women were assigned to the no screening group, and more than 50,000 women to each of the screening groups.

Blood test screening picked up 39% more cancers at an early stage (Stage I/II), while detecting 10% fewer late-stage cancers (Stage III/IV) compared to the no screening group. There was no difference in the stage of cancers detected in the ultrasound group compared to the no screening group.

The initial analysis of deaths in the trial occurred in 2015, but there was not enough data at that time to conclude whether or not screening reduced deaths. By looking at five more years of follow up data from the women involved, researchers are now able to conclude that the screening did not save lives.

Professor Mahesh Parmar, Director of the MRC Clinical Trials Unit at UCL and a senior author on the paper, said: "There have been significant improvements in the treatment of advanced disease in the last 10 years, since screening in our trial ended. Our trial showed that screening was not effective in women who do not have any symptoms of ovarian cancer; in women who do have symptoms early diagnosis, combined with this better treatment, can still make a difference to quality of life and, potentially, improve outcomes. On top of this, getting a diagnosis quickly, whatever the stage of the cancer, is profoundly important to women and their families."

Professor Ian Jacobs, from the University of New South Wales (UNSW Sydney), a co-investigator who has led the ovarian cancer screening research programme since 1985 and who was lead investigator of UKCTOCS from 2001-2014, said: "My thanks to the thousands of women, healthcare professionals and researchers who made this trial possible. The multimodal screening strategy did succeed in detection of ovarian cancer at an earlier stage, but sadly that did not save lives. This is deeply disappointing and frustrating given the hope of all involved that we would save the lives of thousands of women who are affected by ovarian cancer each year."

Professor Jacobs noted: "Population screening for ovarian cancer can only be supported if a test is shown to reduce deaths in a future randomised controlled trial. I remain hopeful that a new effective screening test will be found eventually, but it will take many years to conduct a large trial of the test. Realistically, this means we have to reluctantly accept that population screening for ovarian cancer is more than a decade away."

A huge wealth of samples and data from the trial has been donated by the participants for future research. This resource, referred to as the UKCTOCS Longitudinal Women's Cohort (UKLWC), is now being used by researchers worldwide, helping to improve understanding of ovarian cancer as well as other cancers and other diseases such as cardiovascular disease.

Researchers say that the study has also generated insights into how best to design, conduct and analyse a large-scale randomised clinical trial particularly in individuals who have no signs of disease. These insights will be helpful to future trials in all areas of health. It has also contributed to advances in risk assessment, prevention and diagnosis of ovarian cancer.

The UKCTOCS trial was funded by the NIHR Health Technology Assessment (HTA) Programme and the charities Cancer Research UK and The Eve Appeal.

Michelle Mitchell, Cancer Research UK's Chief Executive, said: "Trials don't always find the result we had hoped for, but we need long-term studies like this to know whether new tests save lives. Cancer Research UK will continue to fund vital research into aggressive forms of ovarian cancer so we can reduce the impact of this disease.

"Screening is for people without symptoms, so it's still important that if you notice unusual or persistent changes to talk to your doctor. Symptoms of ovarian cancer can be quite vague and similar to symptoms caused by less serious conditions, which can make spotting the disease tricky. Whether it's needing to go to the toilet more often, pain, bloating, or something else, raise it with your GP -- in most cases it won't be cancer but it's best to get it checked out."

Professor Nick Lemoine, Medical Director, NIHR Clinical Research Network, said: "These important findings from a large-scale trial, involving 200,000 participants, show that annual screening did not succeed in reducing deaths from ovarian cancer.

"However, it's important to note that negative results can be as important as positive. The study has provided important new evidence and insights into how to conduct and analyse future large-scale randomised clinical trials into ovarian cancer, in the hope that this will prevent and diagnose this disease more effectively in the future.

"We thank every single person who took part."

Athena Lamnisos, CEO, The Eve Appeal, said: "The threshold for introducing a national cancer screening programme is a mortality benefit. Of course this is key -- saving lives. It's disappointing that this research programme did not show a reduction in mortality from ovarian cancer and so can't be recommended as a national screening programme. However, the impact it had on earlier diagnosis is impressive and important.

"Ovarian cancer is so often diagnosed at stage 3 or 4 and shifting diagnosis one stage earlier makes a huge difference to both treatment options and quality of life. Earlier diagnosis will often reduce the amount and intensity of treatment, and this makes all the difference to women and their families who are living with cancer. It may have also given them more precious time with their loved ones."

          https://www.sciencedaily.com/releases/2021/05/210513173552.htm

Inflation Will Kill This Stock Market

By David Haggith for The Great Recession Blog

May 12, 2021 -- I’m not saying nothing else can do the job before inflation fully gets here, just that the kind of inflation I’ve been writing about certainly will do it if nothing else does. That’s what terrifies the market and for a very good reason that may not be the first one that comes to some investors’ minds.

Many talk about the “risk premium” of investing in stocks. As inflation rises, bond yields rise to offset what will be lost to inflation. As bond yields rise, stocks become less competitive.

That’s a problem, but it’s not the big problem. Not this time.

The big problem is that we all know where the money for stocks is coming from — the Federal reserve and the US government by borrowing and distributing the money the Fed prints. So, the big problem is the Fed.

The Fed is getting tangled in a mess of its own making

Having made the case in a number of previous articles that high inflation is now already a given, it won’t be long before the Fed is caught in a trap where it needs to continue creating money in order to keep the market rising and to keep stimulating the economy, but it won’t be able to because it will be blocked by the inflation monsters it is creating. That’s why we hear the Fed talking incessantly about how inflation is “transitory” right now. The Fed NEEDS to have all investors believe that the rapidly dawning period of inflation will be short so it can be ignored. The Fed needs the market to believe it CAN and WILL keep printing money.

However, the Fed is just fooling itself. The longer it claims inflation is temporary so that it can ignore the rapidly rising numbers, the more inflation will move out of control because the Fed and the federal government keep the money printing and the armored cars for transporting it to the masses running around the clock. (Figuratively speaking, of course.)

The Fed may fool itself to its (and our) long-term harm, but it is not likely to fool the market much longer because the inflationary numbers will be coming in too high for the market to ignore. We saw that on Wednesday in how the market responded to news of the highest inflation in years — a number annualized at 4.2% in April, which is well below the level of inflation we’re about to see this summer. That’s just the wind-up for the strike-out pitch.

How inflation will fight the Fed and win

The danger inflation imposes is that, if it rises as high as I am certain it is going to rise (double digits), then the Fed will be forced to raise its interest targets because the market will shove interest up regardless, making the Fed look dumb for claiming an interest target it cannot hold. The Fed won’t be able to what it takes to hold interest down without creating massively greater inflation through its creation of new money.

However, it is not just that the bond vigilantes will wrest control of interest out of the Fed’s hands, it’s that the stock market will force the Fed to deal with inflation by fearing it whether the Fed says it should or not. Consumers will also press congress to press the Fed to deal with inflation. The longer it delays, the more massively the Fed will have to raise interest rates, just as Paul Volker did in the 80’s to get inflation under control.

This conundrum is starting to materialize now at a time when the stock market is at absurdly perilous heights. Faint realizations of inflation are no longer so faint, which is why the market is running out of momentum. Investors are starting to believe the Fed will lose control of interest rates. Investors are starting to doubt the Fed’s words of confidence.

Of course, to crash, momentum has to turn downward, and that won’t likely happen until the market is certain the Fed is going to lose control; but that can happen slowly at first and then quickly as it did in 2018.

Inflation is a time bomb on the Fed’s back. My thesis is that every month now the Fed is going to find it harder and harder to maintain the illusion that it can keep creating money, pumping it into mom-and-pop investor hands (retail investors, the Robinhood crowd, etc.) through government stimulus programs (at the government’s demand) and keep trying to maintain low interest to pump money into the stock market via corporate stock buybacks funded on loans. Inflation will crush easy money. It rules. The Fed can rule over it, but only by taking away money and crashing markets that are utterly dependent on that money.

The plate spinner is starting to lose control of all the plates it has to keep twirling on the ends of little sticks. Today’s action in the market shows the market is starting to pay attention to the clatter of falling plates as inflation shows up worse than investors feared. The real fear — the deep paralyzing fear that is only now being foreshadowed — is not competition from rising bond yields (certain as that is to come) but that inflation will become hot enough that the Fed will be forced to turn off all of its go juice.

Inflation has the power to suddenly turn market sentiment on its head because, well, follow the money back to where it is coming from.

Stocks headed sharply lower as inflation jitters percolated again, following a report showing U.S. inflation in the year to April rose at its fastest pace in about 13 years, amid the recovery from the COVID pandemic.

MarketWatch

Inflation jitters will become inflation panic when it becomes clear that the rise to 4.2 is not just a blip but the first step on the consumer side of many steps to come. Hopefully none of my readers were paying much attention to economists who were forecasting a meager 3.6%.

“Inflation destroys wealth. Period,” said Patrick Leary, head of trading at Incapital, in an interview with MarketWatch. “We see inflation showing up in markets. If it’s indeed transitory, markets can live with it. But if it’s not transitory, that’s when it is going to become troubling for stocks.”

The destruction of wealth is one concern, but the bigger concern, I believe, is the loss of the Amazon-scale, easy-money stream into the market. This is why the market went up when the jobs report was truly horrible. The report of slackening employment eased feelings of concern about inflation causing the Fed to turn off the flow. Its why the market plunged today on solid news to the contrary of higher inflation than many were expecting.

The Fed’s hand may soon be forced by reality; and if you’ve been reading here — particularly the Patron Posts that focused intensively on inflation, you’ve had a good idea of what is coming. One won’t have to wait until the Fed tightens to stop inflation, however; one only has to wait until stock investors become convinced the Fed will have to tighten, regardless of what the Fed claims to assure investors it won’t.

As MarketWatch noted yesterday,

Tuesday is looking dicey for stocks, notably the technology space, as inflation jitters continue to ripple across markets. The sector has been bearing the brunt of concerns that higher inflation may prompt an early end to the Federal Reserve’s COVID-19 pandemic-driven accommodative stance. After last week’s downside jobs surprise, some fear Wednesday’s consumer price data could also deliver a nasty shock.

The market is top-heavy and jittery under its own load to such an extent that it will crash if it merely believes the Fed will be forced to tighten. That’s why it jolted as a foreshock today, but it wasn’t a shock at all if you’ve been reading here. It was expected.

Inflation is the “worst-case scenario” for this ticking-time-bomb market full of complacent investors, warns our call of the day from Thomas H. Kee Jr., president and chief executive of Stock Traders Daily and portfolio manager at Equity Logic.

And here’s the key:

“Arguably, the ONLY reason stimulus has even been possible is because there has been no inflation. If inflation comes back, all of the safeguards investors have been given (free money from stimulus) will be dissolved and won’t be able to come back to save the day,” Kee told MarketWatch…. He said recent jobs data indeed suggest price rises will be “more serious than previously thought….”

“The declines can be much worse than 25% and if the FOMC [Federal Open Market Committee] is handcuffed because of inflation, the swift bounce back that investors have been used to will not happen either,” said Kee. “The fair value multiple on the SPX SPX (^GSPC) is not 30 – [to] 35x. It’s more like 15x….”

What would bring that down to earth is the return of natural-risk perceptions among investors — severely lacking right now. “They have been given free money by the government, stimulus programs are in full effect, and investors don’t perceive any risk at all. That is the most dangerous thing!” Kee said….

“When the big buyer is not there … that is when natural perceptions of risk come back, and if that happens … watch out below!!”

You see, rising inflation has the power to cut the Fed off at the knees. The kind of inflation I’ve been writing about can suck the mojo right out of the Fed, and that is why Powell is already doing his best to convince financial markets that the Fed wants higher inflation and convince them that the higher inflation it wants is temporary before it even begins.

Market susceptibility

Notes Lance Roberts,

There is no way this bull market doesn’t end very badly. We all know that is the reality of this liquidity-fueled market, but we keep investing for “Fear Of Missing Out.”

Seeking Alpha

How much does all that stimulus money from Fed and Feds pouring into the market create the cashflow that made the past year’s insanity possible?

Over the past 5-MONTHS, more money has poured into the equity markets than in the last 12-YEARS combined.

Do the math and ask yourself what happens if the money HAS to be turned off because inflation forces the Fed to stop creating to much new money in an environment of to few goods due to previous COVID-shutdown shortages and the continuing problems they’ve set up.

And, if you don’t think the market is precariously riding high on easy money, look at how much it is rising on rising margin debt (money owed to brokers):

Seeking Alpha

When the Fed is pressed hard to raise interest rates and stop printing money, brokers aren’t going to be so free in lending money. Right now, it’s easy money at almost free rates. More to the point, though, when the market does start coming down because of concerns about the Fed cutting off easy money, all that margin debt starts unwinding in a hurry as people are forced to sell assets and reduce their margin debt.

As you can also see, huge, rapid spikes like this in market debt tend to happen right before severe crashes:

Seeking Alpha

In the short term, fundamentals do not matter. However, in the long term, they matter a lot.

Sentiment can cause investors to overlook economic fundamentals for a long time, but a sudden change in perception of fundamentals long overlooked in an environment of high margin debt and bring a rapid correction of one’s frame of reference.

Currently, investors are overlooking fundamentals on the expectation the economy and earnings will improve to justify the market overvaluation.

That is not likely to happen. Even if it does, perception of the financial landscape (the core value of of money) has been far too optimistic in most circles, as seen by the shock today; but you could see this coming from a year away.

The Fed talks as though it still doesn’t see what is coming, but that’s the same Fed that talked about how easy tightening was going to be. It appears it had no idea that it didn’t have an exit plan that wouldn’t send sentiment sharply south and crash the market. Yet, that, too, could be seen from years away by those who were not worshipping at the feet of Father Fed.

When, or if, expectations of recovery are disappointed, the market will begin to reprice itself for its intrinsic value. Given that the market is currently trading more than twice the level of underlying economic growth, which is where corporate profits come from, such suggests a significant risk.

That’s why the Dow fell 682 points (2%) today, and the S&P fell 2.14% and the NASDAQ, 368 points (2.67%). There wasn’t much of a safe space to be found in stocks.

Don’t tell me inflation doesn’t matter to this market. Worst day in six months. More on this in another Patron Post.

Now let me, once again, do the kind of corrective reporting I said was going to be essential at this time. First, the fake news:

One big reason for the acceleration was base effects – at this time a year ago, the economy was hit with the worst of the Covid pandemic and inflation was unusually low.

CNBC

That isn’t accurate. As I said in my last Patron Post, wherein I also laid out the statistical facts and source to back up my statement,

Food prices and many other prices rose like they normally do last March, in spite of the pandemic. In fact, after March, they rose worse than normal with every month in the remainder of 2020 coming in between 3.5% and 4% on an annualized basis.

“Inflation Tsunami Sirens Are Screaming!“

I noted in particular one economist who said groceries and fuel were now just making up for last time:

So, like groceries, gas is catching up to get back to where we would actually expect it to be….

What predominantly happened last year was that fuel prices plummeted due to nothing being transported and lack of vacationing and lack of commuting, but groceries? Come on!

“Catching up” may be true for gas if you look back to where prices were in 2018, but it’s total horse manure when you embrace groceries in the comment. Groceries have no catching up to do whatsoever. The average rate of inflation for food for all of 2020 was 3.4%, which compares to rates that 0.3%-2.5% for every year going back until 2011 where the average for the year was. 3.6%.

And while overall inflation was less than normal for April through June last year, what does that have to do with this year? [Overall] prices still rose last year; so, it is NOT as if you are comparing to an anomalous year where overall prices fell in those months, meaning some of this year’s gain was just making up for last year’s unusual loss. Then you could truthfully say there was a base effect.

So, inflation is coming in much hotter than the Fed led people to believe; and, as my recent Patron Posts have laid out, there is plenty more inflation already baked in on the producer side that will certainly be passed through. I noted you could expect to see that starting to show up on the consumer side now, and you just did. It’s going to be an inflation-hot summer, which can sour sentiment, so stocks won’t take well to that. To be sure, there is a lot of testosterone still determined to press stocks up no matter what, but a hot and humid summer will zap that sentiment, as it did today; and it will keep zapping it no matter what the charts readers are prognosticating based on current sentimental trends. Trends can change quickly in the face of facts if the facts crash in with enough vigor. I think high inflation is the much-feared fact that can break through by stopping the Fed’s plans from moving forward.

If the Fed does keep moving forward with the same kind of blind ignorance and stubborn resolve to prove itself right that led it to keep pursuing its economic tightening regime (as I claimed it would do for too long in 2018, contrary to good judgment), it will really be making things worse for itself and harder to tame. I think that is not unlikely.

“There are people who think the Fed is not just behind the curve, they’re maybe missing the point and by the time they start to play catch up, it’s too late,” Wall Street veteran Art Cashin said Wednesday

CNBC

As one economist noted,

“We doubt this report will change the view of officials that inflationary pressures are ‘largely transitory,‘” wrote Michael Pearce, senior U.S. economist at Capital Economics. “It’s just that there’s a lot more ‘transitory’ than they were expecting.”

CNBC

Indeed. A lot more. What will they do when they run out of a fake base effect to blame it on?

                   https://thegreatrecession.info/blog/inflation-will-kill-this-stock-market/

World’s First Programmable Digital Computer

The Z3 German computer was a German electromechanical computer designed by Konrad Zuse in 1935, and completed in 1941. It was the world's first working programmable, fully automatic digital computer.  The Z3 was built with 2,600 relays, implementing a 22-bit word length that operated at a clock frequency of about 5–10 Hz.  Program code was stored on punched film. Initial values were entered manually.

 

The Z3 was completed in Berlin in 1941. It was not considered vital, so it was never put into everyday operation.  Based on the work of the German aerodynamics engineer Hans Georg Küssner (known for the Küssner effect), a "Program to Compute a Complex Matrix" was written and used to solve wing flutter problems.  Zuse asked the German government for funding to replace the relays with fully electronic switches, but funding was denied during World War II since such development was deemed "not war-important".

The original Z3 was destroyed on 21 December 1943 during an Allied bombardment of Berlin. That Z3 was originally called V3 (Versuchsmodell 3 or Experimental Model 3) but was renamed so that it would not be confused with Germany's V-weapons.  A fully functioning replica was built in 1961 by Zuse's company, Zuse KG, which is now on permanent display at Deutsches Museum in Munich.

The Z3 was demonstrated in 1998 to be, in principle, Turing-complete.  However, because it lacked conditional branching, the Z3 only meets this definition by speculatively computing all possible outcomes of a calculation.

Thanks to this machine and its predecessors, Konrad Zuse has often been suggested as the inventor of the computer.

Design and Development

Zuse designed the Z1 in 1935 to 1936 and built it from 1936 to 1938. The Z1 was wholly mechanical and only worked for a few minutes at a time at most.  Helmut Schreyer advised Zuse to use a different technology. As a doctoral student at the Berlin Institute of Technology in 1937, he worked on the implementation of Boolean operations and (in today's terminology) flip-flops on the basis of vacuum tubes.  In 1938 Schreyer demonstrated a circuit on this basis to a small audience, and explained his vision of an electronic computing machine – but since the largest operational electronic devices contained far fewer tubes this was considered practically infeasible.  In that year when presenting the plan for a computer with 2,000 electron tubes, Zuse and Schreyer, who was an assistant at Wilhelm Stäblein's de Telecommunication Institute at the Technical University of Berlin, were discouraged by members of the institute who knew about the problems with electron tube technology.  Zuse later recalled: “They smiled at us in 1939, when we wanted to build electronic machines … We said: The electronic machine is great, but first the components have to be developed."  In 1940 Zuse and Schreyer managed to arrange a meeting at the Oberkommando der Wehrmacht (OKW) to discuss a potential project for developing an electronic computer, but when they estimated a duration of two or three years, the proposal was rejected.

Zuse decided to implement the next design based on relays. The realization of the Z2 was helped financially by Kurt Pannke, who manufactured small calculating machines. The Z2 was completed and presented to an audience of the Deutsche Versuchsanstalt für Luftfahrt ("German Laboratory for Aviation") in 1940 in Berlin-Adlershof. Zuse was lucky – this presentation was one of the few instances where the Z2 actually worked and could convince the DVL to partly finance the next design.

Improving on the basic Z2 machine, he built the Z3 in 1941, which was a highly secret project of the German government.  Joseph Jennissen (1905–1977), member of the "Research-Leadership" (Forschungsführung) in the Reich Air Ministry acted as a government supervisor for orders of the ministry to Zuse's company ZUSE Apparatebau.  A further intermediary between Zuse and the Reich Air Ministry was the aerodynamicist Herbert A. Wagner.

The Z3 was completed in 1941 and was faster and far more reliable than the Z1 and Z2. The Z3 floating-point arithmetic was improved over that of the Z1 in that it implemented exception handling "using just a few relays", the exceptional values (plus infinity, minus infinity and undefined) could be generated and passed through operations. The Z3 stored its program on an external tape, thus no rewiring was necessary to change programs.

On 12 May 1941 the Z3 was presented to an audience of scientists including the professors Alfred Teichmann and Curt Schmieden of the Deutsche Versuchsanstalt für Luftfahrt ("German Laboratory for Aviation") in Berlin, today known as the German Aerospace Center in Cologne.

Zuse moved on to the Z4 design, which he completed in a bunker in the Harz mountains, alongside Wernher von Braun's ballistic missile development. When World War II ended, Zuse retreated to Hinterstein in the Alps with the Z4, where he remained for several years.

Z3 as a Universal Turing Machine

It was possible to construct loops on the Z3, but there was no conditional branch instruction. Nevertheless, the Z3 was Turing-complete – how to implement a universal Turing machine on the Z3 was shown in 1998 by Raúl Rojas.  He proposed that the tape program would have to be long enough to execute every possible path through both sides of every branch. It would compute all possible answers, but the unneeded results would be canceled out (a kind of speculative execution).  Rojas concludes, "We can therefore say that, from an abstract theoretical perspective, the computing model of the Z3 is equivalent to the computing model of today's computers. From a practical perspective, and in the way the Z3 was really programmed, it was not equivalent to modern computers."

This seeming limitation belies the fact that the Z3 provided a practical instruction set for the typical engineering applications of the 1940s. Mindful of the existing hardware restrictions, Zuse's main goal at the time was to have a workable device to facilitate his work as a civil engineer.

                      https://en.wikipedia.org/wiki/Z3_(computer)

 

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Afterword by the Blog Author

Thank God German politicians didn’t recognize the importance of these early computers.  The devices could have extended the time of the European theater for World War II or perhaps altered the outcome of the conflict.

Hypersonic Flight Is Closer to Reality

“New technology could bring hypersonic flight into a reality by enabling jets to reach up to Mach 17 [that is 13,000 miles per hour!] without releasing an out of control detonation.”

“Scientists at the University of Central Florida developed a new propulsion system to stabilize the detonation, which is a type of explosion that sends waves faster than the speed of sound.”

Much more at: https://www.msn.com/en-us/news/technology/new-propulsion-system-could-enable-jets-to-reach-speeds-up-to-mach-17/ar-BB1gAiyA?ocid=msedgdhp